Clinical trial NCT02792192
Conditions: Bladder Cancer
Sponsor: Hoffmann-La Roche
Start date: 2016-06-13; Completion date: 2020-09-29
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase Ib/II study is designed to assess the safety, tolerability, pharmacokinetics, immunogenicity, patient reported outcomes (PROs), and preliminary anti-tumor activity of atezolizumab administered by intravenous (IV) infusion alone and in combination with intravesical BCG in high-risk NMIBC participants. The study will be conducted in following cohorts: Cohort 1A, Cohort 1B, Cohort 2, and Cohort 3. Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) every 3 weeks (q3w) for a maximum of 96 weeks. BCG will be administered to evaluate dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD). De-escalation will be allowed for up to three dose levels of BCG (full dose \[50 mg\], 66 percent \[%\] of a full dose, and 33% of a full dose \[Cohort 1B only\]). After the MTD or MAD is determined for Cohort 1B, this dose will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3, unless the MTD is determined to be 33% of a full BCG dose. If MTD is determined to be 33% of a full BCG dose, then, no participants will be enrolled into Cohorts 2 and 3 until an assessment of the safety and activity of the combination of atezolizumab plus 33% of a full BCG dose is completed.

Detailed description:

Arms: arm 1: Participants will receive atezolizumab 1200 mg IV infusion q3w, for a maximum of 32 doses or 96 weeks of therapy, whichever comes first. arm 2: During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. Optional BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course. arm 3: During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course. arm 4: During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
Interventions: intervention 1: Atezolizumab intervention 2: Bacille Calmette-Guérin
Intervention descriptions: intervention 1: Atezolizumab will be administered as per the schedule specified in respective arm. intervention 2: For Cohort 1B, BCG will be administered (intravesically) at de-escalated doses. De-escalation will be allowed for up to three dose levels of BCG: full dose (50 mg), 66% of full dose, and 33% of full dose. After the MTD or MAD is determined for Cohort 1B, MTD/MAD will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3 (provided MAD or MTD is determined to be either full dose or 66% of a full BCG dose).

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local 
affiliates, including Genentech, Inc. in the United States.  The information contained in this 
document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or 
under its control) and therefore is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to 
others without written authorization from Roche except to the extent necessary to obtain 
informed consent from persons to whom the drug may be administered.
Atezolizumab—F. Hoffmann-La Roche Ltd
Protocol WO29635, Version 6
PROTOCOL
TITLE:
A PHASE Ib/II, OPEN-LABEL STUDY OF THE 
SAFETY AND PHARMACOLOGY OF 
ATEZOLIZUMAB ADMINISTERED WITH OR 
WITHOUT BACILLE CALMETTE-GUÉRIN 
IN PATIENTS WITH HIGH-RISK 
NON–MUSCLE-INVASIVE BLADDER CANCER
PROTOCOL NUMBER:
WO29635
VERSION NUMBER:
6
EUDRACT NUMBER:
Not applicable
IND NUMBER:
120827
NCT NUMBER:
NCT02792192
TEST PRODUCT:
Atezolizumab (MPDL3280A)
Bacille Calmette-Guérin
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  7 May 2015
DATES AMENDED:
Version 2:  21 December 2015
Version 3:  27 September 2016
Version 4:  11 January 2018
Version 5:  18 October 2018
Version 6:  See electronic date stamp below.
 
10-Feb-2020 18:55:18
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd
2/Protocol WO29635, Version 6
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol WO29635 has been amended to align the protocol with the most recent
Atezolizumab Investigator’s Brochure (Version 15).  Changes to the protocol, along with 
a rationale for each change, are summarized below:

Background information on atezolizumab has been updated to account for additional 
approved indications (Section 1.3).

Language has been added to clarify that, after withdrawal of consent for 
participation in the Roche Clinical Repository (RCR), remaining RCR samples will 
be destroyed or will no longer be linked to the patient (Section 4.5.12.6).

The list of atezolizumab risks has been updated to include myositis for consistency 
with the list of identified risks in the Atezolizumab Investigator's Brochure 
(Section 5.1.1).

To align with the Atezolizumab Investigator's Brochure, Version 15, 
"immune-related" has been changed to "immune-mediated" when describing events 
associated with atezolizumab (Section 5.1.1 and Appendix 12).

To address a request by the
 
 systemic immune activation has been replaced by 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the 
list of potential risks for atezolizumab (Section 5.1.1) and the management 
guidelines for systemic immune activation have been replaced with management 
guidelines for hemophagocytic lymphohistiocytosis and macrophage activation 
syndrome (Section 5.1.1 and Appendix 12).  In addition, systemic immune activation 
has been removed from the list of adverse events of special interest (Section 5.2.3).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

A new section has been added to describe the implementation of a system to 
manage the quality of the study (Section 9.3).

Language has been revised to clarify that redacted Clinical Study Reports and other 
summary reports will be made available upon request (Section 9.5).

The Appendix 8 (Anaphylaxis Precautions) has been modified to remove the 
requirement for use of a tourniquet.  The application of a tourniquet is no longer 
recommended due to the limited therapeutic benefit and risk of losing time for more 
important measures (Ring J, Beyer K, Biedermann T, et al. Allergo J Int. 
2014;238:96112).

To address a request by the 
, the atezolizumab adverse event 
management guidelines have been revised to add laboratory (e.g., B-type natriuretic 
peptide) and cardiac imaging abnormalities as signs or symptoms that are 
suggestive of myocarditis (Appendix 12).


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
Guidelines for managing patients who experience atezolizumab-associated adverse 
events have been revised to include myositis (Appendix 12).

The management guidelines for infusion-related reactions associated with 
atezolizumab have been updated to include guidelines for cytokine-release 
syndrome (CRS) to align with the definition, grading, and management of CRS 
reflected in a recent publication (Lee et al. 2019) (Appendix 12).
Additional minor changes have been made to correct errors, and improve clarity and 
consistency.  Substantive new information appears in italics.  This amendment 
represents cumulative changes to the original protocol.


Atezolizumab—F. Hoffmann-La Roche Ltd
4/Protocol WO29635, Version 6
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 28
1.1
Non–Muscle-Invasive Bladder Cancer .................................. 28
1.1.1
Classification and Risk Stratification for 
Non–Muscle-Invasive Bladder Cancer .................................. 29
1.1.2
Initial Treatment for Non–Muscle-Invasive 
Bladder Cancer...................................................................... 30
1.1.3
BCG Immunotherapy for High-Risk 
Non–Muscle-Invasive Bladder Cancer .................................. 31
1.1.3.1
Surveillance........................................................................... 37
1.1.4
BCG Failure in High-Risk Non–Muscle-Invasive 
Bladder Cancer...................................................................... 37
1.1.5
Treatment Options following BCG Failure in High 
Risk Non–Muscle-Invasive Bladder Cancer........................... 38
1.1.5.1
Immunotherapy...................................................................... 38
1.1.5.2
Intravesical Chemotherapy.................................................... 39
1.1.5.3
Radiation Therapy ................................................................. 40
1.1.5.4
Radical Cystectomy............................................................... 40
1.2
PD-L1/PD-1 Pathway in Non–Muscle-Invasive 
Bladder Cancer...................................................................... 41
1.3
Atezolizumab......................................................................... 42
1.3.1
Nonclinical Experience .......................................................... 42
1.3.2
Clinical Experience ................................................................ 43
1.3.3
Clinical Safety........................................................................ 43
1.3.4
IMvigor 210 Cohort 1 ............................................................. 44
1.3.4.1
IMvigor 210 Cohort 2 ............................................................. 46
1.3.4.2
Immune-Mediated Adverse Events........................................ 48
1.3.5
Clinical Activity....................................................................... 48
1.3.5.1
PCD4989g:  Clinical Activity in Patients with
2L+mUC ................................................................................ 48
1.4
Study Rationale and Benefit-Risk Assessment...................... 53


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2.
OBJECTIVES.............................................................................................. 54
2.1
Safety Objectives................................................................... 55
2.2
Pharmacokinetic Objective .................................................... 55
2.3
Immunogenicity Objective...................................................... 55
2.4
Efficacy Objective .................................................................. 55
2.5
Patient-Reported Outcome Objective .................................... 55
2.6
Exploratory Objectives........................................................... 55
3.
STUDY DESIGN......................................................................................... 56
3.1
Description of Study .............................................................. 56
3.1.1
Overview of Study Design ..................................................... 56
3.1.2
Study Procedures for All Cohorts .......................................... 61
3.1.3
BCG Dose De-Escalation Scheme (Cohort 1B)..................... 65
3.1.4
Definition of Dose-Limiting Toxicity........................................ 67
3.2
Independent Data Monitoring Committee .............................. 68
3.3
End of Study and Length of Study......................................... 68
3.4
Rationale for Study Design.................................................... 69
3.4.1
Rationale for Patient Population ............................................ 69
3.4.2
Rationale for Atezolizumab Dosage ...................................... 70
3.4.3
Rationale for BCG Dosage .................................................... 71
3.4.4
Rationale for Pharmacokinetic Evaluation 
Schedule................................................................................ 72
3.4.5
Rationale for Blood and Urine Sampling for 
Biomarkers ............................................................................ 72
3.4.6
Rationale for the Collection of Tumor Specimens 
at Screening .......................................................................... 72
3.4.7
Rationale for the Collection of Tumor Specimens 
on Treatment and at Recurrence/Disease............................. 72
3.4.8
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 73
3.5
Outcome Measures ............................................................... 73
3.5.1
Safety Outcome Measures .................................................... 73
3.5.2
Pharmacokinetic Outcome Measures.................................... 73
3.5.3
Immunogenicity Outcome Measure....................................... 74
3.5.4
Efficacy Outcome Measures.................................................. 74


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3.5.5
Patient-Reported Outcome Measure ..................................... 74
3.5.6
Exploratory Biomarker Outcome Measures........................... 74
4.
MATERIALS AND METHODS .................................................................... 75
4.1
Patients.................................................................................. 75
4.1.1
Inclusion Criteria.................................................................... 75
4.1.2
Exclusion Criteria................................................................... 78
4.2
Method of Treatment Assignment and Blinding..................... 81
4.3
Study Treatment.................................................................... 81
4.3.1
Formulation, Packaging, and Handling.................................. 81
4.3.1.1
Atezolizumab......................................................................... 81
4.3.1.2
Bacille Calmette-Guérin......................................................... 81
4.3.2
Dosage, Administration, and Compliance.............................. 82
4.3.2.1
Atezolizumab......................................................................... 82
4.3.2.2
Bacille Calmette-Guérin......................................................... 85
4.3.3
Investigational Medicinal Product Accountability ................... 86
4.3.4
Post-Study Access to Atezolizumab ...................................... 86
4.4
Concomitant Therapy ............................................................ 86
4.4.1
Permitted Therapy................................................................. 86
4.4.2
Prohibited Therapy ................................................................ 87
4.5
Study Assessments ............................................................... 88
4.5.1
Informed Consent Forms and Screening Log........................ 89
4.5.2
Medical History and Demographic Data ................................ 89
4.5.3
Physical Examinations........................................................... 89
4.5.4
Vital Signs.............................................................................. 89
4.5.5
Tumor and Response Evaluations......................................... 90
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 92
4.5.7
Electrocardiograms................................................................ 95
4.5.8
Patient-Reported Outcomes .................................................. 96
4.5.9
Assessments during Treatment............................................. 96
4.5.10
Treatment Discontinuation Visit............................................. 97
4.5.11
Follow-Up Assessments ........................................................ 97
4.5.12
Samples for Roche Clinical Repository.................................. 98


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4.5.12.1
Overview of the Roche Clinical Repository............................ 98
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 98
4.5.12.3
Sample Collection.................................................................. 98
4.5.12.4
Confidentiality........................................................................ 99
4.5.12.5
Consent to Participate in the Roche Clinical 
Repository ........................................................................... 100
4.5.12.6
Withdrawal from the Roche Clinical Repository................... 100
4.6
Patient, Treatment, Study, and Site 
Discontinuation.................................................................... 100
4.6.1
Patient Discontinuation........................................................ 100
4.6.2
Study Treatment Discontinuation......................................... 101
4.6.3
Study and Site Discontinuation............................................ 101
5.
ASSESSMENT OF SAFETY..................................................................... 102
5.1
Safety Plan .......................................................................... 102
5.1.1
Risks Associated with Atezolizumab ................................... 103
5.1.2
Risks Associated with BCG ................................................. 103
5.1.2.1
Constitutional Symptoms (Flu-like Symptoms) .................... 104
5.1.2.2
Local Bladder Symptoms..................................................... 104
5.1.3
Management of Patients Who Experience 
Specific Adverse Events...................................................... 105
5.2
Safety Parameters and Definitions ...................................... 107
5.2.1
Adverse Events ................................................................... 107
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 107
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 108
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 109
5.3.1
Adverse Event Reporting Period ......................................... 109
5.3.2
Eliciting Adverse Event Information..................................... 110
5.3.3
Assessment of Severity of Adverse Events ......................... 110
5.3.4
Assessment of Causality of Adverse Events ....................... 111
5.3.5
Procedures for Recording Adverse Events.......................... 112
5.3.5.1
Diagnosis versus Signs and Symptoms............................... 112


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5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 113
5.3.5.3 
Persistent or Recurrent Adverse Events.............................. 113
5.3.5.4 
Abnormal Laboratory Values ............................................... 113
5.3.5.5 
Abnormal Liver Function Tests............................................ 114
5.3.5.6 
Abnormal Vital Sign Values ................................................. 115
5.3.5.7 
Deaths ................................................................................. 115
5.3.5.8 
Preexisting Medical Conditions............................................ 115
5.3.5.9 
Lack of Efficacy or Worsening of
Non–Muscle-Invasive Bladder Cancer................................ 116
5.3.5.10 
Hospitalization or Prolonged Hospitalization........................ 116
5.3.5.11 
Adverse Events Associated with an Overdose or
Error in Drug Administration ................................................ 117
5.3.5.12 
Patient-Reported Outcome Data ......................................... 117
5.4 
Immediate Reporting Requirements from
Investigator to Sponsor........................................................ 117
5.4.1 
Emergency Medical Contacts.............................................. 118
5.4.2 
Reporting Requirements for Serious Adverse
Events and Adverse Events of Special Interest................... 118
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................. 118
5.4.2.2 
Events That Occur after Study Drug Initiation...................... 118
5.4.3 
Reporting Requirements for Pregnancies............................ 119
5.4.3.1 
Pregnancies in Female Patients.......................................... 119
5.4.3.2 
Abortions ............................................................................. 119
5.4.3.3 
Congenital Anomalies/Birth Defects .................................... 120
5.5 
Follow-Up of Patients after Adverse Events ........................ 120
5.5.1 
Investigator Follow-Up......................................................... 120
5.5.2 
Sponsor Follow-Up .............................................................. 120
5.6 
Adverse Events That Occur after the Adverse
Event Reporting Period........................................................ 120 
5.7 
Expedited Reporting to Health Authorities,
Investigators, Institutional Review Boards, and
Ethics Committees............................................................... 121
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 121
6.1 
Determination of Sample Size ............................................. 121


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6.2
Summaries of Conduct of Study.......................................... 123
6.3
Summaries of Treatment Group Comparability ................... 123
6.4
Efficacy Analyses ................................................................ 123
6.4.1
Primary Efficacy Endpoint.................................................... 123
6.4.2
Secondary Efficacy Endpoints............................................. 123
6.4.2.1
Exploratory Efficacy Analyses ............................................. 124
6.5
Safety Analyses................................................................... 124
6.6
Pharmacodynamic Analyses ............................................... 125
6.7
Pharmacokinetic Analyses................................................... 125
6.8
Patient-Reported Outcome Analyses .................................. 125
6.9
Interim Analysis ................................................................... 125
6.9.1
Planned Interim Analyses.................................................... 125
7.
DATA COLLECTION AND MANAGEMENT ............................................. 125
7.1
Data Quality Assurance....................................................... 125
7.2
Electronic Case Report Forms............................................. 126
7.3
Source Data Documentation................................................ 126
7.4
Use of Computerized Systems ............................................ 127
7.5
Retention of Records........................................................... 127
8.
ETHICAL CONSIDERATIONS.................................................................. 127
8.1
Compliance with Laws and Regulations .............................. 127
8.2
Informed Consent................................................................ 128
8.3
Institutional Review Board or Ethics Committee.................. 129
8.4
Confidentiality...................................................................... 129
8.5
Financial Disclosure ............................................................ 130
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 130
9.1
Study Documentation .......................................................... 130
9.2
Protocol Deviations.............................................................. 130
9.3
Management of Study Quality ............................................. 130
9.4
Site Inspections ................................................................... 131
9.5
Administrative Structure....................................................... 131
9.6
Publication of Data and Protection of Trade 
Secrets ................................................................................ 131


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9.7
Protocol Amendments ......................................................... 132
10. REFERENCES ......................................................................................... 133
LIST OF TABLES
Table 1
Randomized Studies with BCG in High-Risk 
Non–Muscle-Invasive Bladder Cancer........................................ 33
Table 2
Randomized Phase II/III Studies of BCG Maintenance 
Therapy....................................................................................... 36
Table 3
Safety Profiles of IMvigor210 and Study PCD4989g 
(UC Cohort):  Safety-Evaluable Population................................. 44
Table 4
IRF-Assessed ORR and DOR per RECIST v1.1 in 
PCD4989g (mUC Cohort):  Efficacy-Evaluable Population......... 49
Table 5
IRF-Assessed ORR and DOR per RECIST v1.1 in 
1L Patients with mUC:  Efficacy-Evaluable Population in 
IMvigor 210 Cohort 1 (Primary and Updated Analyses).............. 50
Table 6
IRF-Assessed ORR and DOR per RECIST v1.1 in 
2L+Patients with mUC:  Efficacy-Evaluable Population in 
IMvigor 210 Cohort 2 (Primary and Updated Analyses).............. 52
Table 7
Guidelines for the Management of Infusion-Related 
Reactions during the First Atezolizumab Infusion ....................... 84
Table 8
Guidelines for Management of Specific Adverse Events .......... 106
Table 9
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 111
Table 10
Causal Attribution Guidance ..................................................... 112
Table 11
95% CI for Selected Observed 6-Month Complete Response 
Rates in Cohorts 1A and 1B...................................................... 122
Table 12
95% CI for Selected Observed 6-Month Complete Response 
Rates with the Planned Maximum Enrollment of Patients in 
Either Cohort 2 or 3................................................................... 122
LIST OF FIGURES
Figure 1
Serious Adverse Events in 2 Patients:  Safety-Evaluable 
Population in Cohort 1 of IMvigor 210......................................... 45
Figure 2
Serious Adverse Events in 2 Patients:  Safety-Evaluable 
Population in Cohort 2 of IMvigor 210......................................... 47
Figure 3
Overall Survival for All Cohort 1 Efficacy-Evaluable Patients...... 51
Figure 4
Overall Survival for All Cohort 2 Efficacy-Evaluable Patients...... 53
Figure 5
Study Schema............................................................................. 58
Figure 6
Treatment Plans.......................................................................... 64


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LIST OF APPENDICES
Appendix 1
Schedule of Assessments:  Cohort 1A...................................... 140
Appendix 2
Schedule of Assessments:  Cohorts 1B, 2, and 3..................... 146
Appendix 3
BCG and Atezolizumab Treatment and Tumor Assessment 
Calendar for Study Weeks 0108:  Cohorts 1B, 2, and 3 ......... 153
Appendix 4
Schedule of Pharmacodynamic, Pharmacokinetic and 
Biomarker Assessments:  Cohort 1A ........................................ 156
Appendix 5
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments:  Cohorts 1B, 2 and 3.......................................... 158
Appendix 6
Preexisting Autoimmune Diseases ........................................... 160
Appendix 7
Eastern Cooperative Oncology Group  Performance Status 
Scale......................................................................................... 161
Appendix 8
Anaphylaxis Precautions........................................................... 162
Appendix 9
EORTC QLQ-C30 Questionnaire.............................................. 163
Appendix 10
EORTC QLQ-NMIBC24 Questionnaire..................................... 165
Appendix 11
Bladder Map.............................................................................. 166
Appendix 12
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ............................................................................ 167


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE Ib/II OPEN-LABEL STUDY OF THE 
SAFETY AND PHARMACOLOGY OF 
ATEZOLIZUMAB ADMINISTERED WITH OR 
WITHOUT BACILLE CALMETTE-GUÉRIN 
IN PATIENTS WITH HIGH-RISK 
NON–MUSCLE-INVASIVE BLADDER CANCER
PROTOCOL NUMBER:
WO29635
VERSION NUMBER:
6
EUDRACT NUMBER:
Not applicable
IND NUMBER:
120827
NCT NUMBER:
NCT02792192
TEST PRODUCT:
Atezolizumab (MPDL3280A)
Bacille Calmette-Guérin
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 to 
the contact provided to the investigator at study start.  


Atezolizumab—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE Ib/II OPEN-LABEL STUDY OF THE SAFETY AND 
PHARMACOLOGY OF ATEZOLIZUMAB ADMINISTERED WITH 
OR WITHOUT BACILLE CALMETTE-GUÉRIN IN PATIENTS WITH 
HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER
PROTOCOL NUMBER:
WO29635
VERSION NUMBER:
6
IND NUMBER:
120827
NCT NUMBER:
NCT02792192
TEST PRODUCT:
Atezolizumab (MPDL3280A)
Bacille Calmette-Guérin
PHASE:
Ib/II
INDICATION:
Nonmuscle-invasive bladder cancer 
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
This study will evaluate the safety, pharmacokinetics, immunogenicity, patient-reported 
outcomes (PROs), and preliminary anti-tumor activity of atezolizumab administered as a single 
agent and in combination with bacille Calmette-Guérin (BCG) in patients with 
BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC), and in combination with 
BCG in patients with BCG-relapsing, and VHR, BCG-naive NMIBC.
Safety Objectives
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab administered as a single agent and 
in combination with BCG

To identify the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose 
(MTD) or tolerability at the maximum administered dose (MAD) of BCG when administered 
in combination with atezolizumab
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab administered as a single agent and 
in combination with BCG
Immunogenicity Objective
The immunogenicity objective for this study is as follows:

To evaluate the immune response to atezolizumab, as measured by the incidence of 
anti-therapeutic antibodies (ATAs) 


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Efficacy Objective
The efficacy objective for this study is as follows:

To make a preliminary assessment of the anti-tumor activity of atezolizumab administered 
as a single agent and in combination with BCG, as measured by the primary endpoint of 
6-month complete response (CR) rate.  Secondary endpoints include 3-month CR rate, 
duration of CR, RFS rate, bladder-intact DFS, PFS, cystectomy-free survival (CFS), and 
overall survival.
Patient-Reported Outcome Objective
The PRO objective for this study is as follows:

To make a preliminarily assessment of patient-reported symptoms, function, and 
health-related quality of life (HRQoL) associated with atezolizumab administered as a single 
agent and in combination with BCG, as measured by the European Organisation for the 
Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 
(QLQ-C30) and the EORTC QLQ-Non Muscle Invasive Bladder Cancer 24 (NMIBC24)
Exploratory Objectives
The exploratory objectives for this study are as follows:

To make a preliminary assessment of biomarkers that might act as indicators of anti-tumor 
activity of atezolizumab administered as a single agent and in combination with BCG

To make a preliminary assessment of biomarkers that might act as indicators of the 
immunomodulatory effect of atezolizumab administered as a single agent and in 
combination with BCG

To explore the potential relationship between immunogenic response and pharmacokinetics, 
safety, and efficacy
Study Design
Description of Study
This is a Phase Ib/II, open-label, multicenter study designed to assess the safety, tolerability, 
pharmacokinetics, immunogenicity, PROs, and preliminary anti-tumor activity of atezolizumab 
administered by intravenous (IV) infusion as a single agent and in combination with intravesical 
BCG in patients with high-risk NMIBC.
Atezolizumab will be evaluated in the following patient cohorts:

Cohort 1:  Patients with BCG-unresponsive NMIBC
Cohort 1A:  Atezolizumab as a single agent 
Cohort 1B:  Atezolizumab in combination with BCG 

Cohort 2:  Atezolizumab in combination with BCG in patients with BCG-relapsing NMIBC

Cohort 3:  Atezolizumab in combination with BCG in patients with very high-risk (VHR) 
BCG-naive NMIBC
The study will be conducted at approximately 10 to 20 sites in the United States and will enroll 
up to approximately 70 patients across all cohorts.  All patients will be required to have 
histologically confirmed non-muscle invasive urothelial carcinoma of the bladder with carcinoma 
in situ (CIS).  
Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (q3w) for a 
maximum of 96 weeks.  BCG will be administered to evaluate DLTs, MTD, or MAD.  
De-escalation will be allowed for up to three dose levels of BCG (full dose [50 mg], 66% of a full 
dose, and 33% of a full dose [Cohort 1B only]).


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The study will be conducted as follows:

Cohort 1A
Cohort 1A will commence enrollment first.  Cohort 1A will evaluate the safety and 
tolerability of atezolizumab as a single agent in patients with BCG-unresponsive 
NMIBC.  Up to approximately 12 safety- and efficacy-evaluable patients will be 
enrolled into Cohort 1A.

Cohort 1B
Cohort 1B will commence enrollment once 3 patients in Cohort 1A have completed 
one cycle (21 days) of study therapy.  Cohort 1B will evaluate the safety and 
tolerability, DLTs, and MTD or MAD of the combination of atezolizumab and BCG in 
patients with BCG-unresponsive NMIBC.  Data from Cohort 1B will be used to inform 
on the safety and tolerability of combination treatment in NMIBC, as determined at the 
MTD or MAD, as well as the recommended starting BCG dose in Cohorts 2 
(BCG-relapsing NMIBC) and 3 (VHR BCG-naive NMIBC).  Approximately
818 patients will be enrolled into Cohort 1B.  If fewer than 8 patients are required to 
establish MTD or MAD in this cohort, additional patients will be enrolled for a minimum 
of 8 patients in this cohort.

Cohort 1 Expansion 
An expansion cohort will allow enrollment of up to approximately 10 additional patients 
from Cohorts 1A or 1B.  The purpose of this expansion cohort is to provide additional 
safety and efficacy data on these patients, depending on the safety profile observed in 
Cohort 1B.  If few or no DLTs are observed with the combination of atezolizumab and 
BCG, additional Cohort 1B patients will be enrolled to better characterize the safety 
clinical activity of combination therapy.  Alternatively, if the combination of 
atezolizumab and BCG is deemed intolerable in the Cohort 1B population, additional 
Cohort 1A patients will be enrolled to provide additional safety and efficacy data for 
atezolizumab monotherapy in the BCG-unresponsive patients.
Enrollment into Cohorts 2 and 3 will not begin until safety and preliminary anti-tumor activity 
results from approximately 20 patients across Cohort 1 (1A and 1B) are obtained and the 
preliminary benefit/risk has been evaluated.

Cohort 2 
Cohort 2 will commence once the preliminary risk/benefit assessment from Cohorts 1A 
and 1B has demonstrated an acceptable safety and efficacy profile.  Cohort 2 will 
evaluate the safety, tolerability and preliminary efficacy of the combination of 
atezolizumab and BCG (dosed at the MAD or MTD defined by Cohort 1B) in patients 
with BCG-relapsing NMIBC.  Approximately 10 patients will be enrolled into Cohort 2.

Cohort 3
Cohort 3 will commence simultaneously with Cohort 2.  Cohort 3 will evaluate the 
safety, tolerability, and preliminary efficacy of the combination of atezolizumab and 
BCG (dosed at the MAD or MTD defined by Cohort 1B) in patients with VHR 
BCG-naive NMIBC.  Approximately 10 patients will be enrolled in Cohort 3.

Cohorts 2 and 3 Expansion
An expansion cohort will allow enrollment of up to approximately 10 patients in total 
from Cohorts 2 and/or 3.  The purpose of this expansion cohort is to provide additional 
safety and efficacy data for these populations.


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Cohort 1A
Enrollment in Cohort 1A will begin first.  The treatment regimen for Cohort 1A patients is 
atezolizumab 1200 mg IV q3w monotherapy.  Patients may be treated for a maximum of 32 q3w 
cycles of atezolizumab (or for a maximum treatment duration of 96 weeks, whichever comes 
first).  Dosing of the second and third patients will be staggered by a minimum of 1 week relative 
to the first patient. 
Cohort 1B
Enrollment of patients into Cohort 1B will begin once 3 patients in Cohort 1A have completed 
one cycle (21 days) of therapy.  Cohort 1B will follow a “3 3” BCG dose de-escalation scheme 
evaluating up to three dose levels of BCG until the BCG MTD (or MAD) for the two-drug 
combination in BCG-unresponsive NMIBC is defined.  The dose of atezolizumab will be fixed; 
dose de-escalation will occur only for BCG.  The three BCG dose levels to be evaluated in 
Cohort 1B will be the full BCG dose (with a starting dose of 50 mg), followed by 66% of a full 
BCG dose (33 mg), followed by 33% of a full BCG dose (16.5 mg) [Cohort 1B only].  In the first 
course, patients will receive concurrent atezolizumab BCG at the assigned dose.  The MTD or 
MAD will be determined on the basis of DLTs observed during the DLT assessment window 
(defined as Days 121 of BCG Induction Course).  After the MTD or MAD is determined for 
Cohort 1B, this dose will be used for all subsequent patients enrolled into Cohorts 1B, 2, and 3, 
unless the MTD is determined to be 33% of a full BCG dose.  If MTD is determined to be 33% of 
a full BCG dose, then, no patients will be enrolled into Cohorts 2 and 3 until an assessment of 
the safety and activity of the combination of atezolizumab plus 33% of a full BCG dose is 
completed. Atezolizumab plus 33% of a full dose will not be carried into Cohorts 2 and 3 unless 
a favorable risk-benefit profile is demonstrated.  If MTD or MAD is reached before 8 patients 
have been enrolled in Cohort 1B, additional patients will be enrolled up to a minimum of 8 total 
patients.  These additional patients will be treated at the established MTD or MAD.  See the 
protocol for a description of the BCG dose de-escalation scheme and for the definition of DLT.
A minimum of 3 patients will be enrolled into each BCG dose level evaluated.  However, for the 
starting dose level in Cohort 1B, dosing of the second and third patients will be staggered by a 
minimum of 1 week relative to the first patient.  If the first patient does not experience 
unacceptable toxicity during the first week of combination treatment, the second and third 
patients at the first dose level may start combination treatment without delay.  Dosing for 
subsequent dose levels will not be staggered.
The treatment regimen for Cohort 1B patients is as follows:
BCG

BCG Induction Course (12 weeks): BCG induction will begin on study Day 1. BCG will 
be administered at the assigned dose (see protocol) weekly for a total of six doses 
(BCG induction). 

BCG Maintenance Course 1 (12 weeks):  BCG will be administered at the assigned dose 
weekly for a total of three doses (BCG maintenance).  

BCG Maintenance Courses 25 (every 24 weeks, beginning 12 weeks after initiation of 
Maintenance Course 1):  BCG maintenance Courses 25 are optional for patients in 
Cohort 1B.  BCG maintenance Courses 25 may be administered if, at the investigator’s 
discretion, there is felt to be ongoing clinical benefit of BCG.  The Medical Monitor will 
review and approve this on a case-by-case basis.  These patients will receive BCG
administered at the assigned dose weekly for a total of three doses per maintenance course.  
Atezolizumab

Atezolizumab therapy will begin on study Day 1.  All patients will continue to receive 
atezolizumab 1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, whichever 
comes first.  


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Cohort 2
Patients in Cohort 2 will be treated with atezolizumab 1200mg IV q3w in combination with BCG 
dosed at the MAD or MTD determined by Cohort 1B (provided MAD or MTD is determined to be 
either full dose or 66% of a full BCG dose).
The treatment regimen for Cohort 2 patients is as follows:
BCG

BCG Induction Course (12 weeks):  BCG induction will begin on study Day 1. BCG will be 
administered at the assigned dose weekly for a total of six doses (BCG induction). 

BCG Maintenance Course 1 (12 weeks): BCG will be administered at the assigned dose 
weekly for a total of three doses.  

BCG Maintenance Course 25 (every 24 weeks, beginning 12 weeks after initiation of 
Maintenance Course 1):  BCG will be administered at the assigned dose weekly for a total 
of three doses per course.
Atezolizumab  

Atezolizumab therapy will begin on study Day 1.  Patients will receive atezolizumab 
1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, whichever comes first.
Cohort 3
Patients in Cohort 3 will be treated with atezolizumab 1200mg IV q3w in combination with BCG 
dosed at the MAD or MTD determined by Cohort 1B.
The treatment regimen for Cohort 3 patients is as follows:
BCG

BCG Induction Course (12 weeks):  BCG induction will begin on study Day 1.  BCG will be 
administered at the assigned dose weekly for a total of six doses (BCG induction). 

BCG Maintenance Course 1 (12 weeks):  BCG will be administered at the assigned dose 
weekly for a total of three doses.  

BCG Maintenance Course 25 (every 24 weeks, beginning 12 weeks after initiation of 
Maintenance Course 1):  BCG will be administered at the assigned dose weekly for a total 
of three doses per course. 
Atezolizumab

Atezolizumab therapy will begin on study Day 1.  Patients will receive atezolizumab 
1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, whichever comes first.
Number of Patients
The total planned enrollment for this study is up to approximately 70 patients:  up to 
approximately 12 patients in Cohort 1A, approximately 818 patients in Cohort 1B, up to 
approximately 10 patients in the Cohort 1 expansion, approximately 10 patients in Cohort 2,
approximately 10 patients in Cohort 3, and approximately 10 patients in the Cohort 2 and 3 
expansion.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years


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
Histologically confirmed nonmuscle-invasive TCC of the bladder with CIS
Patients with mixed histologies, where the dominant (50% tumor volume) histology 
is TCC, may be considered on a case-by-case basis upon approval by the 
Medical Monitor.
Patients may have Ta/T1 lesions, provided they have been completely resected.

High-risk NMIBC defined by the following:
BCG-unresponsive NMIBC (Cohorts 1A and 1B):
Persistence of high-grade CIS at 6 months following an adequate course of BCG; 
OR 
Stage/grade progression at 3 months after induction BCG; OR
Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) 
following an adequate course of BCG that occurs 6 months after the last 
exposure to BCG
BCG-relapsing NMIBC (Cohort 2):
Recurrence of high-grade CIS after achieving a disease-free state following an 
adequate course of BCG that occurs 6 months after the last exposure to BCG
VHR BCG-naive NMIBC (Cohort 3):
VHR NMIBC, defined as having at least one of the following:  
Multiple and/or large (3 cm) T1, (HG/G3) tumors
T1, (HG/G3) tumor with concurrent CIS
T1, G3 with CIS in prostatic urethra
Micropapillary variant of non-muscle invasive urothelial carcinoma 

For BCG-unresponsive and BCG-relapsing NMIBC, patients must have received an 
adequate course of BCG.  An adequate course of BCG is defined as at least one course of 
induction (minimum of five weekly instillations) and one course of maintenance (minimum of 
two weekly instillations) with the following exceptions:
Patients with grade/stage progression after induction BCG (minimum of five weekly 
instillations) are eligible.
Patients with persistent or recurrence of high-grade disease after two BCG induction 
courses (minimum of five weekly instillations, each) are eligible.
Patients who did not receive an adequate course of BCG as a result of the worldwide 
BCG shortage may be eligible following discussion with the Medical Monitor.

Resection of all pTa/pT1 papillary disease
Prior to enrollment, patients must have undergone repeat transurethral resection of 
bladder tumor (TURBT) to ensure no evidence of residual papillary disease.

No prior radiation to bladder or pelvic region

Eastern Cooperative Oncology Group (ECOG) performance status of 2 

Life expectancy 12 weeks

Adequate hematologic and end-organ function, defined by the following laboratory results 
obtained within 14 days prior to the first study treatment:
ANC 1500/L (without granulocyte colony-stimulating factor support within 2 weeks 
prior to the first dose of study treatment)
WBC counts 2500/L and 15,000/L
Lymphocyte count 300/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to the first dose of 
study treatment)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.


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AST, ALT, and alkaline phosphatase 2.5 upper limit of normal (ULN)
Serum bilirubin 1.5 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.
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent 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 study drug.  Women must refrain from donating eggs during this same 
period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical study and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.

For men receiving BCG:  agreement to remain abstinent (refrain from sexual intercourse) or 
use a condom to prevent transmission of BCG to sexual partners:
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.

Tumor tissue biopsy
A sample of tumor tissue is required within 60 days prior to study entry.  Fresh tissue 
biopsy is preferred; however, an archival specimen may be submitted in lieu of fresh 
tissue if a tissue biopsy is contraindicated owing to patient safety or tumor tissue 
accessibility and the archival specimen was obtained within 60 days of study 
screening.  The specimen may consist of a formalin-fixed paraffin-embedded (FFPE) 
tumor tissue block (preferred) or at least 10 unstained, serial sections.  Patients with 
cystoscopy results indicating pTa/pT1 papillary disease must undergo a TURBT 
procedure for removal of residual papillary disease prior to study entry.

Willingness to complete all study-related procedures including patient-reported 
questionnaires 
Additional Cohort 3Specific Inclusion Criteria

No prior treatment with intravesical BCG
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
Cancer-Specific Exclusions

Evidence of locally advanced or metastatic bladder cancer (including but not limited to 
disease involving renal pelvis, ureter, or prostatic urethra) 

Evidence of muscle-invasive bladder cancer


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
Evidence of extravesical bladder cancer

Any malignancy within 5 years prior to Cycle 1, Day 1, except adequately resected basal 
cell and squamous cell skin cancer or adequately treated carcinoma in situ of the cervix.  
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) may be allowed after discussion with the Medical 
Monitor.
Patients with prostate cancer who are at low risk and are undergoing active 
surveillance (Stage T1/T2a, Gleason score 7 and PSA 10 ng/mL) are eligible.

Treatment with any approved anti-cancer therapy, including chemotherapy (systemic or 
intravesical), radiation therapy (to the bladder or pelvic region), or hormonal therapy within 
3 weeks prior to the first dose of study treatment
Use of hormone-replacement therapy and oral contraceptives is permitted.

Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to the first dose of study treatment
General Medical Exclusions

Pregnant or lactating, or intending to become pregnant during the study
Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to the first dose of study treatment.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells 

Allergy or hypersensitivity to components 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 anti-phospholipid 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 after discussion with and 
approval by the Medical Monitor.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study after discussion with and approval by the Medical Monitor.

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Serum albumin 2.5 g/dL

Positive test for HIV

Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at 
screening) 
Patients with past or resolved hepatitis B (HBV) infection (defined as having a 
negative HBsAg test and a positive anti-hepatitis B core antigen [anti-HBc] antibody 
test) are eligible.  HBV DNA must be obtained in these patients prior to the first dose 
of study treatment.

Active hepatitis C
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction assay is negative for HCV RNA.

Active tuberculosis


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
Severe infections within 28 days prior to the first dose of study treatment, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

Signs or symptoms of infection within 14 days prior to the first dose of study treatment

Treatment with therapeutic oral or IV antibiotics within 14 days prior to the first dose of 
study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible. 

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within the previous 3 months, unstable 
arrhythmias, or unstable angina 

Major surgical procedure other than for diagnosis within 28 days prior to the first dose of 
study treatment, or anticipation of need for a major surgical procedure during the course of 
the study

Administration of a live/attenuated vaccine within 28 days prior to the first dose of study 
treatment, within 5 months following the administration of the last dose of study drug, 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 to May in the Northern Hemisphere and from April through 
September in the Southern Hemisphere).  Patients must agree not to receive 
live/attenuated influenza vaccine (e.g., FluMist) within 28 days prior to first dose of 
study treatment, during treatment or within 5 months following the last dose of 
atezolizumab.

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complications.
Exclusion Criteria Related to BCG

History of prior significant toxicity or intolerance to BCG requiring discontinuation of 
treatment

History of prior systemic BCG infection
Note:  This is applicable to patients receiving combination BCG and atezolizumab 
therapy (Cohorts 1B or 2).  Patients in Cohort 1A may be eligible, pending that they 
have received an adequate course of BCG and meet all other eligibility criteria.

History of immunosuppression, or conditions associated with congenital or acquired 
immune deficiency, whether because of concurrent disease (e.g., AIDS, leukemia, 
lymphoma), cancer therapy (e.g., cytotoxic drugs, radiation), or immunosuppressive therapy 
(e.g., corticosteroids)

Concurrent febrile illness, urinary tract infection, or gross hematuria
Exclusion Criteria Related to Medications

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anticytotoxic T lymphocyteassociated antigen 4, antiPD-1, and antiprogrammed
deathligand 1 (PD-L1) therapeutic antibodies 

Treatment with systemic immunostimulatory agents (including but not limited to interferons 
and interleukin 2 [IL-2]) within 6 weeks or five half-lives of the drug, whichever is shorter, 
prior to the first dose of study treatment


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
Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor 
necrosis factor alpha [TNF-] agents) within 2 weeks prior to the first dose of study 
treatment, or anticipated requirement for systemic immunosuppressive medications during 
the study. 
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 and mineralocorticoids (e.g., fludrocortisone) is 
allowed.  Use of physiologic doses of corticosteroids for adrenal insufficiency is 
allowed.
End of Study
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 120 weeks after the last patient is enrolled in the study.
Length of Study
The study is expected to last approximately 3.5 years after the first patient is enrolled. 
Outcome Measures
Safety Outcome Measures
The safety and tolerability of atezolizumab and BCG will be assessed using the following 
outcome measures:

Incidence, nature, and severity of adverse events, graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0)

Changes in selected vital signs and clinical laboratory results during and following 
administration of atezolizumab alone and in combination with BCG
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum atezolizumab maximum serum concentration (Cmax) after the first infusion of 
atezolizumab

Serum atezolizumab minimum serum concentration (Cmin) prior to the infusion at specified 
timepoints 
Immunogenicity Outcome Measure
The immunogenicity outcome measure for this study is as follows:

Incidence of ATA response to atezolizumab and potential correlation with PK, 
pharmacodynamic, safety, and efficacy parameters 
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is as follows:

CR at the 6-month evaluations after the start of study treatment. Patients must be 
evaluated for CR by both cystoscopy and cytology and bladder biopsies will be required for 
the 6-month CR disease assessment.
The secondary efficacy outcome measures for this study are as follows:

CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology.  

Duration of CR, defined as time from first occurrence of a documented CR until the time of 
recurrence of NMIBC or death from any cause

RFS rate at 6, 12, and 18 months, defined as the proportion of patients who are alive and 
free of persistent/recurrent high-risk NMIBC  


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
Bladder-intact DFS, defined as time from first study treatment to earliest evidence of 
progression to muscle-invasive disease in the bladder, regional pelvic progression, distant 
metastasis, bladder cancerrelated death, or cystectomy or death from any cause 

PFS, defined as the time from first study treatment to the first occurrence of progression to 
muscle-invasive disease or death from any cause

CFS, defined as the time from first study treatment to cystectomy or death from any cause

Overall survival, defined as the time from first study treatment to death from any cause
Patient-Reported Outcome Measure
The exploratory PRO outcome measure for this study is as follows:

Change from baseline in patient-reported symptoms, function, and HRQoL, as measured by 
the EORTC QLQ-C30 and EORTC QLQ-NMIBC24
Exploratory Biomarker Outcome Measures
The following biomarker endpoints will be assessed when appropriate:

PD-L1 status by immunohistochemistry (IHC) in archival tissues and/or fresh biopsies

Status of other exploratory biomarkers related to PD-L1 or immune cell biology (including 
but not limited to CD8 or programmed death1 [PD-1]) and tumor biology
The following exploratory biomarker outcome measures will be assessed when appropriate:

Changes in immune-related markers (including but not limited to CD8, granzyme B, and 
other exploratory markers) in archival and/or fresh tumor tissue prior to and during 
atezolizumab and BCG treatment
Investigational Medicinal Products
Atezolizumab and BCG (OncoTICE) are both considered an investigational medicinal product 
(IMP) in this study.
Test Product (Investigational Drug)
Atezolizumab
The dose level of atezolizumab in this study is 1200 mg administered by IV infusion q3w.  There 
will be no dose reduction of atezolizumab.  
Cohort 1A:  Patients receive atezolizumab 1200 mg IV q3w, for a maximum of 32 doses over 
96 weeks.
Cohort 1B:  During BCG Induction Course (12 weeks), patients receive atezolizumab 1200 mg 
IV q3w for a total of four doses.  During BCG Maintenance Course 1 (12 weeks), patients will 
receive atezolizumab 1200 mg IV q3w for a total of four doses.  Additional BCG maintenance 
courses are not required for patients in Cohort 1B but may be allowed on a case-by-case basis 
after discussion with the Medical Monitor.  BCG Maintenance Courses 25 (each 24 weeks), 
patients receive atezolizumab 1200 mg IV q3w for a total of eight doses per course.  The 
maximum treatment duration of atezolizumab is 96 weeks. 
Cohorts 2 and 3:  During BCG Induction Course (12 weeks), patients receive atezolizumab 
1200 mg IV q3w for a total of four doses.  During BCG Maintenance Course 1 (12 weeks), 
patients will receive atezolizumab 1200 mg IV q3w for a total of four doses.  During BCG 
Maintenance Courses 25 (each 24 weeks), patients receive atezolizumab 1200 mg IV q3w for 
a total of eight doses per course.  The maximum treatment duration of atezolizumab is 
96 weeks.
BCG
BCG will not be administered in Cohort 1A.
Cohort 1B:  The three BCG dose levels to be evaluated in Cohort 1B will be full dose (starting 
dose of 50 mg), followed by 2/3 of a full BCG dose, followed by 1/3 of a full dose.
During BCG Induction Course (12 weeks), patients will receive BCG at the assigned dose 
weekly for a total of six doses.  During BCG Maintenance Course 1 (12 weeks), patients receive 


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BCG at the assigned dose weekly for a total of three doses.  During BCG Maintenance 
Courses 25 (each 24 weeks), patients receive BCG at the assigned dose weekly for a total of 
three doses per course.
Cohorts 2 and 3:  During BCG Induction Course (12 weeks), patients will receive BCG at the 
MTD/MAD (established in Cohort 1B) weekly for a total of six doses.  During BCG Maintenance 
Course 1 (12 weeks), patients receive BCG at the MTD/MAD weekly for a total of three doses.  
During BCG Maintenance Courses 25 (each 24 weeks), patients receive BCG at the 
MDT/MAD weekly for a total of three doses per course.  
Statistical Methods
Primary Analysis
All analyses will be performed by cohort.  Selected analyses may also be performed for all 
cohorts combined as specified below.
All patients treated with any amount of study drug (atezolizumab or BCG) will be included in all 
analyses unless specified otherwise.
Analyses of DLTs will be performed on an ongoing basis.  Analyses of endpoints related to 
anti-tumor activity will be performed periodically among patients with sufficient follow up.  Final 
analyses will be performed after the LPLV has occurred.
Continuous variables will be summarized using means, SDs, medians, and ranges.  Categorical 
variables will be summarized by proportions.  The baseline value of any variable will be defined 
as the last available value prior to the first administration of study treatment.
Determination of Sample Size
The sample sizes for Cohorts 1A, 2, and 3 were based on clinical and operational 
considerations. The sample size for Cohort 1B was based on a 3 3 dose de-escalation design 
appropriate for assessing DLTs and MTD or MAD of BCG in combination with atezolizumab.
An evaluation of results from Cohorts 1A and 1B will be performed prior to initiation of 
enrollment in Cohorts 2 and 3.  The protocol shows the 95% CI for selected observed CR rates 
for a range of sample sizes for Cohorts 1A and 1B pooled. 
Planned Interim Analyses
A preliminary assessment of anti-tumor activity and safety will be performed on Cohorts 1A and 
1B prior to initiation of enrollment into Cohorts 2 and 3. 
Given the nature of this study, the Sponsor may choose to perform additional periodic analyses 
of safety or efficacy on any cohort.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AC
all comers
anti-HBc
anti-hepatitis B core antigen
ATA
anti-therapeutic antibody
AUA
American Urological Association
BCG
bacille Calmette-Guérin
BOR
best overall response
C1D1
Cycle 1, Day 1
CCOD
clinical cutoff date
CFS
cystectomy-free survival
CIS
carcinoma in situ
Cmax
maximum serum concentration
Cmin
minimum serum concentration
CR
complete response
CRO
contract research organization
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration 
DFS
disease-free survival
DLT
dose-limiting toxicity
DOR
duration of response
EAU
European Association of Urology
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC 
European Organisation for Research and Treatment of 
Cancer
FACS
fluorescence-activated cell sorting
FFPE
formalin-fixed paraffin-embedded
FDA
U.S. Food and Drug Administration
GM-CSF
granulocyte macrophage colony-stimulating factor
GU
genitourinary
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus


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Abbreviation
Definition
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life 
IC
PD-L1 tumor-infiltrating immune cell
IFN
interferon
IHC
immunohistochemistry
IL
interleukin
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IUO
investigator use only
IV
intravenous
IxRS
interactive Web/voice response system
LFT
liver function test
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
next generation sequencing 
NMIBC
nonmuscle-invasive bladder cancer 
NMIBC24
QLQ-NonMuscle-Invasive Bladder Cancer 24
ORR
overall response rate
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PD-L
programmed deathligand
PD-L1
programmed deathligand 1
PFS
progression-free survival
PK
pharmacokinetic
PPD
purified protein derivative
PRO
patient-reported outcome
pT1
invasive papillary carcinoma that has invaded in the 
sub-epithelial connective tissue of the bladder
pTa
non-invasive papillary carcinoma that has not invaded 
in the sub-epithelial connective tissue of the bladder


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Abbreviation
Definition
PUNLMP
papillary urothelial neoplasm of low malignant potential
PVC
polyvinyl chloride
q3w
every 3 weeks
QLQ-C30
Quality-of-Life Questionnaire Core 30
OS
overall survival
RCR
Roche Clinical Repository
RDA
recommended daily allowance
RFS
recurrence-free survival
SOC
standard-of-care
SWOG
Southwest Oncology Group
TCC
transitional cell carcinoma
TIMC
tumor-infiltrating mononuclear cell
Tis
carcinoma in-situ
TNF-
tumor necrosis factor-
TSH
thyroid-stimulating hormone
TURBT
transurethral resection of bladder tumor
UC
urothelial carcinoma
ULN
upper limit of normal
VHR
very high-risk (BCG-naive NMIBC)


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1.
BACKGROUND
1.1
NON–MUSCLE-INVASIVE BLADDER CANCER
Urothelial carcinoma (also termed transitional cell carcinoma [TCC]) is the most common 
cancer of the urinary system worldwide, with urothelial carcinoma (UC) of the bladder
being the predominant histologic type and location.  It is estimated that in 2015, there will 
be 74,690 new cases of bladder cancer and 15,580 deaths (about 11,510 in men and 
4490 in women in the United States; American Cancer Society 2015).  Worldwide data 
estimated 429,793 new cases of bladder cancer, with 165,084 deaths, in 2012 
(GLOBOCAN 2012).  Between 75% and 85% of new cases of UC will present at first 
diagnosis as nonmuscle-invasive bladder cancer (NMIBC).  By rough estimates, 
in 2015, there will be 60,000 new cases of NMIBC in the United States alone and 
approximately 340,000 new cases of NMIBC worldwide (Lightfoot et al. 2011).
The primary management of NMIBC is surgical via cystoscopy and transurethral 
resection of bladder tumor (TURBT), which may be curative in rare cases 
(Brausi et al. 2002).  Unfortunately, the overall prognosis for many patients with NMIBC 
can be considered poor and this disease carries a high unmet medical need. 
The natural history of NMIBC is characterized by multiple recurrences in up to 90% of 
patients (over a 5-year period), leading to frequent diagnostic and therapeutic 
interventions including cystoscopy and TURBT, impacting patient-reported health-related 
quality of life (Yoshimura et al. 2005; Wei et al. 2013) and disease progression (with 
radical cystectomy and loss of bladder) in up to 45% of patients (Lightfoot et al. 2011).  
The morbidity and impact of bladder cancer is highest among the elderly in the NMIBC 
setting, as patients require life-long surveillance with cystoscopic examinations, 
intermittent imaging, and intravesical therapies.  These procedures carry the risk of side 
effects, complications that can negatively impact bladder function.  This burden of 
bladder cancer is further compounded by the indirect impact on psychological health and 
quality of life of patients and their families (Mossanen and Gore 2014).  
For patients with NMIBC who experience treatment failure, the gold standard is radical 
cystectomy.  This procedure includes complete removal of the bladder followed by one 
of several techniques to create a urinary diversion.  The significant morbidity that can 
include urinary leakage, frequent self-catheterization, erectile dysfunction, body image 
dissatisfaction, infertility, and high perioperative mortality associated with radical 
cystectomy has been well defined over the years, with postoperative complication rates 
as high as 64% (Donat et al. 2009).  The negative health economic impact of the high 
complication rate is highlighted by a recent comparison of major surgical procedures 
performed in hospitals, which identified cystectomy as having one of the highest 
associated costs (Nathan et al. 2015).


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1.1.1
Classification and Risk Stratification for Non–Muscle-Invasive 
Bladder Cancer
Sylvester et al. (2006) conducted a meta-analysis of seven European Organization for 
Research and Treatment of Cancer (EORTC) studies in NMIBC.  From this analysis, a 
simple scoring system was derived for estimating the risk of disease recurrence and 
disease progression, based on major pathological risk factors.  This scoring system,
commonly referred to as the EORTC risk calculator, is used to assess risk of recurrence 
or progression in NMIBC (Sylvester et al. 2006; Babjuk et al. 2011).
NMIBC comprises a heterogeneous group of tumors with varying outcomes:  

Stage Ta is non-invasive papillary carcinoma that has not invaded in the 
sub-epithelial connective tissue of the bladder. 

Stage T1 is papillary carcinoma that has invaded into the sub-epithelial connective 
tissue (lamina propria) of the bladder lining. 

Carcinoma in-situ (CIS or Tis) consists of flat, non-papillary, high-grade lesions 
characterized by severe cellular dysplasia and localized to the sub-epithelial surface 
of the bladder (Babjuk et al. 2011). 
Approximately 70% of NMIBC presents as predominantly Ta disease, 20% of patients 
present with predominantly T1 disease, and 10% present as predominantly CIS. CIS is 
considered a distinct entity because of the difficulty in detection with standard 
cystoscopy examination and its high propensity for disease progression 
(Nese et al. 2009).  Primary CIS occurs in approximately 3% of all UC; however, it is 
found concurrently with T1 disease in up to 50% of cases (Kim and Steinberg 2001).  
The presence of CIS is associated with a high incidence of progression to invasive 
disease, even after surgical and intravesical therapy. The rate of disease progression to 
muscle invasion with or without TURBT with CIS has been shown to be 50%60% 
(Casey et al. 2015).  In a single institution, where a series of 155 patients with CIS were 
managed with TURBT and intravesical bacille Calmette-Guérin (BCG), the 5-year 
cumulative incidence of progression to T1 or higher disease was 45% (95% CI: 3755).  
In this study, it was observed that diffuse involvement of the mucosa with CIS was 
associated with a particularly aggressive disease, with disease progression in 60%80% 
of such patients (Chade et al. 2010).  From a therapeutic perspective, NMIBC is broadly 
categorized into low-risk and intermediate/high-risk, on the basis of the risk of recurrence 
and/or disease progression (Babjuk et al. 2011).  
High-risk NMIBC is characterized by any one or more of the following:  

T1 tumor 

High-grade tumor

CIS 

Multiple and recurrent and large (3 cm) low-grade Ta lesions (all 3 conditions must 
be met for low-grade Ta lesions).  


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These tumors are at high-risk of recurrence and progression, with progression to muscle 
invasive disease being the primary concern (Sylvester et al. 2006; Babjuk et al. 2013). 
The European Association of Urology (EAU) describes a group of patients with NMIBC 
that falls into an extremely high-risk group, hereafter referred to as “very high-risk” (VHR) 
NMIBC (Babjuk et al. 2013).  These include patients with any of the following:

Multiple and/or large (3 cm) high-grade T1 tumors 

High-grade T1 tumors with concurrent CIS 

High-grade T1 tumors with CIS in the prostatic urethra 

Micropapillary variant NMIBC  
Patients in the first two groups described above have a 1-year recurrence risk of 
25%40% and progression rates of 5%17%.  By year five,60% of patients develop 
recurrence, and 45% exhibit progression to muscle-invasive disease 
(Sylvester et al. 2006; Fernandez-Gomez et al. 2009).  Prostatic urethral involvement 
and micropapillary variant histology are two rare risk factors not well represented in the 
larger meta-analyses.  Smaller studies demonstrate an extremely high risk of 
progression and death from bladder cancer for these subgroups, although exact risk 
estimates are challenging due to small numbers (Palou et al. 2012; 
Giannarini et al. 2014; Jackson et al. 2015).
1.1.2
Initial Treatment for Non–Muscle-Invasive Bladder Cancer
The backbone of therapy for patients with NMIBC is surgical resection with TURBT.  
This procedure is both diagnostic and therapeutic, with the goal of complete removal of 
malignant tumor and histologic review of resected disease to determine the risk of 
recurrence.  One pitfall of this procedure is that it is operator-dependent.  Brausi et al. 
(2002) demonstrated that the quality of TURBT had a major impact on recurrence rates.  
In a study of 83 patients with NMIBC, Grimm et al. (2003) observed that residual disease 
was found in 27% of Ta and 53% of T1 cases.  
Divrik et al. (2010) demonstrated the benefit of repeat TURBT in a prospective, 
randomized study.  Data from this study showed 5-year recurrence-free survival (RFS) 
rates of 59% with re-TURBT, compared with 32% with single TURBT alone.  Similarly, 
the 5-year progression-free survival (PFS) rates were 93% with re-TURBT, compared 
with 79% for the single TURBT alone (Divrik et al. 2010).  As a result, repeat or 
restaging TURBT is routinely recommended, especially for cases of an incomplete initial 
TURBT, absence of muscle layer in the resected specimen (with the exception of Ta 
low-grade tumors and primary CIS), all T1, and all high-grade tumors (except CIS) 
(Babjuk et al. 2011).   


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Use of radical cystectomy, a treatment option for high-risk NMIBC, can be curative but 
remains controversial for most patients (Skinner 2007).  Data from a study by Denzinger 
et al. (2007), evaluating early cystectomy as a treatment option for high-risk NMIBC, 
revealed a 30% incidence of upstaging following cystectomy.  Cancer-specific survival 
rates were prolonged in the early cystectomy group compared with the late cystectomy 
group; the presence of CIS was a major determining factor for outcome 
(Denzinger et al. 2007).  The EAU recommends considering cystectomy as an initial 
treatment option for the subgroup of patients with VHR NMIBC defined in the previous 
section (Babjuk et al. 2013).  
1.1.3
BCG Immunotherapy for High-Risk Non–Muscle-Invasive 
Bladder Cancer
BCG is a live attenuated form of Mycobacterium bovis and the most commonly used 
agent for intravesical therapy.  Per the American Urological Association (AUA) and the 
EAU bladder cancer guidelines it is the standard treatment for patients with high-risk 
NMIBC following a restaging TURBT.
Herr and Morales (2008) were the first to report successful treatment of NMIBC with 
intravesical BCG in 1976.  Although the mechanism of action for intravesical BCG is not 
fully understood, there is evidence to suggest that activity occurs through initiation of an 
inflammatory response with T-cell activation and release of an array of pro-inflammatory 
cytokines and chemokines such as interleukin (IL)1, IL-6, IL-8, tumor necrosis factor
(TNF-, and granulocyte macrophage colony-stimulating factor (GM-CSF).  Following 
T-cell activation, there is an influx of tumor-infiltrating immune cells with formation of 
BCG-induced granulomata in the bladder wall (Redelman-Sidi et al. 2014).  Supportive 
evidence has shown that development of the Th-1 cytokine profile (interferon [IFN]-, 
IL-2, IL-12) is associated with the therapeutic effects of BCG.  In contrast, the presence 
of high levels Th-2 cytokines (e.g., IL-10) is associated with BCG failure (Luo 2014).
Adverse reactions from intravesical BCG are typically local and include dysuria, cystitis, 
frequency, and hematuria.  Less than 10% of these local effects occur with 
Grade 3 toxicity.  Less common local effects observed include granulomatous 
prostatitis, epididymitis, ureteral obstruction, and contracted bladder.  Systemic effects 
observed include fever, influenza-like symptoms, BCG-induced lung infection, 
hepatotoxicity, and BCG-sepsis.  Skin rash, arthralgia, and arthritis have also been 
classified as possible allergic reactions (TICEUSPI).  Results from a study by 
Brausi et al. (2014), showed the frequency of these adverse reactions to be unrelated to 
dose with the majority of these effects occurring within the first year of therapy.


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Sylvester et al. (2005) performed a meta-analysis of studies comparing intravesical BCG 
to intravesical chemotherapy for high-risk NMIBC.  In this meta-analysis, complete 
responses (CRs) for CIS were observed in 68.1% of patients treated with intravesical 
BCG compared with 51.5% with intravesical chemotherapy.  Median follow-up was 
3.6 years with recurrence rates of 34% and 50% for BCG and chemotherapy, 
respectively, with significant superiority of BCG over chemotherapy observed in studies
where maintenance BCG was administered (Sylvester et al. 2005). 
A summary of the studies from these analyses has been provided in Table 1.


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Table 1
Randomized Studies with BCG in High-Risk Non–Muscle-Invasive Bladder Cancer
High-Risk NMIBC (Recurrent Ta/T1 or CIS)
No. of 
Patients
CR (%)
(CIS Only)
2-year DFS (%)
(Duration of Follow-Up)
BCG vs. doxorubicin
BCG vs. doxorubicin vs. thiotepa
BCG Schedule:  15 courses a
202
NA
88 vs. 40/67
(3 years)
SWOG 8216:  BCG vs. Doxorubicin
BCG Schedule:  6-week inductionre-induction 3-week maintenance 
at 3, 6, 12, 18, 24, 30, and 36 months b
262
70 vs. 34
45 vs. 18
(5 years)
EORTC 30906:  BCG vs. Epirubicin
BCG Schedule: 6-week inductionre-induction 3-week maintenance 
at 3, 6, 12, 18, 24, 30, and 36 months c 
168
65 vs. 56
5.1 vs. 1.4 (TTR)
(5.6 years)
BCG vs. MMC
SWOG 8795:  BCG vs. MMC
BCG Schedule: 6-week induction then 6 weekly at 8 and 12 weeks, 
then monthly to 1 year d 
469
55 vs. 46
57 vs. 45
(2 years)
Nijmegen Study:  BCG (TICE/RIVM) vs. MMC
BCG Schedule:  6-week inductionre-induction (no maintenance) e
469
70/47 vs. 42
54/62 vs. 65
(2 years)
BCG (TICE/RIVM) vs. MMC
BCG Schedule:  6-week inductionre-induction (no maintenance) f
437
74/60 vs. 67
42/55 vs. 59
(3 years)
BCG vs. MMC
BCG Schedule:  6-week induction then monthly for 1 year and every 
3 months for Year 2 g 
261
NA
42 vs. 34
(5 years)


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Table 1
Randomized Studies with BCG in High-Risk Non–Muscle-Invasive Bladder Cancer (cont.)
BCGbacille Calmette-Guérin; CIScarcinoma in situ; CRcomplete response; DFSdisease-free survival; EORTCEuropean 
Organisation for Research and Treatment of Cancer; MMCmitomycin C; NAnot applicable; NMIBCnonmuscle-invasive bladder 
cancer; RIVM; SWOGSouthwest Oncology Group; TTRtime to response.
a Martinez-Pineiro JA, Jimenez LJ, Martinez-Pineiro L Jr, et al. Bacillus calmette-guerin versus doxorubicin versus thiotepa: a 
randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990;143:5026.
b Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille 
Calmette–Guerin for transitional-cell carcinoma of the bladder. N Engl J Med 1991;325:12059.
c de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus calmette-guerin versus epirubicin for primary, secondary or concurrent 
carcinoma in situ of the bladder: results of a european organization for the research and treatment of cancer-genitourinary group 
phase III trial (30906). J Urol 2005 ;173 :4059.
d Lamm DL, Blumenstein BA, Crawford DE, et al. Randomized intergroup comparison of bacillus calmette-guerin immunotherapy 
and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group 
study. Urol Oncol 1995;1:11926.
e Witjes JA, vd Meijden AP, Witjes WP, et al. A randomised prospective study comparing Intravesical instillations of mitomycin-C, 
BCG-Tice, and BCG-RIVM in pTa-pT1 tumours and primary carcinoma in situ of the urinary bladder. Dutch southeast cooperative 
urological group. Eur J Cancer 1993;29A:16726.
f
Vegt PD, Witjes JA, Witjes WP, et al. A randomized study of intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus 
Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 1995;153:92933.
g Malmstrom PU, Wijkstrom H, Lundholm C, et al. 5-year follow-up of a randomized prospective study comparing mitomycin C and 
bacillus calmette-guerin in patients with superficial bladder carcinoma. Swedish-Norwegian bladder cancer study group. J Urol 
1999;161:11247.


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Lamm et al. (2000) evaluated the role of adding BCG maintenance therapy in a large, 
randomized, Phase III study from the Southwest Oncology Group (SWOG).  In this study 
(SWOG 8507) of high-grade pTa/T1 and/or CIS disease, patients were randomized to 
receive maintenance therapy with BCG versus no maintenance therapy with BCG 
following an induction course of intravesical and percutaneous BCG.  Maintenance 
therapy with BCG consisted of intravesical and percutaneous BCG administered each 
week for 3 weeks at 3, 6, 12, 18, 24, 30, and 36 months from initiation of induction 
therapy.  Of the 278 patients enrolled with CIS disease, 141 (50.7%) achieved a CR 
following their induction course.  The median RFS was 76.8 months (95% CI: 64.3, 93.2) 
in the maintenance arm compared with 35.7 months (95% CI: 25.1, 56.8) in the no 
maintenance arm (p0.0001).  No Grade 4 toxicities were observed in the
maintenance arm; however, only 16% of 243 maintenance cases were able to receive all 
eight scheduled maintenance courses over the 3-year period. 
A prospective randomized study by the EORTC (EORTC 30962) assessed optimal 
dosing and treatment schedule for intravesical BCG utilizing dosing schema of full dose 
versus 1/3rd dose and a schedule of 1-year maintenance versus 3-year maintenance.  
Results of this 1355 patient study showed no significant difference in toxicity for 1/3rd 
dose compared with full dose; however, the intent-to-treat analysis for disease-free 
interval showed the 1/3rd dose for 1 year to be suboptimal compared with the full dose 
for 3 years (hazard ratio [HR]: 0.75; 95% CI: 0.590.94; p0.01) with highest benefit 
observed in the high-risk group.  These findings were supportive of full-dose BCG with 
3-year maintenance for high-risk NMIBC (Oddens et al. 2013).  
Table 2 summarizes key studies evaluating BCG maintenance dose and scheduling.


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Table 2
Randomized Phase II/III Studies of BCG Maintenance Therapy
High-Risk NMIBC (Recurrent Ta/T1 or CIS) 
No. of 
Patients
RFS (%)
(months)
OS
(%)
BCG: No maintenance vs. maintenance a 
86
18.0 vs. 18.1
NA
BCG:  Full dose, 1 year vs. 3 years
SWOG 8507:  BCG 
intravesicalpercutaneous b
660
35.7 vs. 76.8
57 vs. 45
(5 years)
BCG: 1/3 dose vs. full dose, 1 year vs. 3 years
EORTC-GU 30962 Study c
1355
5-year DFS 
57 vs. 63 
(1 year vs. 3 years)
NA
5-year DFS 
59 vs. 62
(1/3 dose vs. full 
dose)
BCGbacille Calmette-Guérin; CIScarcinoma in situ; DFSdisease-free survival; 
EORTCEuropean Organisation for Research and Treatment of Cancer; GUgenitourinary; 
NAnot applicable; NMIBC nonmuscle-invasive bladder cancer; OSoverall survival; 
RFSrecurrence-free survival; SWOGSouthwest Oncology Group.
a Badalament RA, Herr HW, Wong GY, et al. A prospective randomized trial of maintenance
versus non-maintenance intravesical bacillus calmette-guérin therapy of superficial bladder 
cancer. J Clin Oncol 1987;5:4419.
b Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin 
immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the 
bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:11249.
c Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group 
randomized study of maintenance bacillus calmette-guerin in intermediate- and high-risk Ta, 
T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year 
versus 3 years of maintenance. Eur Urol 2013;63:46272.
On the basis of the result from SWOG8759, SWOG8216, and SWOG8507, the 
U.S. Food and Drug Administration (FDA) approved intravesical BCG in 1990 for the 
treatment of CIS of the bladder.  This indication was later expanded in 1998 to include 
pTa/T1 disease (TICE USPI) and approved also for use in the European Union.  
BCG is now indicated for treatment of primary or concurrent CIS of the urinary bladder 
and for the prevention of recurrence of high-grade and/or relapsing superficial papillary 
TCC of the urinary bladder (TICE USPI; OncoTICESummary of Product 
Characteristics [SmPC]).  To date, BCG immunotherapy has emerged as the standard 
against which all newer therapies are compared.


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BCG Shortage
From 2012 until 2015, a worldwide BCG shortage has led to some patients being treated 
with a less-than-the optimal course of BCG therapy (American Urological Association 
2012).  Although the AUA, with guidance from the FDA, does not support dilution of BCG 
doses (“Shortages & Price Increases in Drugs Used to Treat Urologic Conditions,” 
www.auanet.org), there are reports that some patients did not receive the recommended 
dose or treatment course of BCG (Loftus 2015). 
1.1.3.1
Surveillance
Per current National Comprehensive Cancer Network (NCCN), AUA, and EAU 
surveillance guidelines, patients with high-risk NMIBC after diagnosis and management 
with TURBT and BCG are followed with cystoscopy and urine cytology every 3 months 
for 2 years, followed by every 6 months for 3 years, then annually.  Upper urinary tract 
imaging is recommended for baseline assessment and annually (as clinically indicated) 
(Babjuk et al. 2011; NCCN 2014; Hall et al. 2007). 
1.1.4
BCG Failure in High-Risk Non–Muscle-Invasive Bladder Cancer
Despite the significant activity of BCG in high-risk NMIBC, most patients will experience 
treatment failure with BCG with 50% having disease recurrence within the first year and 
up to 90% within 5 years (Lightfoot et al. 2011). Broadly speaking, any persistence or 
recurrence of disease after an adequate course of BCG therapy can be referred to as 
BCG failure.  Definitions to better clarify the patterns of BCG failure have been put forth 
in a recent consensus meeting of the Genitourinary (GU) Group of the American Society 
of Clinical Oncology in 2015 (Lerner et al. 2015).  New terms defining BCG failure now 
include the following: 

BCG-unresponsive NMIBC is defined as follows:
Persistence of high-grade (Grade 3) disease at 6 months following an adequate 
course of BCG; OR 
Stage/grade progression at 3 months after induction BCG; OR
Recurrence of high-grade (Grade 3) disease after achieving a disease-free 
state (i.e., CR) following induction of an adequate course of BCG that occurs 
6 months after the last exposure to BCG

BCG-relapsing NMIBC is defined as follows:
Recurrence of high-grade (Grade 3) disease after achieving a disease-free 
state following induction of an adequate course of BCG that occurs 6 months 
after the last exposure to BCG

An adequate course of BCG (assuming an adequate BCG supply worldwide)
includes one course of induction (minimum of five weekly instillations) AND one 
course of maintenance (minimum of two weekly instillations)


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Failure to achieve a CR with induction has been associated with increased risk of 
disease recurrence/progression and death in patients with high-risk NMIBC 
(Herr and Dalbagni 2003).  In a follow-up analysis of SWOG 8507 with Lerner et al. 
(2009), the 5-year survival probability was significantly higher in patients with a CR 
following BCG induction (77%) versus those with BCG failure following induction (62%).  
These observations have led the effort to improve the efficacy of BCG in reducing and/or 
preventing recurrence and disease progression (Lerner et al. 2009). 
Solsona et al. (2000) reported on 3-month clinical response to intravesical therapy as a 
predictive factor for disease progression in high-risk NMIBC.  In addition to this, the 
highest risk of disease recurrence is observed within the first 2 years of diagnosis 
(Sylvester et al. 2006).
Shirakawa et al. (2012) reported on 173 patient-case series of BCG-failures.  In this 
series with a median follow-up period from initial BCG failure of 4.7 years, multivariate 
analysis showed high-grade NMIBC at BCG failure (p0.014; risk ratio 2.84) and 
BCG-refractory disease (p0.001; risk ratio 4.68) were independent predictors for stage 
progression.  The 10-year PFS rates were 53.2%, 91.1%, and 93.8% in the 
BCG-refractory, BCG-relapsing, and BCG-intolerant groups, respectively.  The stage 
progression rate was higher in the BCG-refractory than in the BCG-relapsing (p0.001) 
and BCG-intolerant (p0.007) groups.  Similarly, the 10-year disease-specific survival 
rate in the BCG-refractory group was significantly worse than those in the other BCG 
failure groups (p0.001) (Shirakawa et al. 2012).
1.1.5
Treatment Options following BCG Failure in High Risk 
Non–Muscle-Invasive Bladder Cancer
Limited treatment options exist following BCG failure for patients who relapse or recur 
with high-grade NMIBC; both NCCN and EAU guidelines recommend radical cystectomy 
(Babjuk et al. 2011; NCCN 2014; Hall et al. 2007).  A recommendation is also made for 
bladder-sparing approaches with immunotherapy, intravesical chemotherapy, or other 
modalities for patients who are unwilling or unfit to undergo cystectomy 
(Yates et al. 2012). 
1.1.5.1
Immunotherapy
To improve BCG immunotherapy in NMIBC, several approaches have been pursued to 
enhance BCG induction of the Th-1 immune response, including the use of recombinant 
IFN-IL-2, IL-12, IFN-, TNF-and GM-CSF as a single agent or in combination with 
BCG.  Data from O’Donnell et al. (2001) have suggested potential activity of BCG in 
combination with IFN-2b.
There is rationale to support the use of immunotherapy combinations in BCG failure, on 
the basis of the potential mechanism of BCG resistance, which includes dampening of 
the cytokine stimulation and type 1 T-helper cell response.


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BCG in Combination with Interferon
As a biological response modifier, IFN-has shown limited single-agent activity in BCG 
failures with response rates under 15%.  However, in contrast, significant activity has 
been observed with the agent when used in combination with intravesical BCG. 
Joudi et al. (2006) investigated the combination BCG and IFN-in patients with 
BCG-refractory and BCG-naive NMIBC.  In this large, multicenter, Phase II study, 
1007 evaluable BCG-naive and BCG-failure patients were treated with BCG in 
combination with IFN-.  Patients received 50100 MU of IFN-with adjusted doses of 
BCG (on the basis of prior exposure).  At a median of 24 months of follow-up, 
disease-free survival (DFS) rates were 59% and 45% evaluable BCG-naive and 
BCG-failure populations, respectively (p0.0001) (Joudi et al. 2006). 
Nepple et al. (2010) conducted a multicenter prospectively randomized study of 
670 patients; evaluating BCG versus BCG in combination with IFN 2B.  Patients were 
further randomized to recommended daily allowance (RDA) vitamin or megadose 
vitamin preparation.  At a median of 24 months of follow-up, the disease-free rates were 
similar in all groups with 63% in the BCG with RDA vitamin group, 59% in BCG with 
megadose vitamins, 55% in BCG in combination with IFN 2B with RDA vitamin, and 
61% in BCG with BCG in combination with IFN 2B megadose vitamins (p0.05).  
The addition of IFN 2B was associated with a more frequent incidence of fever 
(11% vs. 5%; p0.0037) and constitutional symptoms (18% vs. 11%; p0.00183) 
versus BCG alone (Nepple et al. 2010). 
BCG in Combination with IL-12
To date, this combination has only been studied in a nonclinical setting in mice.  
Intravesical administration of the combination resulted in higher urine and serum levels 
IFNcompared with either agent alone.  Clinical translation is pending 
(O’Donnell et al. 1999; Smith et al. 2015).  
1.1.5.2
Intravesical Chemotherapy
Valrubicin is a cytotoxic anthracycline antibiotic and a derivative of doxorubicin that is 
used a chemotherapeutic agent.  It acts by inhibition of DNA and RNA synthesis via 
inhibition of various nucleosides and topoisomerases.  Valrubicin was approved by the 
FDA in 1998 for use in BCG-refractory CIS on the basis of a single-arm Phase II study of 
90 patients with BCG-refractory CIS with or without concurrent pTa/T1 disease.  Results 
of the study showed an initial CR rate of 21% at the 6-month follow-up assessment with 
8% of all patients enrolled having a durable response with a median follow-up of 
30 months.  The majority of adverse events observed were local with 66% of patients 
reporting frequency, 63% reporting urgency, and 60% reporting dysuria.  Most of the 
local bladder symptoms reported were of mild to moderate severity and none was life 
threatening.  Three of 90 patients enrolled discontinued therapy because of bladder 
symptoms (Steinberg et al. 2000).


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In addition to valrubicin, several approved chemotherapies by intravestical administration 
are being tested, including gemcitabine, docetaxel, and epirubicin.  In addition to this, 
multimodality treatments such as the hyperthermic administration of mitomycin C have 
been examined.
1.1.5.3
Radiation Therapy
Radiation therapy is rapidly becoming an expanding non-surgical option for BCG failures.  
Small patient studies have shown response rates of up to 60% (Chung et al. 2007).  
Harland et al. (2007) reported on one of the largest randomized studies to date in 
patients for radiation therapy, comparing radical radiation therapy to intravesical 
treatment or observation for high-grade T1 NMIBC.  In this study of 210 patients with 
high-grade pT1 Grade 3 NMIBC, radical radiation therapy (60 Gy in 30 fractions) showed 
no difference between treatments in terms of PFS and overall survival for patients with 
unifocal disease, over best supportive care or BCG for those with multifocal disease or 
CIS (Harland et al. 2007).  As a result, radiation therapy alone has largely remained a 
bladder preservation option for patients who are unwilling or unfit to undergo radical 
cystectomy or intravesical treatment.
There are increasing data on the utility of combined radiochemotherapy for high-risk 
NMIBC, particularly following TURBT.  Weiss et al. (2006) reported results on a study 
comparing radiotherapy or radiochemotherapy (utilizing platinum-based chemotherapy) 
in 141 patients with pT1 NMIBC where a CR rate of 88% was achieved.  Tumor 
progression rates at 5 and 10 years were 19% and 30% (13% and 29% for high-grade 
T1 tumors), respectively, and overall disease-specific survival was 82% and 73% (89% 
and 79% for complete responders, 80% and 71% for high-grade T1 tumors), respectively 
(Weiss et al. 2006).
1.1.5.4
Radical Cystectomy
For BCG-failures, in particular BCG-unresponsive NMIBC, radical cystectomy remains 
the recommended treatment (Babjuk et al. 2011; NCCN 2014; Hall et al. 2007).  Reports 
from various studies including Herr and Sogani (2001) and Soloway et al. (2011) have 
demonstrated benefit in survival for patients with high-risk NMIBC who undergo earlier 
cystectomy, particularly in cases of BCG-failure. 
This is in large part because of upstaging that occurs in a significant number of cases of 
high-risk NMIBC with BCG-failure.  Although bladder-sparing approaches for 
BCG-unresponsive and BCG-relapsing NMIBC remain investigational, radical 
cystectomy provides for a definitive treatment.  That said, this procedure carries a 
significant morbidity and mortality rate of up to 28% and 8.3%, respectively 
(Lightfoot et al. 2011).  Complication rates for radical cystectomy vary widely from 
19% to 64%, with a resulting loss of quality of life for many patients (Liedberg 2010).  
In addition, some patients are not candidates for surgery because of comorbid medical 
illness, and others refuse surgery after considering the impact to their quality of life 
despite recognition of the risks of disease progression. To date, there have been no 


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prospective randomized studies comparing cystectomy with second-line intravesical 
therapy for BCG-unresponsive NMIBC and BCG-relapsing NMIBC.  Thus, while 
bladder-sparing approaches continue to be actively developed, radical cystectomy 
remains the standard of care for high-risk NMIBC with BCG failure.
Given the poor outcomes and undesirable therapeutic options for patients with 
BCG-relapsed, BCG-unresponsive, and VHR BCG-naive NMIBC, novel therapies are 
needed.  Immunotherapy, which has demonstrated activity in this disease, holds the 
greatest promise for improving durable responses, preventing progression to muscle 
invasion, and offering an acceptable safety profile for this early disease space. 
1.2
PD-L1/PD-1 PATHWAY IN NON–MUSCLE-INVASIVE BLADDER 
CANCER
Programmed deathligand 1 (PD-L1) is an extracellular protein that down regulates 
immune responses primarily in peripheral tissues through binding to its two receptors 
programmed death1 (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).
In bladder cancer, expression of PD-L1 has been associated with poor prognosis.  
Nakanishi et al. (2007) were one of the first groups to observe an association between 
expression of PD-L1 (B7-H1) and outcomes in advanced urothelial cancers.  In their 
study, PD-L1 (B7-H1) expression was significantly associated with a high frequency of 
disease recurrence and poor survival rate.  Multivariate analysis also showed PD-L1 
(B7-H1) expression to be a more significant prognostic factor than tumor grade 
(Nakanishi et al. 2007).  Zhang et al. (2013) similarly presented data on PD-L1 
expression and outcomes in urothelial carcinoma of the bladder.  Results of this study 
showed PD-L1 expression in 43% of primary bladder cancers with an association 
between immunohistochemistry (IHC) positivity and intensity with tumor grade and 
staging (Zhang et al. 2013).  Faraj et al. (2015) showed high intratumoral CD8T cell 
density to be associated with better overall survival and disease-specific survival in 
advanced bladder cancer.  Bellmunt et al. (2015) reported on PD-L1 expression in 
tumor cells and tumor-infiltrating mononuclear cells (TIMCs).  Results of this study 
showed PD-L1 expression in TIMCs to be associated with, but not predictive of, 
prolonged survival. 


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Clinical investigation of expression of PD-L1 and PD-1 specifically in the NMIBC 
population was conducted by Inman et al. (2007).  A total of 280 patients (44 with 
high-risk NMIBC) were assessed for PD-L1 status with use of IHC with an anti-PD-L1 
antibody (clone 5H1) for assay.  PD-L1 immunostaining was noted in 28% of the 
specimens.  The prevalence of PD-L1 expression increased by stage category and was 
7% for pTa, 16% for pT1, 23% for pT2, 30% for pT3/4, and 45% for CIS 
(Inman et al. 2007). 
In the NMIBC cohort, 16 of 44 patients developed recurrent disease following BCG 
therapy. Only 3 of these patients were PD-L1 positive in their original tumor specimen.  
Upon further follow-up, 11 of 16 recurrences were observed to have BCG-induced 
granulomata positive for PD-L1 expression with diffuse and intense staining (90% of 
the cells).  Findings from this study were supportive of the hypothesis that the 
PD-L1/PD-1 pathway is involved with immune escape in NMIBC following exposure to 
BCG (Inman et al. 2007).
1.3
ATEZOLIZUMAB
Atezolizumab (MPDL3280A) 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 PD-L1 and inhibits its interaction with its receptors, 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 for patients with solid tumors
and hematologic malignancies in humans.
Atezolizumab is approved for the treatment of UC, nonsmall cell lung cancer
(NSCLC), small-cell lung cancer, and triple-negative breast cancer.
1.3.1
Nonclinical Experience
Comprehensive pharmacologic, pharmacokinetic (PK), and toxicologic evaluations have 
been conducted to demonstrate in vitro and in vivo activity, to determine in vivo PK 
behavior, to demonstrate an acceptable safety profile, and to identify a Phase I starting 
dose for atezolizumab. 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical studies.


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1.3.2
Clinical Experience
As of 10 May 2016, atezolizumab has been administered to approximately 6053 patients 
(as monotherapy or in combination with other cancer therapies) in a broad range of 
malignancies including NSCLC, triple-negative breast cancer, melanoma, renal cell 
cancer, gastric cancer, colorectal cancer, head and neck cancer, and urothelial cancer 
(UC).  Currently, no maximum tolerated dose, no dose-limiting toxicities, and no clear 
dose-related trends in the incidences of adverse events have been determined.  Fatigue, 
decreased appetite, nausea, and cough are commonly reported adverse events 
observed with both monotherapy and combination therapy.  
Atezolizumab is currently being studied in urothelial carcinoma in the adjuvant and 
metastatic settings. The following safety and efficacy data are from the Phase Ia study 
PCD4989g and the Phase II study IMvigor210 (GO29293), both of which studied 
atezolizumab monotherapy in patients with locally advanced or metastatic urothelial 
carcinoma.  
PCD4989g is a multicenter, first-in-human, open-label, dose-escalation study evaluating 
the safety, tolerability, immunogenicity, pharmacokinetics, exploratory 
pharmacodynamics, and preliminary evidence of biologic activity of atezolizumab 
administered as a single agent by intravenous (IV) infusion every 3 weeks (q3w) to 
patients with locally advanced or metastatic solid malignancies or hematologic 
malignancies.
Study IMvigor210 is a multicenter, open-label, single-arm Phase II study evaluating 
atezolizumab monotherapy (1200 mg IV q3w) for the treatment of patients with 
metastatic urothelial carcinoma (mUC).  Patients in Study IMvigor210 were enrolled 
into two cohorts.  Cohort 1 comprised patients who were treatment naive (1L) and 
cisplatin-ineligible.  Cohort 2 comprised patients who had disease progression following 
at least one platinum-containing regimen (2L+). Patients who had progressed within 
12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen were 
also considered 2L patients. 
1.3.3
Clinical Safety
As of the clinical cutoff date (CCOD) of 14 March 2016, 119 and 310 patients with mUC 
in Cohort 1 (treatment naive and cisplatin ineligible) and Cohort 2 (2L), respectively, 
received atezolizumab as a single agent.  Despite the different patient populations in 
these two cohorts, the safety profile of atezolizumab in each cohort was consistent with 
the other (see Table 3).  Additionally, the safety profiles of these two cohorts were 
consistent with the UC cohort in Study PCD4989g (CCOD of 15 December 2015), where 
95 safety-evaluable patients with UC from all lines of therapy received atezolizumab 
monotherapy.


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1.3.4
IMvigor 210 Cohort 1
Of the 119 safety-evaluable Cohort 1 patients, 95.8% reported an adverse event 
(see Table 3).  The most frequently reported adverse events (20%) included fatigue 
(45.4%), decreased appetite (2.7%), nausea (21.8%), and diarrhea (21.0%).
Table 3
Safety Profiles of IMvigor210 and Study PCD4989g (UC Cohort):  
Safety-Evaluable Population
Cohort 1 a, b
(n119)
Cohort 2 a, c
(n310)
Study PCD4989g
(UC Cohort) d, e
(n95)
Parameter
Any AE
114 (95.8%)
302 (97.4%)
93 (97.9%)
Related AE
79 (66.4%)
218 (70.3%)
63 (66.3%)
Grade 34
53 (44.5%)
177 (57.1%)
49 (51.6%)
Related Grade 34
18 (15.1%)
51 (16.5%)
8 (8.4%)
Grade 5 
4 (3.4%)
3 (1.0%)
1 (1.1%)
Related Grade 5
1 (0.8%)
0
0 
SAE
43 (36.1%)
143 (46.1%)
45 (47.4%)
Related SAE
10 (8.4%)
36 (11.6%)
5 (5.3%)
AEs leading to 
withdrawal from study 
treatment
7 (5.9%)
9 (2.9%)
4 (4.2%)
AEadverse event; CCOD clinical cutoff date; mUCmetastatic urothelial carcinoma; 
SAEserious adverse event; UCurothelial carcinoma.
a CCOD14 March 2016.
b Cohort 1 consisted of patients with mUC who were treatment naive and cisplatin 
ineligible.
c Cohort 2 consisted of 2Lpatients with mUC.
d CCOD15 December 2015.
e Included patients from all lines of therapy.
Fewer than half (44.5%) of the Cohort 1 patients had a Grade 34 adverse event 
(see Table 3).  The most commonly reported Grade 34 adverse events (2.5% or 
3 patients) were fatigue and anemia (5% each), hyponatremia and blood creatinine 
increased (3.4% each), and small intestinal obstruction, and urinary tract infection, 
decreased appetite, increased ALT, and hypotension (2.5% each).  Fatigue (3.4%) and 
increased ALT (2.5%) were the Grade 34 adverse events most commonly (2.5% or 
3 patients) considered related to atezolizumab.


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Four patients (3.4%) had a Grade 5 adverse event (see Table 3).  These were cardiac 
arrest, myocardial infarction, sepsis (related to atezolizumab), and respiratory failure.
Approximately one-third of Cohort 1 patients (36.1%) had a serious adverse event 
(see Table 3).  Most of these serious adverse events were each reported in 1 patient.  
Those that were reported in 2 patients (1.7%) are detailed in Figure 1.  Ten patients 
(8.4%) had atezolizumab-related serious adverse events.  Renal failure and diarrhea 
were the only related serious adverse events occurring in 2 patients.
Figure 1
Serious Adverse Events in 2 Patients:  Safety-Evaluable 
Population in Cohort 1 of IMvigor 210
Cardiac arrest, myocardial infarction, autoimmune colitis, diarrhea, hypersensitivity, 
sepsis, and respiratory failure were the adverse events that led to 7 patients (5.9%) 
terminating atezolizumab.


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1.3.4.1
IMvigor 210 Cohort 2
Of the 310 safety-evaluable patients in Cohort 2, 97.4% reported an adverse event of 
any grade (see Table 3).  The most frequently reported adverse events (20%) included 
fatigue (50.3%), decreased appetite (26.8%), nausea (26.1%), constipation (25.2%), 
urinary tract infection (23.5%), pyrexia (21.6%), and diarrhea (21.3%).
Slightly more than half of the patients (57.1%) reported a Grade 34 adverse event 
(see Table 3), with the most common (2.3% or 7 patients) being anemia (9.4%), 
urinary tract infection (7.7%), fatigue (5.8%), hyponatremia (3.5%), dehydration and 
dyspnea (3.2% each), hematuria (2.9%), abdominal pain, back pain, and sepsis 
(2.6% each), and pain and pulmonary embolism (2.3% each).  The Grade 34 adverse
events considered related to atezolizumab were generally reported in 1 patient.  
Those reported in 2 patients (0.6%) were fatigue (1.6%), AST and ALT increased 
(1.3% each), and colitis, decreased appetite, dyspnea, pneumonitis, arthralgia, anemia, 
and hypotension (0.6% each).
Grade 5 adverse events of subileus, pulmonary sepsis, and cerebral hemorrhage 
occurred in 1 patient each (see Table 3).  None of the events were considered related to 
atezolizumab.
Slightly fewer than half of the Cohort 2 patients (46.1%) reported a serious adverse 
event (see Table 3).  Figure 2 summarizes the serious adverse events that were 
reported in 2 patients (0.6%).  Urinary tract infection (7.1% or 22 patients) was the 
only serious adverse event that occurred in 5% of the patients.  Thirty-six (11.6%) 
patients had an atezolizumab-related serious adverse event, with the most common 
(0.6% or 2 patients) being pneumonitis and pulmonary embolism (1.0% each) and 
encephalopathy, colitis, and pyrexia (0.6% each).


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Figure 2
Serious Adverse Events in 2 Patients:  Safety-Evaluable 
Population in Cohort 2 of IMvigor 210


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Nine adverse events led to 9 patients being withdrawn from atezolizumab treatment 
(2.9%) in Cohort 2 (see Table 3):  pulmonary sepsis, retroperitoneal infection, sepsis, 
cerebral haemmorhage, posterior reversible encephalopathy syndrome, subileus, fatigue, 
acute kidney injury, and pruritus.  
Refer to the current Atezolizumab Investigator’s Brochure for details regarding 
immune-mediated adverse events observed in patients treated with atezolizumab.  
1.3.4.2
Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
atezolizumab clinical program.  These include potential dermatologic, hepatic, 
endocrine, and respiratory events, as well as events of hepatitis/elevated liver function 
tests (LFTs) and influenza-like illness that are considered potential adverse drug 
reactions associated with atezolizumab.  There is also a potential for immune activation 
being associated with generalized systemic features (e.g., hypotension, respiratory 
failure, and other organ impairment).
Refer to the current Atezolizumab Investigator’s Brochure for details regarding 
immune-mediated adverse events observed in patients treated with atezolizumab.  
1.3.5
Clinical Activity
1.3.5.1
PCD4989g:  Clinical Activity in Patients with 2L + mUC
The single-arm Phase Ia Study PCD4989g evaluates the efficacy of single-agent 
atezolizumab in the treatment of patients with locally advanced or metastatic solid 
tumors or hematologic malignancies, including mUC.  As of the CCOD of 
15 December 2015, 94 1Lpatients with mUC (predominantly 2L) were evaluable 
for efficacy.
IRF-assessed ORR (confirmed responses) per RECIST v1.1 was 25.5% in all patients, 
with 9 CRs and 15 PRs.  An evaluation of ORR by PD-L1 expression subgroup 
suggested that higher levels of PD-L1 expression may be associated with higher ORRs 
(31.8% in IC2/3 vs. 20.8% in IC0/1).  The median DOR was not estimable for the 
94 efficacy-evaluable patients as 62.5% of patients were still event free at the point of 
the CCOD.  


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Table 4 
IRF-Assessed ORR and DOR per RECIST v1.1 in PCD4989g   
(mUC Cohort):  Efficacy-Evaluable Population
Efficacy Endpoint
IC0/1
(n48)
IC2/3
(n22)
Unknown
(n24)
All Patients
(n94)
ORR (%)
10 (20.8) 
7 (31.8)
7 (29.2)
24 (25.5)
  95% CI
(10.5, 35.0) 
(13.9, 54.9) 
(12.6, 51.1) 
(17.1, 35.6)
     Complete response
3
3
3
9
     Partial response
7
4
4
15
Median DOR (months)
NE 
NE 
17.5
NE
  95% CI
(7.5, NE) 
(9.9, NE) 
(17.3, NE) 
(17.3, NE)   
  Patients with event (%)
4 (40.0) 
2 (28.6) 
3 (42.9) 
9 (37.5)
CCODclinical cutoff date; DORduration of response; ICtumor-infiltrating immune cell; 
IUOinvestigational use only; mUCmetastatic urothelial carcinoma; ORRobjective response 
rate; RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
Notes:  The CCOD for these data was 15 December 2015.  These responses were confirmed 
responses.  PD-L1 diagnostic criteria were based on the IUO assay.
IMvigor210 Cohort 1:  Clinical Activity in Patients with
1L Cisplatin-ineligible mUC
As of the clinical cutoff of 14 March 2016, efficacy analyses were performed on the 
119 patients in Cohort 1 of from Study IMvigor210.  The median age of this population 
was 73 years (range: 5192 years), and the group represented a cisplatin-ineligible 
patient population who were previously untreated in the metastatic setting.  The median 
duration on study treatment was 15 weeks.
With a median follow-up duration of 14.4 months, the cisplatin-ineligible mUC patients 
demonstrated clinically meaningful response rates after first-line treatment with 
atezolizumab in all PDL1 IC subgroups:  both IC0/1 and IC2/3 patients had an ORR of 
28.1%.  For patients with upper urinary tract urothelial carcinoma (UTUC) (n33), the 
ORR was 42.4%. 
As of 14 March 2016, the median duration of response (DOR) had not been reached 
in any of the IC subgroups (range: 3.716.6 months), with 21 patients with an ongoing 
response.
The median OS for all patients was 14.8 months (95% CI: 10.1, NE), and over half of the 
patients (52.9%) remained event-free (see Figure 3).


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Table 5
IRF-Assessed ORR and DOR per RECIST v1.1 in 1LPatients with 
mUC:  Efficacy-Evaluable Population in IMvigor 210 Cohort 1 
(Primary and Updated Analyses)
Efficacy 
Endpoint
Primary Analysis a
Updated Analysis b
IC0/1
(n87)
IC2/3
(n32)
All 
Patients
(n119)
IC0/1
(n87)
IC2/3
(n32)
All 
Patients
(n119)
ORR (%)
16 (18.4)   
7 (21.9)    23 (19.3)
19 (28.1)
9 (28.1)
28 (23.5)
  95% CI
(10.9, 
28.1)  
(9.3, 40.0)  
(12.7, 
27.6)
(13.7, 
32.0)
(13.8, 
46.8)
(16.2, 
32.2)
Complete 
response
5
1
6
6
2
8
Partial 
response
11
6
17
13
7
20
Median DOR 
(months)
NE
NE
NE
NE
NE
NE
  95% CI
NE
NE 
NE
(12.8, NE)
(11.1, NE)
(12.8, NE)
Patients 
with event 
(%)
1 (6.3)
0
1 (4.3)
4 (21.1)
3 (33..3)
7 (25.0)
CCOD clinical cutoff date; DOR duration of response; IC tumor-infiltrating immune 
cell; mUC metastatic urothelial carcinoma; ORR objective response rate;   
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  The responses were confirmed responses.
a The CCOD of the primary analysis was 14 September 2015.
b The CCOD of the updated analysis was 14 March 2016.


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Figure 3
Overall Survival for All Cohort 1 Efficacy-Evaluable Patients
IMvigor210 Cohort 2:  Clinical Activity in Patients with 2LmUC
As of the clinical cutoff of 14 March 2016, efficacy analyses were performed on the 
310 Cohort 2 patients from Study IMvigor210.  The median age of this population was 
66 years (range: 3291 years), and the group represented a 2LmUC patient population 
that was previously treated with at least one platinum-containing regimen.  The median 
duration on study treatment was 12 weeks.
With a median follow-up duration of 14.4 months, atezolizumab treatment for 2LmUC 
patients demonstrated clinical activity in in all PD-L1 IC subgroups with higher ORRs 
associated with higher PD-L1 scores:  The IC2/3 subgroup had a clinically meaningful 
ORR of 28.0% (15 CRs and 13 PRs) versus the 10% in the IC0/1 subgroup (6 CRs and 
16 PRs).  The ORR for all patients was 15.8%.
The median duration of response (DOR) for all responders (n49) has not been reached 
in any of the IC subgroups (range: 2.1to 19.2months), with 35 patients with an 
ongoing response.
With patient-event ratio at 70.3%, the median OS was 7.9 months (95% CI: 6.7, 9.3) for 
all patients (see Figure 4).


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Table 6
IRF-Assessed ORR and DOR per RECIST v1.1 in 2L Patients
with mUC:  Efficacy-Evaluable Population in IMvigor 210 Cohort 2 
(Primary and Updated Analyses)
Efficacy 
Endpoint
Primary Analysis a
Updated Analysis b
IC0/1
(n211)
IC2/3
(n100)
All 
Patients
(n311)
IC0/1
(n210)
IC2/3
(n100)
All 
Patients
(n310)
ORR (%)
20 (9.5) 
27 (27.0)
47 (15.1)
21 (10.0)
28 (28.0)
49 (15.8)
  95% CI
(5.9, 14.3)
(18.6, 
36.8)
(11.3, 
19.6)
(6.4, 14.9)
(19.5, 
37.9)
(11.9, 
20.3)
   Complete 
response
4
8
12
6
15
21
   Partial 
response
16
19
35
16
13
28
Median DOR 
(months)
NE
NE
NE
NE
NE
NE
  95% CI
NE
(6.0, NE) 
(6.01, NE)
(10.6, NE)
NE
NE
  Patients with 
event (%)
0
4 (14.8)
4 (8.5)
6 (28.6)
8 (28.6)
14 (28.6)
CCODclinical cutoff date; DORduration of response; ICtumor-infiltrating immune 
cell; mUCmetastatic urothelial carcinoma; ORRobjective response rate; RECIST
v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1.
Note:  These responses were confirmed responses.
a The CCOD of the primary analysis was 5 May 2015.
b The CCOD of the updated analysis was 14 March 2016.


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Figure 4
Overall Survival for All Cohort 2 Efficacy-Evaluable Patients  
Refer to the Atezolizumab Investigator’s Brochure for further information regarding 
efficacy data with atezolizumab.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Despite the activity of BCG in NMIBC, most patients will experience treatment failure 
with BCG with 50% having disease recurrence within the first year and up to 90% within 
5 years (Lightfoot et al. 2011).  In this group of BCG failures, approximately 55%60% 
have BCG-unresponsive NMIBC.  High risk factors for disease progression include BCG 
unresponsive disease and the presence of CIS (Shirakawa et al. 2012).  Combination 
immune therapy with BCG and interferon has shown increased activity, but adoption has 
been limited because of toxicity.
Encouraging clinical data emerging in the field of cancer 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).  
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 


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tumor-specific T-cell immunity.  PD-L1 expression is prevalent in many human tumors, 
and elevated PD-L1 expression on tumor cells is associated with a poor prognosis in 
patients with UC (Nakanishi et al. 2007; Mu et al. 2011).
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies for whom standard-of-care therapies have failed or are not 
tolerated.  In Study PCD4989g, a Phase Ia, dose-escalation and expansion study, 
objective responses with atezolizumab monotherapy were observed in a broad range of 
malignancies (see Section 1.3.2) including UC.
Recent studies suggest that BCG resistance or failure in NMIBC may occur via immune 
escape through PD-L1 tumor expression (Inman et al. 2007).  These data, along with 
results of several studies investigating immunotherapy combinations for NMIBC, have 
formed the rationale to investigate the hypothesis of BCG activation with suppression of 
tumor resistance through PD-L1 blockade with use of a combination approach of 
atezolizumab and BCG in NMIBC (Inman et al. 2007; Zlotta et al. 2009). 
Atezolizumab has been well tolerated in patients with advanced/metastatic urothelial 
carcinoma (see Section 1.3.2).  Adverse events with potentially immune-mediated 
causes consistent with an immunotherapeutic agent, including rash, hypothyroidism, 
hepatitis/transaminitis, colitis, and myasthenia gravis, have been observed.  To date, 
these events have been manageable with treatment.  It is anticipated that treatment with 
atezolizumab in patients with NMIBC either alone or in combination with other treatment 
modalities (e.g., intravesical BCG) will have a manageable safety profile with an 
acceptable benefit-risk assessment for the conduct of the study.
NMIBC is an early disease state that is potentially curable. Toxicity deemed allowable in 
the advanced/metastatic setting would not be considered acceptable in this early 
disease setting. Thus, enrollment of BCG-relapsing (Cohort 2) and very high-risk 
BCG-naive (Cohort 3) patients will not commence until the benefit-risk of atezolizumab in 
BCG-unresponsive patients (as monotherapy and in combination with BCG) has been 
carefully reviewed.
2.
OBJECTIVES
This study will evaluate the safety, pharmacokinetics, immunogenicity, patient-reported 
outcomes (PROs), and preliminary anti-tumor activity of atezolizumab administered as 
a single agent and in combination with BCG in patients with BCG-unresponsive 
NMIBC, and in combination with BCG in patients with BCG-relapsing, and VHR,
BCG-naive NMIBC.


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2.1
SAFETY OBJECTIVES
The safety objectives for this study are as follows:

To evaluate the safety and tolerability of atezolizumab administered as a single 
agent and in combination with BCG

To identify the dose-limiting toxicities (DLTs) and to determine the maximum 
tolerated dose (MTD) or tolerability at the maximum administered dose (MAD) of 
BCG when administered in combination with atezolizumab
2.2
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is as follows:

To characterize the pharmacokinetics of atezolizumab administered as a single 
agent and in combination with BCG
2.3
IMMUNOGENICITY OBJECTIVE
The immunogenicity objective for this study is as follows:

To evaluate the immune response to atezolizumab, as measured by the incidence 
of ATAs
2.4
EFFICACY OBJECTIVE
The efficacy objective for this study is as follows:

To make a preliminary assessment of the anti-tumor activity of atezolizumab 
administered as a single agent and in combination with BCG, as measured by the 
primary endpoint of 6-month CR rate.  Secondary endpoints include 3-month CR 
rate, duration of CR, RFS rate, bladder-intact DFS, PFS, cystectomy-free survival 
(CFS), and overall survival.
2.5
PATIENT-REPORTED OUTCOME OBJECTIVE
The PRO objective for this study is as follows:

To make a preliminarily assessment of patient-reported symptoms, function, and 
HRQoL associated with atezolizumab administered as a single agent and in 
combination with BCG, as measured by the EORTC Quality-of-Life Questionnaire 
Core 30 (QLQ-C30) and the EORTC QLQ-Non Muscle Invasive Bladder Cancer 24 
(NMIBC24)
2.6
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To make a preliminary assessment of biomarkers that might act as indicators of 
anti-tumor activity of atezolizumab administered as a single agent and in 
combination with BCG

To make a preliminary assessment of biomarkers that might act as indicators of the 
immunomodulatory effect of atezolizumab administered as a single agent and in 
combination with BCG


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
To explore the potential relationship between immunogenic response and 
pharmacokinetics, safety, and efficacy
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
3.1.1
Overview of Study Design
This is a Phase Ib/II, open-label, multicenter study designed to assess the safety, 
tolerability, pharmacokinetics, immunogenicity, PROs, and preliminary anti-tumor activity 
of atezolizumab administered by IV infusion as a single agent and in combination with 
intravesical BCG in patients with high-risk NMIBC.
Atezolizumab will be evaluated in the following patient cohorts:

Cohort 1:  Patients with BCG-unresponsive NMIBC
Cohort 1A:  Atezolizumab as a single agent 
Cohort 1B:  Atezolizumab in combination with BCG 

Cohort 2:  Atezolizumab in combination with BCG in patients with BCG-relapsing 
NMIBC

Cohort 3:  Atezolizumab in combination with BCG in patients with VHR BCG-naive 
NMIBC
The study will be conducted at approximately 10 to 20 sites in the United States and will 
enroll up to approximately 70 patients across all cohorts.  All patients will be required to 
have histologically confirmed non-muscle invasive urothelial carcinoma of the bladder 
with CIS.  See Section 4.1.1 for definitions of BCG-unresponsive (Cohorts 1A and 1B),
BCG-relapsing (Cohort 2), and VHR BCG-naive NMIBC (Cohort 3).
Atezolizumab will be administered at a fixed dose of 1200 mg q3w for a maximum of 
96 weeks.  BCG will be administered to evaluate DLTs, MTD, or MAD.  De-escalation 
will be allowed for up to three dose levels of BCG (full dose [50 mg], 66% of a full dose, 
and 33% of a full dose [Cohort 1B only]).
The study will be conducted as follows (see Figure 5):

Cohort 1A
Cohort 1A will commence enrollment first.  Cohort 1A will evaluate the safety 
and tolerability of atezolizumab as a single agent in patients with 
BCG-unresponsive NMIBC.  Up to approximately 12 safety- and 
efficacy-evaluable patients will be enrolled into Cohort 1A.


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
Cohort 1B
Cohort 1B will commence enrollment once 3 patients in Cohort 1A have 
completed one cycle (21 days) of study therapy.  Cohort 1B will evaluate the 
safety and tolerability, DLTs, and MTD or MAD of the combination of 
atezolizumab and BCG in patients with BCG-unresponsive NMIBC.  Data from 
Cohort 1B will be used to inform on the safety and tolerability of combination 
treatment in NMIBC, as determined at the MTD or MAD, as well as the 
recommended starting BCG dose in Cohorts 2 (BCG-relapsing NMIBC) and 3 
(VHR BCG-naive NMIBC).  Approximately 818 patients will be enrolled into 
Cohort 1B.  If fewer than 8 patients are required to establish MTD or MAD in 
this cohort, additional patients will be enrolled for a minimum of 8 patients in 
this cohort.

Cohort 1 Expansion 
An expansion cohort will allow enrollment of up to approximately 10 additional 
patients from Cohorts 1A or 1B.  The purpose of this expansion cohort is to
provide additional safety and efficacy data on these patients, depending on the 
safety profile observed in Cohort 1B.  If few or no DLTs are observed with the 
combination of atezolizumab and BCG, additional Cohort 1B patients will be 
enrolled to better characterize the safety clinical activity of combination therapy.  
Alternatively, if the combination of atezolizumab and BCG is deemed intolerable 
in the Cohort 1B population, additional Cohort 1A patients will be enrolled to 
provide additional safety and efficacy data for atezolizumab monotherapy in the 
BCG-unresponsive patients.  
Enrollment into Cohorts 2 and 3 will not begin until safety and preliminary anti-tumor 
activity results from approximately 20 patients across Cohort 1 (1A and 1B) are obtained 
and the preliminary benefit/risk has been evaluated.  

Cohort 2 
Cohort 2 will commence once the preliminary risk/benefit assessment from 
Cohorts 1A and 1B has demonstrated an acceptable safety and efficacy profile.  
Cohort 2 will evaluate the safety, tolerability and preliminary efficacy of the 
combination of atezolizumab and BCG (dosed at the MAD or MTD defined by 
Cohort 1B) in patients with BCG-relapsing NMIBC.  Approximately 10 patients 
will be enrolled into Cohort 2.

Cohort 3
Cohort 3 will commence simultaneously with Cohort 2.  Cohort 3 will evaluate 
the safety, tolerability, and preliminary efficacy of the combination of 
atezolizumab and BCG (dosed at the MAD or MTD defined by Cohort 1B) in 
patients with VHR BCG-naive NMIBC.  Approximately 10 patients will be 
enrolled in Cohort 3.


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
Cohort 2 and 3 Expansion
An expansion cohort will allow enrollment of up to approximately 10 patients in 
total from Cohorts 2 and/or 3.  The purpose of this expansion cohort is to 
provide additional safety and efficacy data for these populations.
Figure 5
Study Schema
BCG bacille Calmette-Guérin; DLT dose-limiting toxicity; NMIBC nonmuscle-invasive 
bladder cancer.
Note:  In the absence of unacceptable toxicity or evidence of disease progression, patients 
deriving clinical benefit may be offered continued atezolizumab for up to 96 weeks.
Cohort 1A
Enrollment in Cohort 1A will begin first.  The treatment regimen for Cohort 1A patients is 
atezolizumab 1200 mg IV q3w monotherapy (see Figure 6).  Patients may be treated for 
a maximum of 32 q3w cycles of atezolizumab (or for a maximum treatment duration of 
96 weeks, whichever comes first).  Dosing of the second and third patients will be 
staggered by a minimum of 1 week relative to the first patient.
Cohort 1B
Enrollment of patients into Cohort 1B will begin once 3 patients in Cohort 1A have 
completed one cycle (21 days) of therapy.  Cohort 1B will follow a “3 3” BCG dose 


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de-escalation scheme evaluating up to three dose levels of BCG until the BCG MTD 
(or MAD) for the two-drug combination in BCG-unresponsive NMIBC is defined.  
The dose of atezolizumab will be fixed; dose de-escalation will occur only for BCG.  
The three BCG dose levels to be evaluated in Cohort 1B will be the full BCG dose 
(with a starting dose of 50 mg), followed by 66% of a full BCG dose (33 mg), followed by 
33% of a full BCG dose (16.5 mg) [Cohort 1B only].  In the first course, patients will 
receive concurrent atezolizumab BCG at the assigned dose.  The MTD or MAD will be 
determined on the basis of DLTs observed during the DLT assessment window (defined 
as Days 121 of BCG Induction Course).  After the MTD or MAD is determined for 
Cohort 1B, this dose will be used for all subsequent patients enrolled into Cohorts 1B, 2, 
and 3, unless the MTD is determined to be 33% of a full BCG dose.  If MTD is 
determined to be 33% of a full BCG dose, then, no patients will be enrolled into 
Cohorts 2 and 3 until an assessment of the safety and activity of the combination of 
atezolizumab plus 33% of a full BCG dose is completed. Atezolizumab plus 33% of a 
full dose will not be carried into Cohorts 2 and 3 unless a favorable risk-benefit profile is 
demonstrated.  If MTD or MAD is reached before 8 patients have been enrolled in 
Cohort 1B, additional patients will be enrolled up to a minimum of 8 total patients.  
These additional patients will be treated at the established MTD or MAD.  
See Section 3.1.3 for a description of the BCG dose de-escalation scheme and 
Section 3.1.4 for the definition of DLT. 
A minimum of 3 patients will be enrolled into each BCG dose level evaluated.  However, 
for the starting dose level in Cohort 1B, dosing of the second and third patients will be 
staggered by a minimum of 1 week relative to the first patient.  If the first patient does 
not experience unacceptable toxicity during the first week of combination treatment, the 
second and third patients at the first dose level may start combination treatment without 
delay.  Dosing for subsequent dose levels will not be staggered.
The treatment regimen for Cohort 1B patients is as follows (see Figure 6):
BCG

BCG Induction Course (12 weeks): BCG induction will begin on study Day 1. BCG 
will be administered at the assigned dose (see Section 3.1.3) weekly for a total of 
six doses (BCG induction). 

BCG Maintenance Course 1 (12 weeks):  BCG will be administered at the assigned 
dose weekly for a total of three doses (BCG maintenance).  

BCG Maintenance Courses 25 (every 24 weeks, beginning 12 weeks after initiation
of Maintenance Course 1):  BCG maintenance Courses 25 are optional for patients 
in Cohort 1B.  BCG maintenance Courses 25 may be administered if, at the 
investigator’s discretion, there is felt to be ongoing clinical benefit of BCG.  
The Medical Monitor will review and approve this on a case-by-case basis.  
These patients will receive BCG administered at the assigned dose weekly for a 
total of three doses per maintenance course.  


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Atezolizumab

Atezolizumab therapy will begin on study Day 1.  All patients will continue to receive 
atezolizumab 1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, 
whichever comes first.  
Cohort 2
Patients in Cohort 2 will be treated with atezolizumab 1200mg IV q3w in combination 
with BCG dosed at the MAD or MTD determined by Cohort 1B (provided MAD or MTD is 
determined to be either full dose or 66% of a full BCG dose).
The treatment regimen for Cohort 2 patients is as follows (see Figure 6):
BCG

BCG Induction Course (12 weeks):  BCG induction will begin on study Day 1.
BCG will be administered at the assigned dose weekly for a total of six doses 
(BCG induction). 

BCG Maintenance Course 1 (12 weeks): BCG will be administered at the assigned 
dose weekly for a total of three doses.  

BCG Maintenance Course 25 (every 24 weeks, beginning 12 weeks after initiation 
of Maintenance Course 1):  BCG will be administered at the assigned dose weekly 
for a total of three doses per course.
Atezolizumab  

Atezolizumab therapy will begin on study Day 1.  Patients will receive atezolizumab 
1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, whichever 
comes first.  
Cohort 3
Patients in Cohort 3 will be treated with atezolizumab 1200mg IV q3w in combination 
with BCG dosed at the MAD or MTD determined by Cohort 1B.
The treatment regimen for Cohort 3 patients is as follows (see Figure 6):
BCG

BCG Induction Course (12 weeks):  BCG induction will begin on study Day 1.  
BCG will be administered at the assigned dose weekly for a total of six doses 
(BCG induction). 

BCG Maintenance Course 1 (12 weeks): BCG will be administered at the assigned 
dose weekly for a total of three doses.  

BCG Maintenance Course 25 (every 24 weeks, beginning 12 weeks after initiation 
of Maintenance Course 1):  BCG will be administered at the assigned dose weekly 
for a total of three doses per course. 


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Atezolizumab

Atezolizumab therapy will begin on study Day 1.  Patients will receive atezolizumab 
1200 mg IV q3w for a maximum of 32 q3w cycles or 96 weeks, whichever 
comes first.
The total planned enrollment for this study is up to approximately 70 patients:  up to 
approximately 12 patients in Cohort 1A, approximately 818 patients in Cohort 1B, up to 
approximately 10 patients in the Cohort 1 expansion, approximately 10 patients in 
Cohort 2, approximately 10 patients in Cohort 3, and approximately 10 patients in the 
Cohort 2 and 3 expansion.
3.1.2
Study Procedures for All Cohorts
Patients will be required to provide sample tumor tissue showing the presence of CIS, 
to be obtained within 60 days prior to study entry.  Tissue should be submitted as 
formalin-fixed paraffin-embedded (FFPE) blocks (blocks preferred) or at least 
10 unstained slides, with an associated pathology report, for central testing. Patients 
with fewer than 10 unstained slides available at baseline (but no fewer than five) may 
be eligible following discussion with the Medical Monitor.  The Sponsor may replace 
patients who are later found to be unevaluable for tumor PD-L1 expression by 
central testing.
Tumor response assessment via cystoscopy and urine cytology will occur every 
12 weeks for the first 2 years, and every 24 weeks thereafter until 5 years, and 
then yearly.
A mandatory tissue biopsy will be obtained from all patients 6 months after C1D1 of 
atezolizumab. For patients in Cohort 1A, biopsies should be obtained up to 21 days 
prior to atezolizumab administration. For patients in Cohorts 1B, 2, and 3, biopsies 
should be obtained 1421 days prior to BCG intravesical instillation (e.g., Weeks 10, 22, 
46, 70 and 94; see Appendix 3).
The Sponsor may replace patients who are discontinued from the study before the 
required tumor biopsy samples are obtained.
At the 6-month timepoint (Week 24 visit), documentation of a complete response (CR) is 
required to continue on study treatment.
Definition of Complete Response (must meet all 3 criteria):

Cytology: not positive (see below)

Upper Urinary Tract Imaging (if performed): normal, or abnormal but supportive of 
CR (with non-positive selective ureteral cytologies)


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
Cystoscopy: bladder appears normal; or bladder appears abnormal but all biopsies 
are negative; or any grade papilloma, any grade papillary urothelial neoplasm of low 
malignant potential (PUNLMP), or low grade pTa
Interpretation of Urine Cytology:

If results are Unsatisfactory, Atypical Cell, Suspicious, or Indeterminate, then assay 
must be repeated no less than 24 hours and up to 21 days later.

If the results are again Unsatisfactory or Atypical Cell (2 in a row), then treat as if the 
result was negative.

Two consecutive Suspicious or Indeterminate urine cytology specimens require 
further evaluation by cystoscopyand/or upper tract imaging as deemed appropriate 
by the investigator

If cytology results are Suspicious or Indeterminate and the biopsies are negative, 
then treat as if the result was negative 

All occurrences of positive urine cytology will require further evaluation by 
cystoscopy and/or upper tract imaging. A positive cytology result only indicates 
presence of disease and cannot be used alone to determine disease progression.
The date of a positive cytology result can be used for the date of recurrence, if 
the results of the cystoscopy, biopsy, or upper urinary tract assessment shows 
recurrence.
Patients with persistent and/or recurrent high grade NMIBC without progression (stage 
or grade progression of active disease, or the presence of new disease) at 12 weeks 
from treatment initiation may continue on study treatment.
Patients with recurrent low-grade papillary disease will be required to undergo resection 
with TURBT (unless medically contraindicated) and may continue on study and receive 
study treatment.
Indications for Discontinuation from Study for Disease Progression

Stage or grade progression at any timepoint would require discontinuation from 
study therapy. 

Patients with persistent and/or recurrent high-grade NMIBC (any pT1, high grade 
pTa, or CIS) on or after the 6-month biopsy will be discontinued from study 
treatment and offered the option to undergo cystectomy or other bladder-sparing 
modalities as is clinically appropriate. Patients who undergo cystectomy will be 
requested to submit additional tissue from their cystectomy specimens. 

Patients with evidence of disease progression to muscle-invasive or metastatic 
disease at any timepoint will be discontinued from study treatment.


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For all patients, additional evaluation (imaging, exam under anesthesia, biopsies) should 
be performed at investigator discretion for any of the following circumstances:

Abnormal cystoscopy

Positive urine cytology 

Two sequential suspicious or indeterminate urine cytology specimens
Study treatment with atezolizumab may be continued for a maximum of 32 q3w cycles or
a total of 96 weeks of therapy.  BCG treatment (induction and maintenance) may be 
continued for a maximum of 120 weeks (as clinically indicated; see Appendix 3).  All 
study treatment will be discontinued in patients who undergo cystectomy or experience 
disease recurrence/progression or unacceptable toxicity, and in those who are not 
benefiting from study treatment (in the opinion of the investigator or the patient). 
There may be circumstances in which either BCG or atezolizumab is permanently
discontinued, but it may still be possible to continue the remaining study treatment with 
approval of the Medical Monitor.  Patients in Cohorts 1B, 2, or 3 (atezolizumab plus BCG) 
who discontinue atezolizumab after receiving fewer than three cycles may be replaced.
All patients will be closely monitored for serious adverse events or protocol-defined 
events of special interest for 90 days or 30 days for adverse events, following their last 
dose of study therapy (atezolizumab and/or BCG) or initiation of non-protocol anti-cancer 
therapy, whichever occurs first.  Safety assessments will include the incidence, nature, 
and severity of adverse events, changes in selected vital signs and laboratory 
abnormalities graded per NCI CTCAE v4.0.
Serum and plasma 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 plasma, whole blood, and 
urine will be collected for future exploratory biomarker assessments.
A treatment completion/discontinuation visit will be performed for all patients within 
30 days after the last administration of study treatment.
Patients who discontinue study treatment for a reason other than disease 
recurrence/progression or cystectomy (e.g., because of toxicity) will continue to undergo 
tumor assessments per protocol until they experience disease recurrence/progression or 
cystectomy, until the patient dies, withdraws consent, or until the study closes, 
whichever occurs first, for a maximum of 5 years after enrollment.
In addition, all patients will be followed for survival and subsequent anti-cancer therapy 
beginning 6 months after the treatment completion/discontinuation until loss to follow-up, 
death, withdrawal of consent, or study termination by the Sponsor, whichever occurs first, 
for a maximum of 5 years after enrollment.


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Figure 6 presents the treatment plans for each cohort.  The schedules of assessments 
are provided in Appendix 1 and Appendix 2.
Figure 6
Treatment Plans
Cohort 1A
Cohort 1A:  Patients receive atezolizumab 1200 mg IV q3w.
Cohort 1B
BCGbacille Calmette-Guérin. 
Notes:  Cohort 1B:  During BCG Induction Course, patients receive atezolizumab 1200 mg IV 
q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses.  
During BCG Maintenance Course 1, patients receive atezolizumab 1200 mg IV q3w for a total of 
four doses plus BCG at the assigned dose weekly for a total of three doses.  OPTIONAL BCG 
Maintenance Courses 25, patients receive atezolizumab 1200 mg IV q3w for a total of eight 
doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
An optional collection of biopsy samples at disease progression/disease recurrence will be 
performed if clinically feasible.


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Figure 6
Treatment Plans (cont.)
Cohorts 2 and 3
BCG bacille Calmette-Guérin. 
Notes: Cohorts 2 and 3:  During BCG Induction Course, patients receive atezolizumab 1200 mg 
IV q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses.  
During BCG Maintenance Course 1, patients receive atezolizumab 1200 mg IV q3w for a total of 
four doses plus BCG at the assigned dose weekly for a total of three doses.  During BCG 
Maintenance Courses 25, patients receive atezolizumab 1200 mg IV q3w for a total of eight 
doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
3.1.3
BCG Dose De-Escalation Scheme (Cohort 1B)

This protocol will follow a 3 3 dose de-escalation scheme. MTD or MAD requires 
that either 0 of 3 or 2 of 6 patients treated at a BCG dose level experience a DLT.  
If 2 of 6 DLT-evaluable patients experience a DLT at the BCG dose level 
evaluated, that BCG dose level would be considered the MTD or MAD.

A minimum of 3 patients will initially be treated at each BCG dose level evaluated. 

The following patients will not be considered evaluable for DLTs and will be 
replaced:
Patients who withdraw from either study treatment during the DLT assessment 
window (Days 121 of BCG Induction Course) for any reason other than a DLT
Patients who miss two or more doses of BCG or whose infusion of 
atezolizumab is delayed for 7 days during the DLT assessment window 
(Days 121 of BCG Induction Course) for any reason other than a DLT
Full-Dose BCG
Treatment starts at the full, standard doses of both BCG and atezolizumab:

If 0 of 3 DLT-evaluable patients experience a DLT, MAD will be established and 
full-dose BCG and atezolizumab will be considered tolerable. 


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
If 1 of 3 DLT-evaluable patients experiences a DLT, 3 more patients will be enrolled 
at this dose level.  

If 2 of 6 DLT-evaluable patients experience a DLT, MAD will be established, full 
doses of BCG and atezolizumab will be considered tolerable, and no BCG dose 
de-escalation will be implemented. 

If 2 of 3 or 2 of 6 DLT-evaluable patients receiving the full standard doses 
experience a DLT, the BCG dose will be reduced to 66% of full dose, and a 
minimum of 3 patients will be enrolled at 66% of full-dose level.  
Sixty-Six Percent Dose Level of BCG

If 0 of 3 DLT-evaluable patients experience a DLT, MTD will be established and the 
66% of full BCG dose and atezolizumab will be considered tolerable. 

If 1 of 3 DLT-evaluable patients experiences a DLT, 3 additional patients will be 
enrolled at this dose level. 

If 2 of 6 DLT-evaluable patients experience a DLT, MTD will be established as 66% 
of full dose BCG and full dose atezolizumab.  

If 2 of 3 or 2 of 6 DLT-evaluable patients receiving 66% of a full BCG dose 
experience a DLT, the BCG dose will be reduced to 33% of a full dose, and a 
minimum of 3 patients will be enrolled at the 33% of full dose level. 
Thirty-Three Percent Dose Level of BCG

If 0 of 3 DLT-evaluable patients experience a DLT, MTD will be established and the 
33% of full BCG dose and atezolizumab will be considered tolerable. 

If 1 of 3 DLT-evaluable patients experiences a DLT, 3 additional patients will be 
enrolled at this dose level. 

If2 of 6 DLT-evaluable patients experience a DLT, MTD will be established as 33% 
of full-dose BCG and full-dose atezolizumab.  

If 2 of 3 or 2 of 6 DLT-evaluable patients receiving the 33% of a full BCG dose 
experience a DLT at this dose level, this dosing schedule of combination BCG (33%) 
and atezolizumab will be considered intolerable, and Cohort 1B will be closed.

BCG dose levels will be evaluated as described above until the MTD or MAD has 
been determined, or until the last of the BCG dose levels has been evaluated. 
For patients in Cohort 1B, if 33% of a full BCG dose is determined to be intolerable 
in combination with atezolizumab and further therapy with BCG is not permitted, 
patients may be allowed to continue in the study with single-agent atezolizumab 
1200 mg IV q3w (for a total of 96 weeks)

No atezolizumab dose reductions will be permitted. 
On the basis of a review of available safety and PK data during this and other studies 
with both agents, BCG dose de-escalation may be halted or modified by the Sponsor in 
consultation with the Study Investigators and/or Steering Committee.


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3.1.4
Definition of Dose-Limiting Toxicity
DLT definitions reflect the known and expected toxicities of atezolizumab and BCG.
A DLT is defined as one of the following toxicities occurring during the DLT assessment 
window (Induction Course, Days 121) that is considered by the investigator to be 
related to atezolizumab or the combination of atezolizumab and BCG (see Table 10 for 
causality assessment).  For potential overlapping toxicities, including those described in 
Section 5.1.1, investigators are encouraged to perform additional tests to determine the 
underlying etiology and most appropriate attribution (see Appendix 6 for immune-related 
adverse event criteria).  BCG dose reductions or delays will not, in themselves, 
constitute DLTs.
The following adverse events are considered to be DLTs (pending causality):

Grade 4 neutropenia (ANC 500/L) 

Grade 3 febrile neutropenia

Grade 4 thrombocytopenia

Grade 4 anemia

Grade 3 symptomatic hepatic toxicities lasting for 48 hours, or Grade 3 
asymptomatic hepatic toxicities lasting for 72 hours
NOTE:  Patients with Grade 2 AST, ALT, and/or alkaline phosphatase abnormality 
at baseline will be excluded from enrollment.

Grade 3 dysuria lasting 72 hours following the BCG dose

Grade 3 frequency (urinary) lasting 72 hours following the BCG dose

Grade 3 hematuria lasting 48 hours following the BCG dose

Grade 3 cystitis lasting 48 hours following the BCG dose

Grade 3 urgency or nocturia lasting 72 hours following the BCG dose

Grade 2 visual changes (limiting instrumental activities of daily living) that do not 
resolve to baseline within 72 hours

Grade 4 visual disturbance of any duration

Grade 3 non-hematologic, non-hepatic organ toxicity, excluding the following:
Grade 3 nausea, vomiting, or diarrhea that resolves to Grade 1 within 7 days of 
appropriate supportive therapy
Grade 3 asymptomatic or mildly symptomatic rash that can be adequately 
managed with supportive care, or resolves to become asymptomatic and/or 
Grade 2 within 7 days with appropriate supportive therapy 
Grade 3 fatigue that resolves to Grade 2 within 7 days
Grade 3 elevation of serum creatinine kinase level that is asymptomatic 
(i.e., not accompanied by signs, symptoms, or other laboratory abnormalities 
associated with rhabdomyolysis or myocardial injury), that is deemed by the 


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investigator to be clinically insignificant, and that returns to Grade 2 within 
14 days with treatment interruption 
Grade 3 arthralgia that can be adequately managed with supportive care or that 
resolves to Grade 2 within 7 days
Grade 3 fever (in the absence of any clinically significant source of fever) that 
resolves to Grade 2 within 7 days with supportive care
Grade 3 laboratory abnormality that is asymptomatic and deemed by the 
investigator not to be clinically significant
Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be 
managed by endocrine therapy that would not necessitate initiation of systemic 
corticosteroids
All DLTs must be reported via the paper Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form (see Section 5.3).  All DLTs will be considered adverse 
events of special interest for this protocol and must be reported to the Sponsor in an 
expedited manner, as indicated in Section 5.4.
BCG dose de-escalation decisions will be made by the Sponsor in consultation with the 
Study Investigators and/or the Steering Committee after review of available relevant data.  
See Section 4.5, Appendix 1, and Appendix 2 for the schedule of study assessments.
3.2
INDEPENDENT DATA MONITORING COMMITTEE
An external independent Data Monitoring Committee (iDMC) will monitor the study and 
assess the risk-benefit profile.  The iDMC will evaluate study safety and efficacy data on 
a periodic basis, approximately every 4 months, according to policies and procedures 
detailed in the iDMC Charter.  Members of the iDMC will be external to the Sponsor and 
will follow the charter that outlines their roles and responsibilities.  
All summaries and analyses for iDMC review will be prepared by an external 
independent data coordinating center (iDCC).  The safety and efficacy data will include 
but are not limited to demographic data, adverse events, serious adverse events, 
relevant laboratory data, as well as tumor assessment data.  Following their data review, 
the iDMC will provide a recommendation as to risk-benefit; the final decision will rest with 
the Sponsor.
3.3
END OF STUDY AND LENGTH OF STUDY
END OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur approximately 120 weeks after the last patient is enrolled in 
the study (see Appendix 3).
LENGTH OF STUDY
The study is expected to last approximately 3.5 years after the first patient is enrolled. 


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3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for Patient Population
This study is designed to obtain safety and efficacy data for single-agent atezolizumab 
as treatment for patients with BCG-unresponsive NMIBC and the combination of 
atezolizumab with BCG as treatment for patients with BCG-unresponsive, 
BCG-relapsing, or VHR BCG-naive NMIBC.  Only patients who fulfill eligibility criteria will 
be enrolled into the study.  These criteria are based on the safety data from Phase I/II
studies (for atezolizumab) and Phase II/III studies (for BCG). 
Cohort 1A (atezolizumab monotherapy) will enroll patients with BCG-unresponsive 
NMIBC.  Selection of this population is on the basis of the high unmet need in patients 
who have experienced persistent/recurrent disease despite BCG treatment.  
Single-agent atezolizumab has already demonstrated significant single-agent activity in 
patients with advanced UC (Powles et al. 2014). 
Cohort 1B (atezolizumab BCG dose de-escalation) will enroll patients with 
BCG-unresponsive NMIBC.  Selection of this population is on the basis of the high 
unmet need in patients who have experienced persistent/recurrent disease despite BCG 
treatment.  Single-agent atezolizumab has already demonstrated significant single-agent 
activity in patients with advanced UC (Powles et al. 2014).  Cohort 1B will evaluate both 
the safety and potential activity of the combination of BCG and atezolizumab.
Cohort 2 (atezolizumab BCG) will enroll patients with BCG-relapsing NMIBC.  No 
current standard therapies exist for this indication, with the exception of valrubicin, which 
while approved for use (United States only), is rarely used in NMIBC.  Given the high 
unmet need in this population, these patients represent an appropriate population to first 
assess the safety, tolerability, and pharmacokinetics of novel therapies and 
combinations intended for the treatment of NMIBC with the aim of bladder preservation 
and delaying cystectomy.  
Cohort 3 (atezolizumab BCG) will enroll patients with VHR BCG-naive NMIBC.  
Selection of this population was based on the known mechanism of action of 
atezolizumab, the hypothesis that PD-L1 expression is a pathway for immune tolerance 
to BCG in NMIBC (Inman et al. 2007), and data from Lerner et al. (Lerner et al. 2007) 
demonstrating poorer outcomes in patients with high-risk NMIBC who fail to achieve a 
CR following BCG induction.  This study will enroll patients with VHR BCG-naive NMIBC, 
as this population demonstrates significantly higher recurrence rates (up to 78% by 
5 years) after BCG therapy and a 45% rate of progression to muscle-invasive disease by 
5 years (Babjuk et al. 2008; Palou et al. 2012; Giannarini et al. 2014). 


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3.4.2
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 the following:  1) 95% tumor-receptor saturation is 
needed for efficacy and 2) the tumor-interstitial concentration to plasma ratio is 0.30 
based on tissue distribution data in tumor-bearing mice.
The atezolizumab dose is also informed by available clinical activity, safety, PK, and 
immunogenicity data.  Anti-tumor activity has been observed with doses of 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 whether administration of higher doses to patients with both detectable 
ATAs and reduced exposure would necessarily restore exposure to expected levels.  
No clear relationship between the development of measurable ATAs and safety or 
efficacy has been observed.  Available data suggest that development of detectable 
ATAs does not appear to have a significant impact on pharmacokinetics for doses of 
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 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 
fixed dose or dose adjusted for weight (Bai et al. 2012).  On the basis of this analysis, a 
fixed dose of 1200 mg was selected (equivalent to a body weightbased dose of 
15 mg/kg).


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Selection of a q3w dosing interval is supported by this preliminary PK evaluation and 
allows for a convenient integration with common chemotherapeutic regimens.
The optimal duration of immunotherapy for patients with NMIBC is not known.  Current 
practice patterns in the use of BCG maintenance vary dramatically and support 
treatment for between 1 and 3 years.  The EORTC meta-analysis of patients with 
NMIBC treated with BCG demonstrated that only patients treated with BCG maintenance 
therapy observed a reduction in progression.  Maintenance schedules varied 
significantly; however, a separate meta-analysis demonstrated that at least 1 year of 
BCG maintenance was required to show an improvement in recurrence or progression.  
This supports a longer duration of therapy for immunotherapy to provide benefit. 
In the studies of atezolizumab and other checkpoint inhibitors in patients with metastatic 
disease, delayed responses have been observed, and some of those patients remain 
long-term disease-free responders, suggesting that some patients require longer 
duration of immunotherapy.  Additionally, while the majority of these responses have 
been durable, disease relapses have been observed in some responders who 
discontinued treatment after 1 or 2 years of therapy.  
Considering the historical maintenance BCG studies as well as experience to date using 
immune checkpoint inhibitors, the Sponsor selected the 2-year treatment duration to 
ensure adequate exposure in potentially delayed responders yet balance patient-specific 
considerations such as inconvenience, toxicity, and economic impact.
3.4.3
Rationale for BCG Dosage
Dosing for BCG in this study was selected on the basis of prior immunotherapy 
combination studies investigating BCG in combination with IFN--2B.  In a study of 
1007 evaluable patients with NMIBC, combination therapy was assessed using full dose 
IFN and varying doses of BCG (full dose for BCG-naive patients and 1/3rd to 1/10th for 
patients with prior BCG exposure).  Results from this study showed RFS rates of 59% 
and 45% for the BCG-naive and BCG-failure groups, respectively (Joudi et al. 2006).  
The lowest dose tested will be 33% of a full BCG dose.  Thirty-three percent of a full 
BCG dose has been shown previously to be equivalent in efficacy to a full dose of BCG 
in all but the highest risk patients (Martínez-Piñeiro et al. 2002; Martínez-Piñeiro et al. 
2005).  The rationale for co-administration of BCG with atezolizumab is based on the 
observed improvement in DFS and RFS rates for combination immunotherapy in 
patients for whom BCG therapy has failed (O’Donnell et al. 2001) and also from data 
demonstrating PD-L1 expression as a potential pathway for resistance to BCG 
(Inman et al. 2007).  If 33% of a full BCG dose is the MTD reached in Cohort 1B, further 
assessment would be needed for the combination of atezolizumab and BCG at 33% of a 
full dose to support using this dosing schedule in Cohorts 2 and 3. 


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3.4.4
Rationale for Pharmacokinetic Evaluation Schedule
The proposed sampling scheme for atezolizumab and BCG concentration assessments 
will contribute to the characterization of atezolizumab and BCG pharmacokinetics.  
The atezolizumab and BCG concentration results may be compared with available data 
from other atezolizumab clinical studies and correlated with safety events in this study as 
appropriate.
3.4.5
Rationale for Blood and Urine Sampling for Biomarkers
Changes in different blood and urine biomarkers may provide evidence for biologic 
activity of atezolizumab in humans and may allow for the development of a blood- or 
urine-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 and urine samples.
3.4.6
Rationale for the Collection of Tumor Specimens at Screening
Published results suggest that expression of PD-L1 in tumor cells and tumor-infiltrating 
immune cells correlates with response to antiPD-1 and antiPD-L1 therapy 
(Herbst et al. 2014).  This correlation was also observed with atezolizumab in a cohort of 
patients with advanced stage UC enrolled in Study PCD4989g (Powles et al. 2014).  
In the current study, tumor specimens from patients meeting eligibility criteria will be 
tested for PD-L1 expression by IHC at a central laboratory.  Collection of tissue at 
screening may occur at the time of initial TURBT or repeat TURBT per institutional 
standard of care.
To enable evaluation of the potential for prior therapies to alter tumor expression of 
PD-L1, patients who have received at least one line of prior systemic therapy for UC
should submit archival specimens obtained after completion of their most recent prior 
therapy.  An archival specimen, if available, may also be submitted in patients who 
choose to undergo a fresh tissue biopsy.
In addition to assessment of PD-L1 status, other exploratory markers, such as potential 
markers that are related to response or clinical benefit of atezolizumab, tumor 
immunobiology, mechanisms of resistance, or tumor type markers, may also be 
analyzed.
3.4.7
Rationale for the Collection of Tumor Specimens on Treatment
and at Recurrence/Disease 
The assessment of immunomodulation and PD-L1/PD-1 pathway inhibition in tumor 
tissue may guide selection of the appropriate dose and exposure for atezolizumab in 
combination BCG for future studies.  Biopsy samples will be collected for the study of PD 
changes related to the additive or synergistic effects of atezolizumab and BCG (changes 
in PD-L1 and infiltration of CD8T cells and other exploratory biomarkers).  The timing 
of on-treatment biopsy was selected to allow assessment of potential synergistic effect 


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of atezolizumab and BCG (following BCG induction) as well as to assess CR, disease 
recurrence, and/or disease progression (optional) and to allow adequate healing after 
biopsy and prior to the next BCG administration.  A biopsy at tumor 
recurrence/progression will enable the evaluation of the role of immune and tumor 
typerelated, as well other exploratory biomarkers (including but not limited to T-cell 
markers and tumor mutation status) associated with disease progression.
The presence of disease at 3 months after initiation of BCG induction has been shown to 
be predictive for disease recurrence and disease progression (Solsona et al. 2000; 
Sylvester et al. 2006); however, the use of maintenance BCG has been shown to 
increase response rates between 3 and 6 months. Therefore, 6 months is the 
recommended timepoint for disease response assessment (Lamm et al. 2000; 
Jarow et al. 2014). 
3.4.8
Rationale for Patient-Reported Outcome Assessments
PROs provide an understanding of the impact a treatment has on a patient.  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.  The EORTC QLQ-NMIBC24 is an NMIBC-specific module 
that can provide information on disease and treatment-related symptoms and functional 
interference that are specific to this patient population.
3.5
OUTCOME MEASURES
3.5.1
Safety Outcome Measures
The safety and tolerability of the combination of atezolizumab and BCG will be assessed 
using the following outcome measures:

Incidence, nature, and severity of adverse events, graded according to the 
NCI CTCAE v4.0

Changes in selected vital signs and clinical laboratory results during and following 
administration of atezolizumab alone and in combination with BCG
3.5.2
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Serum atezolizumab maximum serum concentration (Cmax) after the first infusion of 
atezolizumab

Serum atezolizumab minimum serum concentration (Cmin) prior to the infusion at 
specified timepoints


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3.5.3
Immunogenicity Outcome Measure
The immunogenicity outcome measure for this study is as follows:

Incidence of ATA response to atezolizumab and potential correlation with PK, PD, 
safety, and efficacy parameters
3.5.4
Efficacy Outcome Measures
The primary efficacy outcome measure for this study is as follows:

CR at the 6-month evaluations after the start of study treatment.  Patients must be 
evaluated for CR by both cystoscopy and cytology and bladder biopsies will be 
required for the 6-month CR disease assessment.
The secondary efficacy outcome measures for this study are as follows:

CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology.  

Duration of CR, defined as time from first occurrence of a documented CR until the 
time of recurrence of NMIBC or death from any cause

RFS rate at 6, 12, and 18 months, defined as the proportion of patients who are 
alive and free of persistent/recurrent high-risk NMIBC  

Bladder-intact DFS, defined as time from first study treatment to earliest evidence of 
progression to muscle-invasive disease in the bladder, regional pelvic progression, 
distant metastasis, bladder cancerrelated death, or cystectomy or death from 
any cause 

PFS, defined as the time from first study treatment to the first occurrence of 
progression to muscle-invasive disease or death from any cause

CFS, defined as the time from first study treatment to cystectomy or death from 
any cause

Overall survival, defined as the time from first study treatment to death from 
any cause
3.5.5
Patient-Reported Outcome Measure
The exploratory PRO outcome measure for this study is as follows:

Change from baseline in patient-reported symptoms, function, and HRQoL, as 
measured by the EORTC QLQ-C30 and EORTC QLQ-NMIBC24
3.5.6
Exploratory Biomarker Outcome Measures
The following biomarker endpoints will be assessed when appropriate:

PD-L1 status by IHC in archival tissues and/or fresh biopsies

Status of other exploratory biomarkers related to PD-L1 or immune cell biology 
(including but not limited to CD8 or PD-1) and tumor biology


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The following exploratory biomarker outcome measures will be assessed when 
appropriate:

Changes in immune-related markers (including but not limited to CD8, granzyme B, 
and other exploratory markers) in archival and/or fresh tumor tissue prior to and 
during atezolizumab and BCG treatment 
4.
MATERIALS AND METHODS
4.1
PATIENTS
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Ability to comply with protocol

Age 18 years

Histologically confirmed nonmuscle-invasive TCC of the bladder with CIS 
Patients with mixed histologies, where the dominant (50% tumor volume) 
histology is TCC, may be considered on a case-by-case basis upon approval 
by the Medical Monitor.
Patients may have Ta/T1 lesions, provided they have been completely 
resected. 

High-risk NMIBC defined by the following:
BCG-unresponsive NMIBC (Cohorts 1A and 1B):
Persistence of high-grade CIS at 6 months following an adequate course of 
BCG; OR 
Stage/grade progression at 3 months after induction BCG; OR
Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) 
following an adequate course of BCG that occurs 6 months after the last 
exposure to BCG
BCG-relapsing NMIBC (Cohort 2):
Recurrence of high-grade CIS after achieving a disease-free state following 
an adequate course of BCG that occurs 6 months after the last exposure 
to BCG
VHR BCG-naive NMIBC (Cohort 3):
VHR NMIBC, defined as having at least one of the following:  
Multiple and/or large (3 cm) T1, (HG/G3) tumors
T1, (HG/G3) tumor with concurrent CIS
T1, G3 with CIS in prostatic urethra
Micropapillary variant of non-muscle invasive urothelial carcinoma 


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
For BCG-unresponsive and BCG-relapsing NMIBC, patients must have received an 
adequate course of BCG.  An adequate course of BCG is defined as at least one 
course of induction (minimum of five weekly instillations) and one course of 
maintenance (minimum of two weekly instillations) with the following exceptions:
Patients with grade/stage progression after induction BCG (minimum of five 
weekly instillations) are eligible.  
Patients with persistent or recurrence of high-grade disease after two BCG 
induction courses (minimum of five weekly instillations, each) are eligible.  
Patients who did not receive an adequate course of BCG as a result of the 
worldwide BCG shortage may be eligible following discussion with the Medical 
Monitor.

Resection of all pTa/pT1 papillary disease
Prior to enrollment, patients must have undergone repeat TURBT to ensure no 
evidence of residual papillary disease.

No prior radiation to bladder or pelvic region

Eastern Cooperative Oncology Group (ECOG) performance status of 2 
(see Appendix 7)

Life expectancy 12 weeks

Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:
ANC 1500/L (without granulocyte colony-stimulating factor support within 
2 weeks prior to the first dose of study treatment)
WBC counts 2500/L and 15,000/L
Lymphocyte count 300/L
Platelet count 100,000/L (without transfusion within 2 weeks prior to the first 
dose of study treatment)
Hemoglobin 9.0 g/dL
Patients may be transfused or receive erythropoietic treatment to meet this 
criterion.
AST, ALT, and alkaline phosphatase 2.5ULN
Serum bilirubin 1.5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.
Creatinine clearance 30 mL/min (calculated using the Cockcroft-Gault formula)


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent 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 study drug.  Women must refrain from donating 
eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, established proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.

For men receiving BCG:  agreement to remain abstinent (refrain from sexual 
intercourse) or use a condom, as further explained in Section 4.3.1.2 and 
Section 5.1.2:
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.

Tumor tissue biopsy
A sample of tumor tissue is required within 60 days prior to study entry.  Fresh 
tissue biopsy is preferred; however, an archival specimen may be submitted in 
lieu of fresh tissue if a tissue biopsy is contraindicated owing to patient safety 
or tumor tissue accessibility and the archival specimen was obtained within 
60 days of study screening.  The specimen may consist of a FFPE tumor tissue 
block (preferred) or at least 10 unstained, serial sections. Patients with 
cystoscopy results indicating pTa/pT1 papillary disease must undergo a 
TURBT procedure for removal of residual papillary disease prior to study entry.

Willingness to complete all study-related procedures including patient-reported 
questionnaires 
Additional Cohort 3Specific Inclusion Criteria

No prior treatment with intravesical BCG


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry.
Cancer-Specific Exclusions

Evidence of locally advanced or metastatic bladder cancer (including but not limited 
to disease involving renal pelvis, ureter, or prostatic urethra) 

Evidence of muscle-invasive bladder cancer

Evidence of extravesical bladder cancer

Any malignancy within 5 years prior to Cycle 1, Day 1, except adequately resected 
basal cell and squamous cell skin cancer or adequately treated carcinoma in situ of 
the cervix.  Patients with malignancies of a negligible risk of metastasis or death 
(e.g., risk of metastasis or death 5% at 5 years) may be allowed after discussion 
with the Medical Monitor.
Patients with prostate cancer who are at low risk and are undergoing active 
surveillance (Stage T1/T2a, Gleason score 7 and PSA 10 ng/mL) are 
eligible.

Treatment with any approved anti-cancer therapy, including chemotherapy 
(systemic or intravesical), radiation therapy (to the bladder or pelvic region), or 
hormonal therapy within 3 weeks prior to the first dose of study treatment
Use of hormone-replacement therapy and oral contraceptives is permitted.

Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent within 28 days prior to the first dose of study treatment
General Medical Exclusions

Pregnant or lactating, or intending to become pregnant during the study
Women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test 
result within 14 days prior to the first dose of study treatment.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells 

Allergy or hypersensitivity to components 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 anti-phospholipid 
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 after discussion 
with and approval by the Medical Monitor.


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Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
may be eligible for this study after discussion with and approval by the Medical 
Monitor.

Prior allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

Serum albumin 2.5 g/dL

Positive test for HIV

Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] 
test at screening) 
Patients with past or resolved hepatitis B (HBV) infection (defined as having a 
negative HBsAg test and a positive anti-hepatitis B core antigen [anti-HBc] 
antibody test) are eligible.  HBV DNA must be obtained in these patients prior 
to the first dose of study treatment.

Active hepatitis C
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction assay is negative for HCV RNA.

Active tuberculosis

Severe infections within 28 days prior to the first dose of study treatment, including 
but not limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia

Signs or symptoms of infection within 14 days prior to the first dose of study 
treatment

Treatment with therapeutic oral or IV antibiotics within 14 days prior to the first dose 
of study treatment
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible. 

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within the previous 3 months, 
unstable arrhythmias, or unstable angina 

Major surgical procedure other than for diagnosis within 28 days prior to the first 
dose of study treatment, or anticipation of need for a major surgical procedure 
during the course of the study


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
Administration of a live/attenuated vaccine within 28 days prior to the first dose of 
study treatment, within 5 months following the administration of the last dose of 
study drug, 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 to May in the Northern Hemisphere and from April 
through September in the Southern Hemisphere).  Patients must agree not to 
receive live/attenuated influenza vaccine (e.g., FluMist) within 28 days prior to 
first dose of study treatment, during treatment or within 5 months following the 
last dose of atezolizumab.

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complications.
Exclusion Criteria Related to BCG

History of prior significant toxicity or intolerance to BCG requiring discontinuation of 
treatment

History of prior systemic BCG infection
Note:  This is applicable to patients receiving combination BCG and 
atezolizumab therapy (Cohorts 1B or 2).  Patients in Cohort 1A may be eligible, 
pending that they have received an adequate course of BCG and meet all other 
eligibility criteria.

History of immunosuppression, or conditions associated with congenital or acquired 
immune deficiency, whether because of concurrent disease (e.g., AIDS, leukemia, 
lymphoma), cancer therapy (e.g., cytotoxic drugs, radiation), or immunosuppressive 
therapy (e.g., corticosteroids) 

Concurrent febrile illness, urinary tract infection, or gross hematuria
Exclusion Criteria Related to Medications

Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anticytotoxic T lymphocyteassociated antigen 4, antiPD-1, and 
antiPD-L1 therapeutic antibodies 

Treatment with systemic immunostimulatory agents (including but not limited to IFNs 
and IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to 
the first dose of study treatment


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
Treatment with systemic immunosuppressive medications (including but not limited 
to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti–TNF-agents) within 2 weeks prior to the first dose of study treatment, or 
anticipated requirement for systemic immunosuppressive medications during 
the study. 
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 and mineralocorticoids (e.g., fludrocortisone) 
is allowed.  Use of physiologic doses of corticosteroids for adrenal insufficiency 
is allowed.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label study.  The investigator will determine the appropriate cohort for 
each patient.
4.3
STUDY TREATMENT
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Atezolizumab
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  
The vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may 
contain more than the stated volume to enable delivery of the entire 20 mL volume. 
For information on the formulation and handling of atezolizumab, refer to the 
Investigator's Brochure and Pharmacy Manual.
4.3.1.2
Bacille Calmette-Guérin
OncoTICEBCG for intravesical use is an attenuated, live culture preparation of the 
BCG strain of Mycobacterium bovis.  The freeze-dried BCG preparation is delivered in 
glass vials, each containing 1 to 8108 CFU of OncoTICE BCG, which is equivalent to 
approximately 50 mg wet weight.  No preservatives have been added.
A single dose consists of one reconstituted vial.  For intravesical use, the entire vial is 
reconstituted with sterile saline.  OncoTICE BCG is viable upon reconstitution.  
Patients should minimize fluid intake before treatment with BCG.  Additionally, complete 
bladder drainage should occur via catheter drainage placed immediately prior to BCG 
administration.
In the event of a supply shortage of OncoTICE BCG, sites may be allowed to use a local 
stock of BCG on a case-by-case basis after approval by the Sponsor.
For detailed information on the formulation and handling of BCG, see the local 
OncoTICE prescribing information.


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The following summarizes AUA voiding instructions and other precautions to patients 
following BCG exposure:
Precautions post procedure: after the first void and for the next 6 hours include:
a)
Sit to void to avoid urine splashing. Do not use public toilets or void outside.
b)
After each void, add 2 cups undiluted bleach to toilet, close the lid, and wait 
1520 minutes, and then flush the toilet. Repeat with each void for 6 hours.
c)
Increase fluid intake to dilute the urine. Begin after the first void post procedure.
d)
Common side effects within 24 hours post procedure: blood in urine; low-grade 
fever (99100 F); tiredness; urinary frequency, urgency, and burning with urination; 
and muscle or joint achiness. You will be given prescriptions to address the urinary 
symptoms (frequency, urgency, and burning on urination) if needed.
e)
If sexually active, wear a condom with intercourse throughout the entire treatment 
course and for six weeks after treatment has ended.
f)
Urinary incontinence: Immediately wash clothes in clothes washer. Do not wash 
with other clothes.
g)
If wearing incontinence pad, pour bleach on pad, allow to soak in, then place in 
plastic bag, and discard in trash.
h)
Call urology clinic or provider if patient develops fever more than 101.3 F (38.5 °C), 
chills, or rigors.
i)
May use acetaminophen or ibuprofen for fever and body aches.
j)
May need antispasmodic medication to help with frequency and urgency.
4.3.2
Dosage, Administration, and Compliance
Atezolizumab and BCG are investigational medicinal products (IMPs) in this study.  
4.3.2.1
Atezolizumab
The dose level of atezolizumab in this study is 1200 mg administered by IV infusion q3w.  
There will be no dose reduction of atezolizumab.  
Cohort 1A:  Patients receive atezolizumab 1200 mg IV q3w, for a maximum of 32 doses 
or 96 weeks of therapy, whichever comes first.
Cohort 1B:  During BCG Induction Course (12 weeks), patients receive atezolizumab 
1200 mg IV q3w for a total of four doses.  During BCG Maintenance Course 1 
(12 weeks), patients will receive atezolizumab 1200 mg IV q3w for a total of four doses.  
Additional BCG maintenance courses are not required for patients in Cohort 1B, but may 
be permitted following discussion with the Medical Monitor.  During BCG Maintenance 
Courses 25 (each 24 weeks), patients receive atezolizumab 1200 mg IV q3w for a total 
of eight doses per course.  Patients who stop BCG maintenance at any time may 
continue atezolizumab 1200mg IV q3w.  The maximum atezolizumab treatment duration 
is 96 weeks.  Atezolizumab may be administered before or after intravesical BCG on 


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days when these infusions coincide, however both the atezolizumab infusion and 
intravesical BCG infusion must be completed within 24 hours of one another.
Cohorts 2 and 3:  During BCG Induction Course (12 weeks), patients receive 
atezolizumab 1200 mg IV q3w for a total of four doses.  During BCG Maintenance 
Course 1 (12 weeks), patients will receive atezolizumab 1200 mg IV q3w for a total of 
four doses.  During BCG Maintenance Courses 25 (each 24 weeks), patients receive 
atezolizumab 1200 mg IV q3w for a total of eight doses per course.  Patients who stop 
BCG maintenance at any time may continue atezolizumab 1200mg IV q3w.  
The maximum treatment duration is 96 weeks.  Atezolizumab may be administered 
before or after intravesical BCG on days when these infusions coincide; however, both 
the atezolizumab infusion and intravesical BCG infusion must be completed within 
24 hours of one another.
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 regarding administration, refer to the 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 infusion and at the end of the infusion.  Patients will 
be informed about the possibility of delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such symptoms.
No premedication is indicated for the administration of atezolizumab in Cycle 1.  Patients 
who experience an infusion-related reaction with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions (see Table 7).


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Table 7
Guidelines for the Management of Infusion-Related Reactions 
during the First Atezolizumab Infusion
Toxicity
Severity
Management
Infusion-related 
reaction
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 tolerated, the infusion rate may then 
be increased to the original rate. 
Grade 2 

Interrupt atezolizumab infusion.

Administer aggressive symptomatic 
treatment.

Restart only after the symptoms have 
adequately resolved to baseline grade.

The infusion rate at restart should be 
half of the infusion rate that was in 
progress at the time of the onset of the 
IRR.

At next cycle, administer oral 
premedication with antihistamine and 
anti-pyretic and monitor closely for 
infusion reaction.
Grade 3 or 4 

Stop infusion.

Proper medical management which 
may include oral or IV antihistamine, 
anti-pyretic, glucocorticoids, 
epinephrine, bronchodilators, and 
oxygen.

Discontinue atezolizumab.

Contact the Medical Monitor if 
atezolizumab is discontinued.
For anaphylaxis precautions, see Appendix 8.
The atezolizumab dose may be interrupted for up to 12 weeks for Grade 3 toxicity or 
adverse event.  If the adverse event does not resolve to Grade 1 within 12 weeks of 
last dose of atezolizumab, further treatment with atezolizumab will be discontinued. 


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There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 12 weeks 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 12 weeks beyond the last dose, then the patient will be 
discontinued from atezolizumab treatment and will be followed up for safety and efficacy 
as specified in Section 4.5.11. 
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from 
atezolizumab after a hold of 12 weeks, 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 12 weeks from the last dose until steroids are 
discontinued or reduced to prednisone dose 10 mg/day (or dose equivalent).  
The acceptable length of interruption will depend on an agreement between the 
investigator and the Medical Monitor. 
Guidelines for treatment interruption or discontinuation and for the management of 
specific adverse events are provided in Section 5.1.3.
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.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
4.3.2.2
Bacille Calmette-Guérin
Cohort 1B:  The three BCG dose levels to be evaluated in Cohort 1B will be full dose 
(starting dose of 50 mg), followed by 66% and 33% of a full BCG dose.
Cohorts 2 and 3:  BCG will be administered at the MTD or MAD determined by dose 
de-escalation in Cohort 1B provided the MTD or MAD is determined to be full dose or 66% 
of a full BCG dose.
During BCG Induction Course (12 weeks), patients will receive BCG at the assigned 
dose weekly for a total of six doses.  During BCG Maintenance Course 1 (12 weeks), 
patients receive BCG at the assigned dose weekly for a total of three doses.  During 
BCG Maintenance Courses 25 (each 24 weeks), patients receive BCG at the assigned 
dose weekly for a total of three doses per course.  
BCG will not be administered in Cohort 1A.


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For detailed information on the formulation and handling of BCG, see the local 
OncoTICE prescribing information.
Guidelines for treatment interruption or discontinuation and for the management of 
specific adverse events are provided in Section 5.1.3.
Any overdose or incorrect administration of BCG should be noted on the BCG 
Administration eCRF. Adverse events associated with an overdose or incorrect 
administration of BCG should be recorded on the Adverse Event eCRF.
4.3.3
Investigational Medicinal Product Accountability
The Sponsor or designee will provide BCG to investigational sites as an IMP.  Following 
Sponsor notification, BCG may be sourced locally in emergency situations (e.g., site is 
out of stock of IMP and patient is ready to receive dose) in countries where BCG is 
commercially available.  In these cases, sites will be responsible for sourcing and using 
the material according to local regulations.  The Sponsor will provide atezolizumab as 
an IMP.
The study site will acknowledge receipt of study treatments with use of the interactive 
Web/voice response system (IxRS) to confirm the shipment condition and content.  
Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Study Access to Atezolizumab
Currently, the Sponsor does not have any plans to provide atezolizumab or any other 
study treatments or interventions to patients who have completed the study.  The 
Sponsor will evaluate whether to continue providing atezolizumab in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product, available 
at the following Web site:  
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
4.4.1
Permitted Therapy
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the treatment discontinuation visit.


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Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another 
H2 receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 8).
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 after consultation with the Medical Monitor.  If feasible, 
alternatives to corticosteroids should be considered.  Premedication may be 
administered for the second and subsequent infusions at the discretion of the treating 
physician after consultation with the Medical Monitor.  The use of inhaled corticosteroids 
and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or 
adrenocortical insufficiency is allowed.  Megestrol administered as an appetite stimulant 
is acceptable while the patient is enrolled in the study.
Influenza vaccination should be given during influenza season only (approximately 
October to May in the Northern Hemisphere and from April through September in the 
Southern Hemisphere).  Patients must not receive live/attenuated influenza vaccine 
(e.g., FluMist®) within 28 days prior to the first dose of study treatment, during study 
treatment, or within 5 months following the last atezolizumab dose.  Patients may 
receive inactivated vaccines.
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as lowmolecular weight heparin or warfarin at 
a stable dose level), or other allowed maintenance therapy should continue their use.
Females of reproductive potential should use highly effective means of contraception, as 
described in Section 4.1.1.
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF.
4.4.2
Prohibited Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authorityapproved or experimental, is prohibited.  This includes but is not limited to the 
following:

Chemotherapy, hormonal therapy (outside of usage outlined in Section 4.4.1), 
immunotherapy, radiotherapy, investigational agents, or herbal therapy (except for 
maintenance therapies outlined in Section 4.4.1)


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
Traditional herbal medicines should not be administered because the ingredients 
of many herbal medicines are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause or confound assessment 
of toxicity
Initiation or increased dose of granulocyte colony-stimulating factors 
(e.g., granulocyte colony-stimulating factor, GM-CSF, and/or pegfilgrastim) is strongly 
discouraged.
Patients are not allowed to receive immunostimulatory agents, including but not limited 
to IFN-, IFN-, or IL-2, during the entire study.  These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions.
Patients should also not receive immunosuppressive medications, including but not 
limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These 
agents could potentially alter the activity and the safety of atezolizumab.  Systemic 
corticosteroids and antiTNF-agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of the 
treating physician after consultation with the Medical Monitor.  If feasible, alternatives to 
these agents should be considered.
In addition, all patients (including those who discontinue the study early) should not 
receive other immunostimulatory agents for 10 weeks after the last dose of atezolizumab.
4.5
STUDY ASSESSMENTS
EAU and NCCN guidelines recommend surveillance monitoring for high-risk NMIBC with 
cystoscopy and urine cytology every 36 months for the first 2 years, which is consistent 
with the tumor assessment schedule for this study (Babjuk et al. 2011; NCCN 2014). 
See Appendix 1and Appendix 2 for the schedules of assessments performed during the 
study.
Patients will be closely monitored for safety and tolerability throughout the study.  
All assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose of atezolizumab and BCG; 
dosing will occur only if the clinical assessment and local laboratory test values are 
acceptable.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits scheduled according to the original schedule.


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4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-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 enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, 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 screening visit.  A history of pleural or pericardial effusion or of ascites requiring 
intervention should be entered in the medical history.
Demographic data will include age, sex, and self-reported race/ethnicity.
Cancer history will include an assessment of prior treatment for NMIBC (in the case of 
recurring disease) including but not limited to TURBT intravesical therapy, radiation, or a 
combination of these.
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.  Height and 
weight should be measured and recorded in the eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of pulse rate, respiratory rate, systolic and 
diastolic blood pressures while the patient is in a seated position, and temperature.
For the first infusion, the patient’s vital signs (pulse rate, respiratory rate, blood pressure, 
and temperature) should be determined within 60 minutes before, during (every 


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15 [5] minutes), and 30 (10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before infusion and at the end of the 
infusion.  Patients will be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop such symptoms.
4.5.5
Tumor and Response Evaluations
Screening and tumor response assessment will be in accordance with national (EAU 
AUA, and NCCN) guidelines, which recommend cystoscopic examination and urine 
cytology every 12 weeks for the first 2 years, and every 24 weeks thereafter (or as 
clinically appropriate) until 5 years, and then yearly.  Upper tract imaging with CT 
urography or intravenous pyelogram will be performed at the 6- and 18-month disease 
assessments.  Annual upper tract imaging thereafter is recommended as clinically 
indicated. 
Screening assessments must include imaging of the upper tract collecting system, which 
may include any one or more of the following:  intravenous pyelogram, CT urography, 
renal ultrasound with retrograde pyelogram, ureteroscopy, or magnetic resonance 
imaging urogram.  Pelvic CT before TURBT may be considered, but is not required.
Primary assessment of tumor (at screening and while on study) will be with cystoscopy 
and urine cytology.
White-light cystoscopy, narrow band imaging cystoscopy, or fluorescent (blue-light) 
cystoscopy will be acceptable for baseline assessment.  The same methodology used to 
assess disease sites at screening should be used throughout the study except when 
medical contraindicated (e.g., the same cystoscopy protocol and urine examination).
The Sponsor may replace patients who have had a change in the type of cystoscopy 
(e.g., screening with white-light cystoscopy and follow-up evaluation with blue-light 
cystoscopy) to ensure consistent evaluation over time.  All known sites of disease must 
be documented at screening and re-assessed at each subsequent tumor evaluation.  
A Bladder Map template (Appendix 11) has been provided and should be used to 
document the approximate size and location of abnormalities observed at screening, 
baseline, and on study cystoscopy/TURBT assessments.
Mandatory bladder biopsies will be performed at the 6-month tumor assessment.
In absence of visible tumor, template biopsies should be obtained from all quadrants of 
the bladder.  Template biopsies may be performed under anesthesia, at the discretion of 
the investigator.  Regions of the template biopsies should include the trigone, left lateral 
wall, right lateral wall, posterior wall, and dome.  Where feasible, the same evaluator 
should perform assessments if possible to ensure internal consistency across visits.
At the investigator’s discretion, cystoscopy and/or urine cytology may be repeated at any 
time if progressive or recurrent disease is suspected.


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At the 6 month timepoint (24 week visit), documentation of a complete response (CR) is 
required to continue on study treatment.
Definition of Complete Response (must meet all 3 criteria):

Cytology: not positive (see below)

Upper Urinary Tract Imaging (if performed): normal, or abnormal but supportive of 
CR (with non-positive selective ureteral cytologies)

Cystoscopy: bladder appears normal; or bladder appears abnormal but all biopsies 
are negative; or any grade papilloma, any grade PUNLMP, or low grade pTa
Interpretation of Urine Cytology:

If results are Unsatisfactory, Atypical Cell, Suspicious, or Indeterminate, then assay 
must be repeated no less than 24 hours and up to 21 days later

If the results are again Unsatisfactory or Atypical Cell (2 in a row), then treat as if the 
result was negative

Two consecutive Suspicious or Indeterminate urine cytology specimens require 
further evaluation by cystoscopyand/or upper tract imaging as deemed appropriate 
by the investigator

If cytology results are Suspicious or Indeterminate and the biopsies are negative, 
then treat as if the result was negative 

All occurrences of positive urine cytology will require further evaluation by 
cystoscopy and/or upper tract imaging. A positive cytology result only indicates 
presence of disease and cannot be used alone to determine disease progression.
The date of a positive cytology result can be used for the date of recurrence, if 
the results of the cystoscopy, biopsy, or upper urinary tract assessment shows 
recurrence.
Patients with persistent and/or recurrent high grade NMIBC without progression (stage 
or grade progression of active disease, or presence of new disease) at 12 weeks from 
treatment initiation may continue on study treatment. to muscle-invasive disease.
Patients with recurrent low-grade papillary disease will be required to undergo resection 
with TURBT (unless medically contraindicated) and may continue on study and receive 
study treatment.


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Indications for Discontinuation from Study Treatment for Disease Progression

Stage or grade progression at any timepoint would require discontinuation from 
study therapy. 

Patients with persistent and/or recurrent high-grade NMIBC (any pT1, high grade 
pTa, or CIS) on or after the 6-month biopsy will be discontinued from study 
treatment and offered the option to undergo cystectomy or other bladder-sparing 
modalities as is clinically appropriate. Patients who undergo cystectomy will be 
requested to submit additional tissue from their cystectomy specimens. 

Patients with evidence of disease progression to muscle-invasive or metastatic 
disease at any timepoint will be discontinued from study treatment.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
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 panel (aPTT and INR)

Serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation)

Creatinine clearance (calculated using the Cockcroft-Gault formula)

Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood)

Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4)

All patients will have a QuantiFERON blood test done locally prior to inclusion into 
the study

HBV serology (HBsAg, antibodies against HBsAg, antihepatitis B core antibody 
[HBc Ab])
HBV DNA should be obtained prior to the first dose of study treatment if the 
patient has positive serology for anti-HBc Ab.

HCV serology (anti-HCV)

HIV serology


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Central laboratories will coordinate the collection of archival and tumor tissue as well as 
blood samples for the assessment of atezolizumab pharmacokinetics and biomarkers, 
ATA assays, and auto-antibody testing.  The following assessments will be performed at 
a central laboratory or at Roche:

ATA assays
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of validated immunoassays.

PK assay
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.

Biomarker assays in blood
Blood samples will be obtained at various timepoints, including at disease 
progression, 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 4 and Appendix 5.  Specifically, at 
disease progression, samples will be processed to obtain EDTA plasma for the 
determination of changes in blood-based biomarkers. Whole blood samples 
may be processed to obtain peripheral blood mononuclear cells (PBMCs) and 
their derivatives (e.g., RNA).
Blood samples will also be evaluated using the TruCultureSystem.  
TruCulture system is designed to test the ex vivo immune response of 
peripheral blood immune cells to BCG.  The supernatant of this culture will be 
tested for immune cell cytokine production (e.g., IL2, IFNg).  Of note, 
TruCulture tubes stimulated with BCG will be processed based on the site’s 
own local rules.  The Institutional Biosafety Committee (IBC) at each site will 
review the requirements for handling BCG.

Biomarker assays in urine
Urine 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 4 and Appendix 5. 
Serum samples collected for PK and immunogenicity analysis, which may be used for 
additional method development, assay validation, and characterization, will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.
Refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.

Tumor tissue and archival samples collected at screening: 
Fresh TURBT representative tumor specimens either FFPE (preferred) or at 
least 10 unstained slides, with an associated pathology report is required for 
study entry; tumor specimens will be evaluated for PD-L1 expression.  


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In addition, exploratory biomarkers (including but not limited to markers related 
to immune or UC biology) may be evaluated.
Tumor tissue obtained from TURBT 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).
Additional archival tumor specimens should be submitted if available.  
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.

Bladder biopsy while in the study
Patients will undergo a mandatory biopsy within 60 days prior to study entry. 
Fresh tissue biopsy is preferred; however, an archival specimen may be 
submitted in lieu of fresh tissue if a tissue biopsy is contraindicated owing to 
patient safety or tumor tissue accessibility and the archival specimen was 
obtained within 60 days of study screening.  The specimen may consist of a 
formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) or at 
least 10 unstained, serial sections. Patients with cystoscopy results indicating 
pTa/pT1 papillary disease must undergo a TURBT procedure for removal of 
residual papillary disease prior to study entry.
Patients will undergo a mandatory biopsy at 6 months (see Appendix 1 and 
Appendix 2) and as clinically indicated.  Tissue biopsies should include any foci 
of disease (if present) as well as template biopsies obtained from all quadrants 
of the bladder.  Regions of the template biopsies should include the trigone, left 
lateral wall, right lateral wall, posterior wall, and dome.  Additional tissue
biopsies may also be obtained over the course of the study to evaluate disease 
per investigator assessment.

Bladder biopsy at disease progression/recurrence
Collection of biopsy samples at disease progression/disease recurrence will be 
optional and should include any foci of disease as well as template biopsies 
obtained from all quadrants of the bladder.  

For patients who consent to the optional collection of tumor samples for the Roche 
Clinical Repository (RCR):
Patients may agree to provide optional tumor biopsy samples 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 preferably, per investigator 
discretion, at the time of disease progression.
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.


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
Use and storage of remaining samples from study-related procedures
The remaining samples obtained for study-related procedures will be destroyed 
no later than 5 years after the end of the study or earlier depending on local 
regulations.  If the patient provides optional consent for storing samples into the 
RCR for future research (see Section 4.5.12), the samples will be destroyed no 
later than 15 years after the date of final closure of the clinical database.

The status of immune-related and tumor typerelated and other exploratory 
biomarkers (including but not limited to T-cell markers and non-inherited biomarkers 
identified through next generation sequencing (NGS) on extracted DNA and/or RNA) 
in tumor tissue samples may be evaluated. 
NGS may be performed by Foundation Medicine.  If performed by Foundation 
Medicine, the investigator can obtain results from the samples collected at the 
time of disease progression in the form of an NGS report, which is available 
upon request directly from Foundation Medicine.  The investigator may share 
and discuss the results with the patient, unless the patient chooses otherwise.  
The Foundation Medicine NGS assay has not been cleared or approved by the 
U.S. Food and Drug Administration (FDA); results from these investigational 
tests should not be used to guide future treatment decisions.

Please refer to the laboratory manual for additional details on laboratory
assessments and sample handling.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Remaining biological samples obtained for study-related procedures will be destroyed no 
later than 5 years after the end of the study, or earlier depending on local regulations.  
If the patient provides optional consent for storing samples into the RCR for future 
research (see Section 4.5.12), the samples will be destroyed no later than 15 years after 
the date of final closure of the clinical database.
4.5.7
Electrocardiograms
A 12-lead ECG is required at screening and as clinically indicated.  ECGs should be 
obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper or electronic 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.


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4.5.8
Patient-Reported Outcomes
PRO data will be collected via questionnaires to more fully characterize the clinical 
profile of atezolizumab as a single agent and in combination with BCG.  The 
questionnaires will be translated as required into the local language.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires scheduled for administration during a clinic visit should be completed 
prior to the performance of non-PRO assessments and the administration of study 
treatment.  PROs are required at C1D1, and then every 6 weeks/2 cycles starting 
with C2D1.
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 HRQoL, 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 9).  Scale scores can be obtained for 
the multi-item scales.  The EORTC QLQ-C30 takes approximately 510 minutes to 
complete. 
The EORTC QLQ-NMIBC24 is a NMIBC-specific module that accompanies the EORTC.  
The validated and reliable self-report measure (Blazeby et al. 2014) consists of 
24 questions assessing the following NMIBC-specific disease and treatment domains:  
urinary symptoms; malaise; future worries; bloating and flatulence; sexual function, 
enjoyment, intimacy, and problems; and intravesical treatment.  Scale scores can be 
obtained for the multi-item scales (see Appendix 10). 
4.5.9
Assessments during Treatment
All visits must occur within 3 days from the scheduled date unless otherwise noted 
(see Appendix 1 and Appendix 2).  All assessments involving cystoscopy and urine 
cytology will be performed within 21 days prior to atezolizumab treatment and for 
patients in Cohorts 1b, 2, and 3, 1421 days prior to BCG dosing unless otherwise 
specified.
See the study flowchart provided in Appendix 1and Appendix 2 for the schedule of 
treatment period assessments.
If scheduled dosing and study assessments are precluded because of a holiday, 
weekend, or other event, then dosing may be postponed to the soonest following date, 
with subsequent dosing continuing on the original 12-week schedule (for atezolizumab 
and BCG Induction course/Maintenance Course 1), 24-week schedule (for atezolizumab 
and BCG Maintenance Courses 25), or 21-day cycle schedule (for single-agent 
atezolizumab).  If treatment was postponed for fewer than 3 days, the patient can 
resume the original schedule.  Resumption of therapy beyond 3 days will require 
approval by the Medical Monitor. 


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Following the eighth cycle of atezolizumab, one of three subsequent administrations may 
be delayed by 28 days in the combination cohorts to allow for vacations.  Following the 
eighth cycle of atezolizumab, one of three subsequent administrations may be delayed 
by 1 week for atezolizumab alone cohort to allow for vacations.
4.5.10
Treatment Discontinuation Visit
Patients who discontinue early from treatment for recurrence/progression or toxicity will 
be asked to return to the clinic within 30 days after the last administration of study 
treatment or before another anti-cancer therapy is initiated, whichever is earlier.  
The visit at which a tumor assessment shows progressive disease resulting in treatment 
discontinuation may be used as the treatment discontinuation visit.
See the study flowcharts provided in Appendix 1and Appendix 2 for assessments to be 
performed at the treatment discontinuation visit.
4.5.11
Follow-Up Assessments
See the study flowchart provided in Appendix 1and Appendix 2 for specified follow-up 
assessments.
Ongoing Tumor Assessments
Patients who discontinue study treatment for a reason other than disease 
recurrence/progression or cystectomy will continue to undergo tumor assessments per 
study protocol, until they experience disease recurrence/progression or cystectomy, until 
the patient dies, or withdraws consent, or until the study closes, whichever occurs first, 
for a maximum of 5 years after enrollment.
Patients who start a new anti-cancer therapy in the absence of disease 
recurrence/progression should continue to be followed for recurrence/progression 
according to the protocol schedule of response assessments unless consent is 
withdrawn or the patient experiences disease recurrence/progression or death or until 
study termination or withdrawal from study, whichever occurs first.
Adverse Events
See Sections 5.25.5 for information on reporting adverse events. 
Survival and Subsequent Anti-Cancer Therapy Follow-Up
All patients will be followed for survival and subsequent anti-cancer therapy beginning 
6 months after the treatment completion/discontinuation visit.  Survival and subsequent 
anti-cancer therapy follow-up information will be collected via telephone calls, patient 
medical records, and/or clinic visits approximately every 6 months until loss to follow-up, 
death, withdrawal of consent, or study termination by the Sponsor, whichever occurs first, 
for a maximum of 5 years after enrollment.  Request to withdraw from follow-up must be 
documented in the source documents and signed by the investigator.  If the patient 


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withdraws from study treatment but not from follow-up, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only.
4.5.12
Samples for Roche Clinical Repository
4.5.12.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, and 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
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (see Section 4.5.10) will not be 
applicable at that site.
4.5.12.3
Sample Collection
The following samples may be collected for patients who have signed the RCR optional 
consent:

Optional freshly collected biopsy samples during the study (preferably at disease 
progression, if clinically feasible)

Remaining fluids (urine, plasma, and whole blood 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.


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For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the laboratory manual.  
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.12.4
Confidentiality
Confidentiality for All RCR Specimens
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  
The aggregate results of any research conducted using RCR specimens will be available 
in accordance with the effective 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.
Additional Confidentiality for Specimens Used for Genetic Research
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  
Upon receipt by the RCR, specimens for genetic research are "double-coded" 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.  


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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.
4.5.12.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.12.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  If a 
patient wishes to withdraw consent to the testing of his or her specimens, the 
investigator must inform the Medical Monitor in writing of the patient's wishes through 
use of the RCR Subject Withdrawal Form and, if the study is ongoing, must enter the 
date of withdrawal on the RCR Research Sample Withdrawal of Informed Consent eCRF.  
The patient will be provided with instructions on how to withdraw consent after the study
is closed.  A patient’s withdrawal from Study WO29635 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 WO29635.
If a patient wishes to withdraw consent to the testing of his or her specimens after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following:

Patient withdrawal of consent at any time


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
Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient 

Patient non-compliance
Every effort should be made to obtain information on patients who withdraw from the 
study.  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.
4.6.2 
Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:

Persistence/recurrence of disease with high grade lesion (any pT1, high-grade Ta,
or CIS) detected any time on or after the 6-month bladder biopsy.
Patients with persistent and/or recurrent high-grade NMIBC without progression
at 12 weeks may continue in the study, provided there is no evidence of 
progression to muscle-invasive disease.

Disease progression (e.g., muscleinvasive or metastatic UC)

Symptomatic deterioration (i.e., uncontrollable pain secondary to disease or
unmanageable ascites, etc.) attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status.

Intolerable toxicity related to atezolizumab or the combination of BCG and 
atezolizumab, including development of an immune-mediated adverse event
determined by the investigator to be unacceptable given the individual patient’s 
potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

Use of another non-protocol anti-cancer therapy (see Section 4.4.2)

Pregnancy
The primary reason for study treatment discontinuation must be documented in            
the eCRF.
4.6.3 
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following:

The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.


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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation Guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of inclusion and exclusion criteria (see Section 4.1.1 and Section 4.1.2) 
and close monitoring (as indicated below and in Section 4.5).  
An iDMC has also been incorporated into the study design to periodically review 
aggregate safety and efficacy data (please refer to the iDMC Charter for a detailed 
monitoring plan).
BCG is an approved treatment for patients with NMIBC.  Additional information on the 
risks and precautions associated with BCG therapy are provided in the OncoTICE 
prescribing information.  
Eligibility
Eligibility criteria were selected to guard the safety of patients in this study.  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 28 days before Day 1 are excluded from the study 
(see Section 4.1.2).
Monitoring
Safety will be evaluated in this study through the monitoring of all serious adverse 
events, defined and graded according to NCI CTCAE v4.0.  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).  Laboratory values must be reviewed prior 
to each infusion.


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During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection.  All serious adverse events and 
protocol-defined events of special interest (see Sections 5.2.2 and 5.2.3) will be reported 
in an expedited fashion (see Section 5.4.2).  In addition, the Medical Monitor will review 
and evaluate observed adverse events on a regular basis.  An iDMC will review safety 
and efficacy data as described in the Section 3.2.
Patients who experience a serious adverse event or protocol defined events of special 
interest will be followed for safety for 90 days following their last dose of study drug or 
until they receive another anti-cancer therapy, whichever comes first.  Patients who 
experience all other adverse events will be followed for safety for 30 days following their 
last dose of study drug or until they receive another anti-cancer therapy, whichever 
comes first.
Patients who have an ongoing study treatment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.
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize such toxicities, are outlined in the following sections. Refer to the 
Atezolizumab Investigator's Brochure for a complete summary of safety information.
5.1.1
Risks Associated with Atezolizumab
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, and myositis.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage 
activation syndrome (considered to be potential risks for atezolizumab).  Refer to
Appendix 12 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 BCG
Although intravesical BCG is generally well tolerated, the potential for adverse effects 
and severe complications exists with prolonged therapy and include local and systemic 
infectious complications.  Adverse events commonly seen with BCG treatment include 
but are not limited to the following:  urinary tract infection, anorexia, unclassified cardiac 
disorders, nausea/vomiting, diarrhea, liver involvement, skin rash, 
arthralgia/myalgia/arthritis, dysuria, hematuria, urinary frequency, urinary urgency, BCG 
cystitis, bladder cramps/pain, urinary incontinence, contracted bladder, fever, malaise, 


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and chills (Lamm et al. 1991).  Additional complications include clinical granulomatous 
prostatitis, pneumonitis, hepatitis, ureteral obstruction, epididymitis, renal abscess, 
sepsis, arthritis, osteomyelitis, and cytopenias (Brausi et al. 2014).
The proper administration of BCG is essential for avoiding intravascular dissemination of 
the bacillus.
The following is a summary of AUA guidelines for avoiding BCG transmission to others 
after BCG exposure:
To avoid transmission of BCG to others, for 6 hours after treatment, patients should void 
(urinate) while seated to avoid splashing of urine. Urine voided during this time should 
be disinfected with 2 cups of household bleach in the toilet water and allowing it to stand 
for 152 minutes before flushing.
Men receiving BCG treatment can pass on BCG during sex. To protect their partner 
from coming into contact with BCG, men should not have sex for 48 hours after each 
treatment. Men should use condoms while taking BCG and for six weeks after treatment 
has ended.
Both men and women should not conceive a child (get pregnant) while taking BCG 
treatments. Barrier methods of contraception, such as condoms, are recommended 
while taking BCG. Men and women should discuss with their doctor when it is safe to 
conceive a child after therapy.
Women should not breastfeed while taking this medication.
5.1.2.1
Constitutional Symptoms (Flu-like Symptoms)
Flu-like symptoms (malaise, fever and chills) may occur with both BCG treatment and
atezolizumab.  In patients who develop flu-like symptoms, disseminated BCG infection 
should be evaluated and ruled out before attributing to atezolizumab. The management 
of disseminated BCG infection requires the administration of antibiotics and steroids 
would be contraindicated.  Patients should be monitored for the presence of symptoms 
and signs of toxicity after each intravesical treatment.  Flu-like symptom attributable to 
BCG may be managed per the OncoTICE prescribing information.  
Additional guidelines for management of patients who develop flu-like symptoms are 
provided in Table 8. 
5.1.2.2
Local Bladder Symptoms
Symptoms of bladder irritability (i.e., bladder pain, bladder spasm), related to the 
inflammatory response induced, are reported in approximately 60% of patients receiving 
BCG (Brausi et al. 2014).  The symptoms typically begin 46 hours after instillation and 
last 2472 hours.


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Grade 3 dysuria occurs in 11% of patients and usually seen after the third instillation 
and tends to increase in severity with each subsequent administration.  The mechanism 
of action has not been firmly established, but is most consistent with an immunological 
mechanism.  Then is no evidence that dose reduction or anti-tuberculous drug therapy 
can prevent or lessen the irritative toxicity of BCG. 
Guidelines for management of patients who develop local bladder symptoms are 
provided in Table 8.
5.1.3
Management of Patients Who Experience Specific Adverse 
Events
There will be no dose reduction for atezolizumab in this study.  Patients may temporarily 
suspend atezolizumab for up to 12 weeks beyond last dose if they experience adverse 
events that require a dose to be withheld.  If atezolizumab is withheld because of related 
adverse events for 12 weeks beyond the last dose, then the patient will be 
discontinued from atezolizumab and will be followed for safety and efficacy as specified 
in Section 5.5.  If, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from resuming atezolizumab after a hold 12 weeks, atezolizumab 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 withheld for an additional time beyond 12 weeks 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 agreement between the investigator and 
the Medical Monitor.
Note, if systemic corticosteroids must be initiated in patients receiving weekly BCG 
installations, either during BCG induction or any BCG maintenance course, BCG must 
be withheld throughout the duration of systemic corticosteroid therapy to minimize the 
risk of systemic BCG infection.  BCG instillations should not be resumed until the patient 
has discontinued systemic corticosteroids. 
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.
Guidelines for the management of fever, local bladder symptoms, and influenza-like 
illness are presented in Table 8, as these events may result from or be potentiated by 
the combination of BCG and atezolizumab.  Refer to Appendix 12 for additional 
management guidelines for immune-mediated adverse events.
See Section 4.3.2.1 for guidelines for the management of infusion-related reactions and 
Appendix 8 for precautions for anaphylaxis.


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Table 8
Guidelines for Management of Specific Adverse Events
Severity
Management
Influenza-like illness
Arthralgia/chills
Grade 2

Continue atezolizumab.  

Treat symptoms with non-steroidal anti-inflammatory 
drugs (e.g., ibuprofen).
Grade 3/4

Withhold atezolizumab.

Consider starting 10 mg/day oral prednisone or 
equivalent, with taper over 12 weeks.

Resume atezolizumab if symptoms resolve and 
corticosteroid dose is equivalent to 10 mg/day.

Refer to the TICE prescribing information for additional 
management guidelines pertaining to BCG.
Fever
101° F (38.3° C)
101° F (38.3° C)

Continue atezolizumab and BCG (patients receiving 
induction or maintenance BCG at time of symptom)

Treat symptoms with non-steroidal anti-inflammatory 
drugs (e.g., ibuprofen).

Withhold BCG and atezolizumab.

For fever 24 hours, and in absence of other new 
grade 2 symptoms, evaluate and rule out co-existing 
infection including urine and blood culture, blood tests, 
and chest X-ray.  Consider consultation with infectious 
disease specialist.

For fever 24hours, would recommend immediate 
consultation with infectious disease specialist, 
discontinuation of BCG instillations, urine and blood 
culture, blood tests, and chest X-ray. Consider initiation 
of 2 antimicrobial agents including coverage with anti-
tuberculosis therapy while diagnostic evaluation is being 
conducted.

Refer to the TICE prescribing information for additional 
management guidelines pertaining to BCG.  
Local bladder symptoms
Dysuria

Refer to the TICE prescribing information for 
management guidelines pertaining to BCG.
Frequency

Refer to the TICE prescribing information for 
management guidelines pertaining to BCG.
Hematuria

Refer to the TICE prescribing information for 
management guidelines pertaining to BCG.
Local inflammation (e.g., 
epididymitis, prostatitis, orchitis)

Refer to the TICE prescribing information for 
management guidelines pertaining to BCG.
BCGbacille Calmette-Guérin; GGOground-glass opacity; IVintravenous; LFTliver function 
test; TNF-tumor necrosis factor-; TSHthyroid-stimulating hormone; ULNupper limit of 
normal.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the International Council for Harmonisation (ICH) guideline for Good 
Clinical Practice, an adverse event is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product, regardless of causal 
attribution.  An adverse event can therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

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 5.3.5.10)


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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 (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 
see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (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:

DLTs

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 and based on the following observations:
Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)
Treatment-emergent ALT or AST 3 baseline value in combination with 
clinical jaundice

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.


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
Pneumonitis

Colitis

Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis

Hepatitis, including AST or ALT 10 ULN

Systemic lupus erythematosus

Neurologic disorders:  Guillain-Barre syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis

BCG infection

Events suggestive of hypersensitivity, infusion-related reactions, cytokine release
syndrome, influenza-like illness, and systemic inflammatory reaction syndrome

Nephritis

Ocular toxicities (e.g., uveitis, retinitis)

Myositis

Myopathies, including rhabdomyolysis

Grade 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
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 Section 5.4, Section 5.5, 
Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of protocol treatment, 
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). 
See Section 5.4.2 for instructions for reporting serious adverse events.


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After initiation of study drug, all adverse events and serious adverse events 
regardless of attribution will be collected until 90 days following the last administration of 
study treatment or until study discontinuation/termination or until initiation of subsequent 
anti-cancer therapy, whichever occurs first.  Patients will be contacted at 30 days after 
the last dose of study treatment to determine if any new adverse events have occurred.  
After this period, investigators should report only serious adverse events that are 
considered to be related to prior study treatment (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
For each adverse event and serious adverse event the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity, and 
causality and record on the Adverse Event eCRF.
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  See Table 9 for assessing severity for adverse 
events that are not specifically listed in the NCI CTCAE.


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Table 9
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
or limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE(v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding 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 to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 10):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (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


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Table 10 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
Adverse events will be considered related, unless they fulfill the criteria as specified 
below.
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 


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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
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:

Is accompanied by clinical symptoms


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
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology studies, certain abnormal values may not qualify as 
adverse events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).


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5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.7
Deaths
All on-study deaths, regardless of relationship to study drug, must be recorded on the 
eCRF and immediately reported to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
During survival follow-up, deaths attributed to progression of UC should be recorded 
only on the Death Page eCRF.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of NonMuscle-Invasive Bladder 
Cancer
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 cystoscopic assessment.  In rare cases, the determination 
of clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is a result of disease progression, it should be 
reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization 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 condition.
The patient has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for outpatient care outside of normal clinic operating hours that is 
required per protocol or per local standard of care


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5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  No safety data 
related to overdosing of atezolizumab are available.
5.3.5.12
Patient-Reported Outcome Data
The PRO measurements are described in Section 4.5.8.  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 study.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
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 and 
Medical Monitor contact information will be distributed to all investigators (see Protocol 
Administrative and Contact Information & List of Investigators).
Medical Monitor Contact Information for All Sites
Medical Monitor:
 M.D.
E-mail:
Telephone No.:
Mobile Telephone No.:
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.  
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., within 
24 hours) on the Adverse Event eCRF and submit the report via the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form.
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form and Fax 
Coversheet should be completed and faxed or e-mailed immediately (i.e., no more than 
24 hours after learning of the event), as follows.  Ensure that information is also entered 
in the EDC system.
Fax:  
1-866-807-4325
E-mail:
cann.sae@scri-innovations.com 
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 or until they 
receive another anti-cancer therapy, whichever comes first.  After initiation of study drug, 
all adverse events will be reported until 30 days (see guidance and table in Section 5.3.1) 
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 Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form.


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The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form with use of the fax number or e-mail address 
provided to investigators.  All information will also need to be entered and submitted via 
the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and faxed or e-mailed immediately as follows below (i.e., no more than 
24 hours after learning of the event).  
Fax: 
1-866-807-4325
Email:
Cann.sae@scri-innovations.com
Pregnancy should not be recorded on the Adverse Event eCRF or the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form.  The investigator should 
discontinue all study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form and Adverse 
Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available. 
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor or designee immediately via the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.


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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF and reported to the Sponsor or designee immediately via the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
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 or adverse 
event of special interest 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.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events with use of the following reference documents:

Atezolizumab Investigator's Brochure 

Local prescribing information for BCG (OncoTICE)  
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
All analyses will be performed by cohort.  Selected analyses may also be performed for 
all cohorts combined as specified below.
All patients treated with any amount of study drug (atezolizumab or BCG) will be 
included in all analyses unless specified otherwise.
Analyses of DLTs will be performed on an ongoing basis as described in Section 3.1.  
Analyses of endpoints related to anti-tumor activity will be performed periodically among 
patients with sufficient follow-up.  Final analyses will be performed after the LPLV has 
occurred.
Continuous variables will be summarized using means, SDs, medians, and ranges.  
Categorical variables will be summarized by proportions.  The baseline value of any 
variable will be defined as the last available value prior to the first administration of study 
treatment.
6.1
DETERMINATION OF SAMPLE SIZE
The sample sizes for Cohorts 1A, 2, and 3 were based on clinical and operational 
considerations. The sample size for Cohort 1B was based on a 33 dose de-escalation 
design appropriate for assessing DLTs and MTD or MAD of BCG in combination with 
atezolizumab.  


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An evaluation of results from Cohorts 1A and 1B will be performed prior to initiation of 
enrollment in Cohorts 2 and 3.  Table 11 shows the 95% CI for selected observed CR 
rates for a range of sample sizes for Cohorts 1A and 1B pooled. 
Table 11 95% CI for Selected Observed 6-Month Complete Response 
Rates in Cohorts 1A and 1B
Cohort
N
Number of Patients with CR 
(Observed CR Rate)
95% CI for CR Rate a
Cohorts 1A 
and 1B 
pooled
12
5 (42%)
(15%, 72%)
6 (50%)
(21%, 79%)
15
6 (40%)
(16%, 68%)
7 (47%)
(21%, 73%)
20
8 (40%) 
(19%, 64%)
9 (45%)
(23%, 68%)
CRcomplete response.
a Clopper-Pearson method.
Table 12 shows the 95% CI for selected observed CR rates with the planned maximum
enrollment of patients in either Cohorts 2 or 3.
Table 12 95% CI for Selected Observed 6-Month Complete Response 
Rates with the Planned Maximum Enrollment of Patients in Either 
Cohort 2 or 3
Cohort
N
Number of Patients with CR 
(Observed CR rate)
95% CI for CR Rate a
Cohorts 2 or 3
20
10 (50%)
(27%, 73%)
12 (60%)
(36%, 81%)
14 (70%)
(46%, 88%)
16 (80%)
(56%, 94%)
18 (90%)
(68%, 99%)
CRcomplete response.
a Clopper-Pearson method.


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6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, major protocol deviations including major deviations of inclusion/exclusion 
criteria, and reasons for discontinuation from the study will be summarized by cohort and 
among pooled cohorts for the treated population.  Study treatment administration and 
reasons for discontinuation from the study treatment will be summarized by cohort and 
among pooled cohorts for all treated patients.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic variables such as age, sex, race/ethnicity, baseline characteristics 
(e.g., prior therapy, time since initial diagnosis, site[s] of disease, number of site[s], 
EORTC risk score, smoking status, and ECOG performance status) will be summarized 
by cohort and among pooled cohorts for all treated patients.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy outcome measure for this study is CR at 6 months after the start of 
study treatment as assessed by the investigator on the basis of cystoscopic assessment 
and urine cytology.  The CR rate will be summarized by timepoint for each cohort, and 
the corresponding 95% CI will be calculated on the basis of the Clopper-Pearson 
method.
6.4.2
Secondary Efficacy Endpoints
All assessments will be based on investigator assessments of tumor 
response/recurrence/progression and cause of death.  The secondary efficacy endpoints 
for this study are as follows.  

CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology.

Duration of CR will be defined for patients with a CR as the time from the first 
occurrence of a documented complete response to recurrence of high-grade NMIBC 
or death from any cause.  Data for patients without an event will be censored at the 
last date known to be alive and recurrence free.

RFS rate at 6, 12, and 18 months, defined as the proportion of patients who are 
alive and free of persistent/recurrent high-grade NMIBC.  Data for patients without 
an event will be censored at the last date known to be alive and free of 
persistent/recurrent NMIBC.  

Bladder-intact DFS will be defined as the time from the first study treatment to 
earliest evidence of progression to muscle-invasive disease in the bladder, regional 
pelvic progression, distant metastasis, bladder cancerrelated death, or cystectomy.  
Data for patients without an event will be censored at the last date known to be alive 
and event-free.  Data for patients who died from causes other than bladder cancer 
will be censored at the day of death.


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
PFS, defined as the time from the first study treatment to the first occurrence of 
progression to muscle-invasive disease based on cystoscopy and urine cytology or 
death from any cause.  Data for patients without a PFS event will be censored at the 
last date known to be alive and progression-free.

Cystectomy-free survival, defined as from start of study treatment to bladder 
removal for any cause or death from any cause.  Data for patients alive without 
cystectomy will be censored at the last date known to be alive without cystectomy.

Overall survival, defined as the time from the first dose of study treatment to death 
from any cause.  Data for patients who have not died will be censored at the last 
date known to be alive.
Data for patients without the respective post-baseline assessment will be censored at 
the time of start of treatment plus one day.  Time-to-event endpoints (duration of CR, 
bladder-intact DFS, PFS, cystectomy-free survival, and overall survival) will be 
summarized by cohort with use of the Kaplan-Meier method.  Kaplan-Meier curves 
will be presented.  Kaplan-Meier estimates of event rates at landmark timepoints (e.g., 6-, 
12-, and 18-months) and median time to the event will be presented with the 
corresponding 95% CI.  RFS rates and the corresponding 95% CI will be summarized at 
the 6-, 12-, and 18-month timepoints.
6.4.2.1
Exploratory Efficacy Analyses
Summaries of efficacy endpoints may be provided by subgroups defined by 
demographic and baseline characteristics as appropriate.
6.5
SAFETY ANALYSES
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, and changes in selected vital signs.  Safety analyses will be performed for 
treated patients by cohort.  Selected analyses will be performed by BCG dose level.
All adverse events with onset on or after treatment on Day 1 (treatment-emergent 
adverse events) will be summarized by mapped term, appropriate thesaurus levels, and 
NCI CTCAE v4 toxicity grade.  All adverse events, NCI CTCAE v4 Grade 3 adverse 
events, adverse events leading to withdrawal of treatment and serious adverse events 
will be summarized overall and for treatment related events.  In addition, all deaths 
including cause of death will be summarized.  All adverse events and deaths will be 
listed. 
All DLTs will be listed for DLT-evaluable patients (see Section 3.1.3 for a definition of 
DLT-evaluable patients).  
NCI CTCAE v4 Grade 3 and 4 laboratory data will be listed; in addition changes in 
selected laboratory data will be summarized by grade with use of the NCI CTCAE v4.  
Selected vital signs and selected laboratory data will be summarized.  The incidence of 
antibodies to atezolizumab will be summarized.


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6.6
PHARMACODYNAMIC ANALYSES
PD analyses will include assessments of PD biomarkers in both tumor tissue and whole 
blood.  Changes in PD and biomarkers potentially related to outcomes will be listed by 
dose, cohort, and response status.  Change from baseline will be reported descriptively 
as means, medians, and ranges and as a function of the response.
6.7
PHARMACOKINETIC ANALYSES
Available atezolizumab serum concentrations data (Cmin and Cmax) will be tabulated and 
summarized for each course or cycle, as appropriate.  Descriptive statistics will include 
means, medians, ranges, and SDs, as appropriate.
Additional PK analyses may be conducted as appropriate.
6.8
PATIENT-REPORTED OUTCOME ANALYSES
Cycle scores and change from baseline in symptoms, function, and HRQoL, as 
measured by the EORTC QLQ-C30 and the EORTC QLQ-NMIBC24 will be reported 
descriptively by cohort as means, SDs, medians, and ranges.
6.9
INTERIM ANALYSIS
6.9.1
Planned Interim Analyses
A preliminary assessment of anti-tumor activity and safety will be performed on Cohorts 
1A and 1B prior to initiation of enrollment into Cohorts 2 and 3.  
Given the nature of this study, the Sponsor may choose to perform additional periodic 
analyses of safety or efficacy on any cohort.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will supply eCRF specifications for this study.  A contract research 
organization (CRO) 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 CRO will request data clarification from the sites, which the sites will 
resolve electronically in the EDC system.
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the CRO, with use 
of the CRO’s standard procedures to handle and process the electronic transfer of 
these data.
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 


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standard procedures will be used 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 at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of the CRO’s EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical study.
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.


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for study-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-reported outcome data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug application (IND) will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 


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European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
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.


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Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.7).
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 be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data 
and will implement plans for evaluating and controlling these risks.  Risk evaluation 
and control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and 
monitoring of quality tolerance limits will be provided in a Quality Tolerance Limit 
Management Plan.


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9.4
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.
9.5
ADMINISTRATIVE STRUCTURE
A Steering Committee will consist of expert investigators selected from three academic 
institutions participating in the study.  During the study, the Committee’s role will be to 
review safety data with the Sponsor.  
The study site will acknowledge receipt of study treatments with use of the IxRS to 
confirm the shipment condition and content.
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 biomarkers, ATA assays, and auto-antibody testing.  Specified 
laboratory tests may be performed at a central laboratory.
9.6
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  
For all clinical studies 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 study results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical studies 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 studies 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.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy 
for bladder cancera current perspective. Nat Rev Urol 2014;11:15362.
Saint F, Patard JJ, Maille P, et al. Prognostic value of a T helper 1 urinary cytokine 
response after intravesical bacillus calmette-guerin treatment for superficial 
bladder cancer. J Urology 2002;167:3647.
Shirakawa H, Kikuchi E, Tanaka N, et al. Prognostic significance of bacillus 
calmette-guérin failure classification in non-muscle-invasive bladder cancer. BJU 
Int 2012;110:E21621.
Skinner EC. The best treatment for high-grade T1 bladder cancer is cystectomy. Urol 
Oncol 2007;25:5235.
Smith SG, Koppolu BP, Ravindranathan S, et al. Intravesical chitosan/interleukin-12 
immunotherapy induces tumor-specific systemic immunity against murine bladder 
cancer. Cancer Immunol Immunother 2015 Mar 10. [Epub ahead of print].
Soloway MS, Hepps D, Katkoori D, et al. Radical cystectomy for BCG failure: has the 
timing improved in recent years? BJU Int 2011;108:1825.
Solsona E, Iborra I, Dumont R, et al. The 3-month clinical response to intravesical 
therapy as a predictive factor for progression in patients with high risk superficial 
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Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the 
treatment of bacillus calmette-guerin refractory carcinoma in situ of the bladder. 
The Valrubicin Study Group. J Urol 2000;163:7617.
Sylvester RJ, van der Meijden AP, Witjes JA, et al. Bacillus calmette-guerin versus 
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Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and 
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Urol 2006;49:46677.
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Atezolizumab—F. Hoffmann-La Roche Ltd
140/Protocol WO29635, Version 6
Appendix 1
Schedule of Assessments:  Cohort 1A
Study Procedures
Screening 
Days –28
to –1
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
Signed Informed Consent Form c 
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories d
x
Demographic e
x
ECOG performance status
x
x f
x
Complete physical examination g
x
Limited physical examination h
x f
x
Weight
x
Height
x
Vital signs i
x
x f
x
12-lead ECG j
x
Upper tract imaging with CT urography or IV 
pyelogram k, l
x
Prior to atezolizumab treatment Cycles 9 
and 29, then annually as indicated 
Hematology m, n
x n
x f
x
Serum chemistry n, o
x n
x f
x
Coagulation panel (aPTT, INR) n
x n
x
Urinalysis n, p
x
Creatinine clearance
x
TSH, free T3, free T4
x
q6w [C2D1 and then every other cycle 
thereafter (e.g., C4D1, C6D1, etc.)]
HIV, HBV, HCV serology q
x


Appendix 1
Schedule of Assessments:  Cohort 1A (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
141/Protocol WO29635, Version 6
Study Procedures
Screening 
Days –28
to –1
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
TB test r
x
Serum pregnancy test n, s
x
q3w f
x
Archival/screening FFPE tumor tissue 
specimen or 10 unstained slides t
x
Serum PK sample u
See Appendix 4
Serum ATA sample u
See Appendix 4
Plasma PD biomarker
See Appendix 4
Atezolizumab infusion v
x
Tissue biopsy (mandatory sample) w
Prior to Cycle 9 (before Week 24)
Tumor biopsy (optional sample)
x
x
x
Tumor assessment x
x
Every 12 weeks x, l
x
x y
Patient reported outcomes z
Cycle 1 Day 1, Cycle 2 Day 1, and every 
6 weeks thereafter
x
Concomitant medications aa
x aa
x
x
Adverse events bb
x aa
x
x
x
Survival and anti-cancer therapy follow-up 
assessment cc
x
Blood samples for pharmacodynamics and 
biomarkers dd
See Appendix 4


Appendix 1
Schedule of Assessments:  Cohort 1A (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
142/Protocol WO29635, Version 6
Study Procedures
Screening 
Days –28
to –1
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
Urine samples for biomarker analysis ee
See Appendix 4
Whole blood TruCulture
See Appendix 4
Whole blood FACS
See Appendix 4
ATAanti-therapeutic antibody; BCGbacille Calmette-Guérin; CT computed tomography; DCdiscontinuation; ECOGEastern Cooperative 
Oncology Group; eCRFelectronic Case Report Form; EORTCEuropean Organisation for the Research and Treatment of Cancer; FACS = 
Fluorescence-activated cell sorting; FFPEformalin-fixed paraffin-embedded; HBVhepatitis B virus; HCVhepatitis C virus; IVintravenous; 
MRImagnetic resonance imaging; NMIBCnonmuscle-invasive bladder cancer; NMIBC24QLQ nonmuscle-invasive bladder cancer; 
PBMCperipheral blood mononuclear cell; PDpharmacodynamic; PKpharmacokinetic; PPDpurified protein derivative;  q3wevery 3 
weeks; q6wevery 6 weeks; QLQ-C30Quality of Life Questionnaire Core 30; qw weekly; TBtuberculosis; TSHthyroid-stimulating hormone; 
TURBTtransurethral resection of bladder tumor; UCurothelial carcinoma.
Note:  Each atezolizumab cycle is 3 weeks.  All assessments should be performed within 3 days of the scheduled visit, unless otherwise 
specified.  Assessments scheduled on the days of study treatment administration should be performed before the infusion unless otherwise 
noted.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend that precludes the visit, the visit should be scheduled on 
the nearest following feasible date, with subsequent visits scheduled according to the original schedule.
a In the absence of unacceptable toxicity or compelling evidence of disease progression, patients deriving clinical benefit may be offered 
continued study treatments for up to 96 weeks (in total).
b Patients will be asked to return to the clinic within 30 days after the last administration of study treatment or before another anti-cancer therapy 
is initiated, whichever is earlier.  The visit at which a tumor assessment shows progressive disease resulting in treatment discontinuation may 
be used as the treatment discontinuation visit.
c Written informed consent is required before 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 Cycle 1, Day 1 (except where otherwise specified) may be used for screening assessments rather than repeating 
such tests.


Appendix 1
Schedule of Assessments:  Cohort 1A (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
143/Protocol WO29635, Version 6
d Cancer history includes stage, date of diagnosis, and surgical resection procedure used as frontline treatment (if applicable). 
e Demographic information includes sex, age, and self-reported race/ethnicity.
f
Required on Day 1 of every atezolizumab cycle.
g Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
h Perform a limited, symptom-directed examination at every atezolizumab cycle and at treatment completion/DC visit, or as clinically indicated.  
Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  For the first atezolizumab infusion, the patient’s vital signs 
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 infusion and at the end of the infusion.  
j
ECG recordings will be obtained during the screening period and when clinically indicated.  Patients should be resting and in a supine position for 
at least 10 minutes prior to each ECG collection.  
k Baseline upper urinary tract imaging with CT urography, intravenous pyelogram, renal ultrasound with retrograde pyelogram, ureteroscopy or 
MRI urogram.  Pelvic CT before TURBT may be considered but is not required.  Assessment should be within 28 days prior to starting study 
treatment. Upper tract imaging using the same modality as was used at baseline should be performed at the 6-month (atezolizumab Cycle 9, 
Day 1) and 18-month (atezolizumab Cycle 29, Day 1) assessments, and then annually as indicated.
l
Patients with recurrent low-grade papillary disease will be required to undergo resection with TURBT (unless medically contraindicated) and may 
continue in the study and receive study treatment.  Patients with persistent and/or recurrent high-grade NMIBC without progression at 12 weeks 
may continue in the study, provided there is no evidence of progression to muscle-invasive disease.  Patients with persistent and/or recurrent 
high-grade NMIBC at the 6-month assessment will be discontinued from study therapy.  Patients with progression to muscle invasion at any time 
will be discontinued from study therapy.
m Includes RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, 
basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated.  
n Laboratory results to be obtained within 14 days prior to the first dose of atezolizumab treatment.
o Includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline 
phosphatase, LDH, total protein, and albumin.  


Appendix 1
Schedule of Assessments:  Cohort 1A (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
144/Protocol WO29635, Version 6
p Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).
q HIV testing to be performed in accordance with national and/or institutional guidelines.  HBV DNA must be collected on or before Cycle 1, Day 1 
in patients who have negative serology for hepatitis B surface antigen and positive serology for anti-HCV.  
r
All patients will have a QuantiFERONtest done locally prior to inclusion into the study.
s Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented 
as negative within 14 days prior to Cycle 1, Day 1, q3w, and at treatment completion/discontinuation.  
t
A sample of tumor tissue is required at study entry.  Fresh tissue biopsy is preferred; however, an archival specimen may be submitted in lieu of 
fresh tissue if a tissue biopsy is contraindicated owing to patient safety or tumor tissue accessibility and the archival specimen was obtained 
within 2 months of study screening.  The specimen may consist of a FFPE tumor tissue block (preferred) or at least 10 unstained, serial sections. 
u See Appendix 4 for a detailed schedule of sample collection timepoints.  Plasma PD biomarker, whole blood PBMC, urine biomarker, and whole 
blood FACS analysis will be performed at disease progression.  Post-atezolizumab dose samples should be collected 3010 minutes after the 
end of atezolizumab infusion. 
v Atezolizumab will be administered by IV infusion q3w for a maximum of 32 cycles of 96 weeks, whichever occurs first.
w All patients will undergo a mandatory tumor biopsy sample collection at 6 months (prior to Cycle 9 of atezolizumab).  Biopsy must be scheduled 
1421 days prior to BCG administration.  Fresh tissue biopsies will also be obtained as clinically indicated (e.g., if patient experiences signs of 
progression).  Mandatory fresh tissue biopsies should include any foci of disease (if present) as well as template biopsies obtained from all 
quadrants of the bladder.  Regions of the template biopsies should include the trigone, left lateral wall, right lateral wall, posterior wall, and dome.  
The Bladder Map template (Appendix 11) should be used to document the approximate size and location of any abnormalities, as well as the 
approximate location of template biopsies.  Additional tissue biopsies may also be obtained over the course of the study to evaluate disease per 
investigator assessment.
x Primary assessment of tumor will be with cystoscopy and urine cytology.  Tumor response assessment will occur every 12 weeks for the first 
2 years, and every 24 weeks thereafter (or as clinically appropriate) until 5 years, and then yearly.  White-light cystoscopy, narrow band imaging 
cystoscopy, or fluorescent (blue-light) cystoscopy will be acceptable for baseline assessment.  The same methodology used to assess disease 
sites at screening should be used throughout the study except when medically contraindicated (e.g., the same cystoscopy protocol and urine 
examination).  All known sites of disease must be documented at screening and re-assessed at each subsequent tumor evaluation.  Random 
biopsies must include all four quadrants of the bladder.  The same evaluator should perform assessments if possible to ensure internal 
consistency across visits.  The Bladder Map template (Appendix 11) should be used to document the approximate size and location of any 
abnormalities, as well as the approximate location of any biopsies performed.  For all patients, additional evaluation (imaging, exam under 
anesthesia, biopsies) should be performed at investigator discretion for any of the following circumstances:


Appendix 1
Schedule of Assessments:  Cohort 1A (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
145/Protocol WO29635, Version 6
Abnormal cystoscopy
Positive urine cytology
Two sequential suspicious/indeterminate urine cytology specimens
y Patients who discontinue all study treatment for a reason other than disease recurrence/progression or cystectomy will continue to undergo 
tumor assessments every 6 months until they experience disease recurrence/progression or cystectomy, until the patient dies, or withdraws 
consent, or until the study closes, whichever occurs first, for a maximum of 5 years after enrollment.
z Health-related quality of life will be assessed using the EORTC QLQ-C30 and EORTC QLQ-NMIBC24.
aa 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 informed consent should be documented.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded.
bb After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all serious adverse events or protocol-defined events of special interest will 
be followed for 90 days following their last dose of study drug or until they receive another anti-cancer therapy, whichever comes first.  All other 
adverse events will be followed for safety for 30 days following their last dose of study drug or until they receive another anti-cancer therapy, 
whichever comes first.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study treatment (see Section 5.6).  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 or adverse events of special interest considered to be related to the study drug 
or study-related procedures until a final outcome can be reported.  Treatment-related serious adverse events or adverse events of special 
interest should be reported regardless of the time after the end of treatment or study.
cc All patients will be followed for survival and subsequent anti-cancer therapy beginning 6 months after the treatment completion/discontinuation 
visit.  Survival and subsequent anti-cancer therapy follow-up information will be collected via telephone calls, patient medical records, and/or 
clinic visits every 6 months (1 month) until loss to follow-up, withdrawal of consent, or study termination by the Sponsor, for a maximum of 
5 years after enrollment.  Request to withdraw from follow-up must be documented in the source documents and signed by the investigator. 
If the patient withdraws from treatment but not from follow-up, the study staff may use a public information source (e.g., county records) to obtain 
information about survival status only.
dd See Appendix 4 for details of the pharmacodynamic sampling schedule.
ee Acquisition of urine biomarker samples will be performed prior to administration of study drug.


Atezolizumab—F. Hoffmann-La Roche Ltd
146/Protocol WO29635, Version 6
Appendix 2
Schedule of Assessments:  Cohorts 1B, 2, and 3
Study Procedures
Screening 
(Days –28
to –1)
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
Signed Informed Consent Form c 
x
Review of eligibility criteria
x
Medical, surgical, and cancer histories d
x
Demographic e
x
ECOG performance status 
x
x f
x
Complete physical examination g
x
Limited physical examination h
x f
x
Weight
x
Height
x
Vital signs i
x
x f
x
12-lead ECG j
x
Upper tract imaging with CT urography 
or IV pyelogram k, l
x
Prior to atezolizumab Cycles 9 and 29, then 
annually as indicated
Hematology m, n
x n
x f
x
Serum chemistry m, n,o
x n
x f
x
Coagulation panel (aPTT, INR) n
x n
x
Urinalysis n, p
x
Creatinine clearance
x
TSH, free T3, free T4 n
x m
q6w [C2D1 and then every other cycle 
thereafter (e.g., C4D1, C6D1, etc.)]


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
147/Protocol WO29635, Version 6
Study Procedures
Screening 
(Days –28
to –1)
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
HIV, HBV, HCV serology q
x
TB test r
x
Serum pregnancy test n, s
x
q3w f
x
Archival/screening FFPE tumor tissue 
specimen or 10 unstained slides t
x
Serum PK sample u
See Appendix 5
Serum ATA sample u
See Appendix 5
Plasma PD Biomarker
See Appendix 5
Atezolizumab infusion v
x
BCG administration w
BCG Induction:  weekly for 6 weeks 
(Weeks 011)
BCG Maintenance Course 1:  weekly for 
3 weeks (Weeks 1223)
BCG Maintenance Course 2:  weekly for 
3 weeks (Weeks 2447)
BCG Maintenance Course 3:  weekly for 
3 weeks (Weeks 4871)
BCG Maintenance Course 4:  weekly for 
3 weeks (Weeks 7295)
BCG Maintenance Course 5: weekly for 
3 weeks (Weeks 96120)
Tissue biopsy (mandatory sample) x
Prior to Cycle 9


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
148/Protocol WO29635, Version 6
Study Procedures
Screening 
(Days –28
to –1)
Weeks 196 a
Disease 
Progression
Treatment 
Completion/
DC Visit b
Follow-Up
Tissue biopsy (optional sample)
x
x
x
Tumor assessment y
x
Every 12 weeks following initiation of 
atezolizumab y, l
x z
x z
Patient-reported outcomes aa
Cycle 1, Day 1, Cycle 2 Day 1, and every 6 
weeks thereafter
x
Concomitant medications bb
x bb
x
x
Adverse events cc
x cc
x
x
x
Survival and anti-cancer therapy 
follow-up assessment dd
x
Blood samples for pharmacodynamics
and biomarkers ee
See Appendix 5
Urine samples for biomarker analysisff
See Appendix 5
Whole blood TruCulture
See Appendix 5
Whole blood FACS
See Appendix 5


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
149/Protocol WO29635, Version 6
ATAanti-therapeutic antibody; BCG bacille Calmette-Guérin; CT computed tomography; DCdiscontinuation; ECOGEastern Cooperative Oncology 
Group; eCRFelectronic Case Report Form; EORTCEuropean Organisation for the Research and Treatment of Cancer; FACSFluorescence-activated 
cell sorting; FFPEformalin-fixed paraffin-embedded; HBVhepatitis B virus; HCVhepatitis C virus; IVintravenous; MRImagnetic resonance imaging; 
NMIBCnonmuscle-invasive bladder cancer; NMIBC24QLQ nonmuscle-invasive bladder cancer; PBMCperipheral blood mononuclear cells; 
PDpharmacodynamic; PK pharmacokinetic; PPDpurified protein derivative; q3wevery 3 weeks; q6wevery 6 weeks; QLQ-C30Quality of Life 
Questionnaire Core 30; qwevery week; TBtuberculosis; TSHthyroid-stimulating hormone; TURBT transurethral resection of bladder tumor; 
UCurothelial carcinoma.
Note:  All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified. Assessments scheduled on the days of study 
treatment administration should be performed before the infusion unless otherwise noted.  All assessments (with cystoscopy and urine cytology) will be 
performed within 21 days prior to treatment and must occur 14 days prior to BCG dosing (for patients receiving BCG) unless otherwise specified.
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend that precludes the visit, the visit should be scheduled on the nearest 
following feasible date, with subsequent visits scheduled according to the original schedule.
a
In the absence of unacceptable toxicity or compelling evidence of disease progression, patients deriving clinical benefit may be offered continued atezolizumab treatments 
for up to 96 weeks (in total).
b
Patients will be asked to return to the clinic within 30 days after the last administration of study treatment or before another anti-cancer therapy is initiated, whichever is 
earlier.  The visit at which a tumor assessment shows progressive disease resulting in treatment discontinuation may be used as the treatment discontinuation visit.
c
Written informed consent is required before 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 atezolizumab Cycle 1, Day 1 
(except where otherwise specified) may be used for screening assessments rather than repeating such tests.  
d
Cancer history includes stage, date of diagnosis, and surgical resection procedure used as frontline treatment (if applicable).  
e
Demographic information includes sex, age, and self-reported race/ethnicity.
f
Required on Day 1 of every atezolizumab cycle.
g
Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
h
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
150/Protocol WO29635, Version 6
i
Vital signs include heart rate, respiratory rate, blood pressures, and temperature.  For the first atezolizumab infusion, the patient’s vital signs 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 
infusion and at the end of the infusion.  
j
ECG recordings will be obtained during the screening period and when clinically indicated.  Patients should be resting and in a supine position for at least 10 minutes prior 
to each ECG collection.  
k
Baseline upper urinary tract imaging with CT urography, intravenous pyelogram, renal ultrasound with retrograde pyelogram, ureteroscopy or MRI urogram.  Pelvic CT 
before TURBT may be considered but is not required.  Assessment should be within 28 days prior to starting study treatment.  Upper tract imaging using the same 
modality as was used at baseline should be performed at the 6-month (atezolizumab Cycle 9, Day 1) and 18-month (atezolizumab Cycle 29, Day 1) assessments, and then 
annually as indicated.
l
Patients with recurrent low-grade papillary disease will be required to undergo resection with TURBT (unless medically contraindicated) and may continue in the study and 
receive study treatment.  Patients with persistent and/or recurrent high-grade NMIBC without progression at 12 weeks may continue in the study provided there is no 
evidence of progression to muscle invasive disease.  Patients with persistent and/or recurrent high-grade NMIBC at the 6-month assessment will be discontinued from 
study therapy.  Patients with progression to muscle invasion at any time will be discontinued from study therapy.
m Includes RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and 
platelet count.  A manual differential can be done if clinically indicated.  
n
Laboratory results to be obtained within 14 days prior to the first dose of atezolizumab treatment.
o
Includes BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total 
protein, and albumin.  
p
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood).  
q
HIV testing to be performed in accordance with national and/or institutional guidelines.  HBV DNA must be collected on or before Cycle 1, Day 1 in patients who have 
negative serology for hepatitis B surface antigen and positive serology for anti HCV.  
r
All patients will have a QuantiFERONtest done locally prior to inclusion into the study.
s
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as negative within 
14 days prior to Cycle 1, Day 1 and at treatment completion/discontinuation.
t
A sample of tumor tissue is required at study entry.  Fresh tissue biopsy is preferred; however, an archival specimen may be submitted in lieu of fresh tissue if a tissue 
biopsy is contraindicated owing to patient safety or tumor tissue accessibility and the archival specimen was obtained within 2 months of study screening.  The specimen 
may consist of a FFPE tumor tissue block (preferred) or at least 10 unstained, serial sections.
u
See Appendix 5 for a detailed schedule of sample collection timepoints.  Plasma PD biomarker, whole blood PBMC, urine biomarker, and whole blood FACS analysis will 
be performed at disease progression.  Post-atezolizumab dose samples should be collected 30 10 minutes after the end of atezolizumab infusion.
v
Atezolizumab will be administered by IV infusion.  During BCG Induction Course (12 weeks), patients receive atezolizumab 1200 mg IV q3w for a total of four doses.  


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
151/Protocol WO29635, Version 6
During BCG Maintenance Course 1 (12 weeks), patients will receive atezolizumab 1200 mg IV q3w for a total of four doses.  During BCG Maintenance Course 25
(each 24 weeks), patients receive atezolizumab 1200 mg IV q3w for a total of eight doses per course.  The maximum treatment duration is 96 weeks or 32 cycles, 
whichever occurs first.
w BCG will be administered intravesically.  During BCG Induction Course (12 weeks), patients will receive BCG at the assigned dose weekly for a total of six doses.  During 
BCG Maintenance Course 1 (12 weeks), patients receive BCG at the assigned dose weekly for a total of three doses. 
During BCG Maintenance Courses 25 (each 24 weeks), patients receive BCG at the assigned dose weekly for a total of three doses per course.  In the absence of 
unacceptable toxicity or compelling evidence of disease progression, patients deriving clinical benefit may be offered continued study treatments for up to 24 months 
(in total).
x
All patients will undergo a mandatory tumor biopsy sample collection at 6 months (prior to Cycle 9  of atezolizumab).  Biopsy must be scheduled 1421 days prior to BCG 
administration.  Fresh tissue biopsies will also be obtained as clinically indicated (e.g., if patient experiences signs of progression.  Mandatory fresh tissue biopsies should 
include any foci of disease (if present) as well as template biopsies obtained from all quadrants of the bladder.  Regions of the template biopsies should include the trigone, 
left lateral wall, right lateral wall, posterior wall, and dome.  Bladder Map template (Appendix 11) should be used to document the approximate size and location of any 
abnormalities, as well as the approximate location of template biopsies.  Additional tissue biopsies may also be obtained over the course of the study to evaluate disease 
per investigator assessment.
y
Primary assessment of tumor will be with cystoscopy and urine cytology.  Tumor response assessment will occur every 12 weeks for the first 2 years, and every 24 weeks 
thereafter (or as clinically appropriate) until 5 years, and then yearly.  Cystoscopy that falls prior to BCG should be performed at least 14 days prior to BCG administration.  
White-light cystoscopy, narrow band imaging cystoscopy, or fluorescent (blue-light) cystoscopy will be acceptable for baseline assessment.  The same methodology used 
to assess disease sites at screening should be used throughout the study except when medically contraindicated (e.g., the same cystoscopy protocol and urine 
examination).  All known sites of disease must be documented at screening and re-assessed at each subsequent tumor evaluation.  Random biopsies must include all four 
quadrants of the bladder.  The same evaluator should perform assessments if possible to ensure internal consistency across visits.  Bladder Map template (Appendix 11) 
should be used to document the approximate size and location of any abnormalities, as well as the approximate location of any biopsies performed.  For all patients, 
additional evaluation (imaging, exam under anesthesia, biopsies) should be obtained as clinical indicated or if progression is suspected, performed at investigator 
discretion for any of the following circumstances:
Abnormal cystoscopy
Positive urine cytology
Two sequential suspicious/indeterminate urine cytology specimens 
z
Patients with recurrent low-grade papillary disease will be required to undergo resection with TURBT (unless medically contraindicated) and may continue in the study and 
receive study treatment.  Patients with persistent and/or recurrent high-grade NMIBC without progression at 12 weeks may continue in the study provided there is no 
evidence of progression to muscle invasive disease.  Patients with persistent and/or recurrent high-grade NMIBC at the 6-month assessment will be discontinued from 
study therapy.  Patients with progression to muscle invasion at any time will be discontinued from study therapy.
aa Health-related quality of life will be assessed using the EORTC QLQ-C30 and EORTC QLQ-NMIBC24.


Appendix 2
Schedule of Assessments:  Cohorts 1b, 2, and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
152/Protocol WO29635, Version 6
bb 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 informed consent should be documented.  At subsequent visits, changes to current medications or medications used since the last documentation of medications will be 
recorded.
cc After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated intervention should be 
reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study treatment.  After this period, the Sponsor should be 
notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study treatment (see Section 5.6).  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 study-related procedures until a final 
outcome can be reported.
dd All patients will be followed for survival and subsequent anti-cancer therapy beginning 6 months after the treatment completion/discontinuation visit.  Survival and 
subsequent anti-cancer therapy follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits every 6 months (1 month) until loss 
to follow-up, withdrawal of consent, or study termination by the Sponsor, for a maximum of 5 years after enrollment.  Request to withdraw from follow-up must be 
documented in the source documents and signed by the investigator. If the patient withdraws from treatment but not from follow-up, the study staff may use a public 
information source (e.g., county records) to obtain information about survival status only.
ee See Appendix 5 for details of the pharmacodynamic sampling schedule.
ff
Acquisition of urine biomarker samples will be performed prior to administration of study drugs.


Atezolizumab—F. Hoffmann-La Roche Ltd
153/Protocol WO29635, Version 6
Appendix 3
BCG and Atezolizumab Treatment and Tumor Assessment Calendar for Study Weeks 0108:  
Cohorts 1B, 2, and 3
Week on Study
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Study Month
3
6
Atezolizumab 
Cycle # (Day 1)a,b
1
2
3
4
5
6
7
8
9
10
11
BCG
Administration b,c
x
x
x
x
x
x
x
x
x
x
x
x
Cystoscopy/
Cytology d
x
x
Upper Tract
Imaging b,e
x
Week on Study
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Study Month
12
Atezolizumab 
Cycle # (Day 1) a,b
12
13
14
15
16
17
18
19
20
21
BCG
Administration b,c
x
x
x
Cystoscopy/
Cytology d
x
x
x
Upper Tract 
Imaging b,e


Appendix 3
BCG and Atezolizumab Treatment and Tumor Assessment Calendar for Study Weeks 0108:  
Cohorts 1B, 2 and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
154/Protocol WO29635, Version 6
Week on Study
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
Study Month
18
Atezolizumab 
Cycle # (Day 1) a,b
22
23
24
25
26
27
28
29
30
31
BCG
Administration b,c
x
x
x
Cystoscopy/
Cytology d
x
x
Upper Tract 
Imaging b,e
x
Week on Study
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108 f
Study Month
24
Atezolizumab 
Cycle # (Day 1)
a,b
32
BCG
Administration b,c
x
x
x
Cystoscopy/
Cytology d
x
x
Upper Tract
Imaging b,e


Appendix 3
BCG and Atezolizumab Treatment and Tumor Assessment Calendar for Study Weeks 0108:  
Cohorts 1B, 2 and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
155/Protocol WO29635, Version 6
a Atezolizumab will be administered by IV infusion.  During BCG Induction Course (12 weeks), patients receive atezolizumab 1200 mg IV q3w for 
a total of four doses.  During BCG Maintenance Course 1 (12 weeks), patients will receive atezolizumab 1200 mg IV q3w for a total of four 
doses.  During BCG Maintenance Course 25 (each 24 weeks), patients receive atezolizumab 1200 mg IV q3w for a total of eight doses per 
course.  The maximum treatment duration is 96 weeks or 32 cycles, whichever occurs first.
b All visits must occur within 3 days from the scheduled date unless otherwise noted.  
c BCG will be administered intravesically.  During BCG Induction Course (12 weeks), patients will receive BCG at the assigned dose weekly for a 
total of six doses.  During BCG Maintenance Course 1 (12 weeks), patients receive BCG at the assigned dose weekly for a total of three doses.  
During BCG Maintenance Courses 25 (each 24 weeks), patients receive BCG at the assigned dose weekly for a total of three doses per 
course.
d All assessments involving cystoscopy and urine cytology will be performed within 21 days prior to atezolizumab treatment and must occur 
1421 days prior to BCG dosing (for patients receiving BCG) unless otherwise specified.  All patients will undergo a mandatory tumor biopsy 
sample collection at 6 months (prior to Cycle 9 of atezolizumab).  Biopsy must be scheduled 1421 days prior to BCG administration.  Fresh 
tissue biopsies will also be obtained as clinically indicated (e.g., if patient experiences signs of progression).  Mandatory fresh tissue biopsies 
should include any foci of disease (if present) as well as template biopsies obtained from all quadrants of the bladder.  Regions of the template 
biopsies should include the trigone, left lateral wall, right lateral wall, posterior wall, and dome.  Additional tissue biopsies may also be obtained 
over the course of the study to evaluate disease per investigator assessment.
e Baseline upper urinary tract imaging with CT urography, intravenous pyelogram, renal ultrasound with retrograde pyelogram, ureteroscopy or 
MRI urogram.  Pelvic CT before TURBT may be considered but is not required.  Assessment should be within 28 days prior to starting study 
treatment.  Upper tract imaging using the same modality as was used at baseline should be performed at the 6-month (atezolizumab Cycle 9, 
Day 1) and 18-month (atezolizumab Cycle 29, Day 1) assessments, and then annually as indicated.
f
The 2-year timepoint falls between Week 96 and Week 108 cystoscopy/cytology assessments.  The Week 108 cystoscopy/cytology assessment 
should be performed and then the every 24 week assessment schedule should be followed after the Week 108 UC assessment, until 5 years. 


Atezolizumab—F. Hoffmann-La Roche Ltd
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Appendix 4
Schedule of Pharmacodynamic, Pharmacokinetic and Biomarker 
Assessments:  Cohort 1A
Visit a
Timepoint
Sample Type
Study Week 0/
Atezolizumab Cycle 1
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood TruCulture
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Post-atezolizumab dose b
Serum atezolizumab PK
Study Week 3/
Atezolizumab Cycle 2
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Study Week 6/
Atezolizumab Cycle 3
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA 
Study Week 9/
Atezolizumab Cycle 4
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD Biomarker
Whole blood TruCulture
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Study Weeks 21, 45, and 69 
Atezolizumab Cycles 8, 16, 
and 24
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Disease Progression
NA
Plasma PD Biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS


Atezolizumab—F. Hoffmann-La Roche Ltd
157/Protocol WO29635, Version 6
Appendix 4
Schedule of Pharmacodynamic, Pharmacokinetic and Biomarker 
Assessments:  Cohort 1A (cont.)
Visit a
Timepoint
Sample Type
Atezolizumab treatment 
completion/discontinuation 
visit c
NA
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS
120 days 30 days after last 
atezolizumab dose d
NA
Serum atezolizumab PK
Serum atezolizumab ATA
ATAanti-therapeutic antibody; FACSfluorescence-activated cell sorting; NAnot 
applicable; PDpharmacodynamic; PKpharmacokinetic; PBMCperipheral blood 
mononuclear cells.
Note:  Each atezolizumab cycle is 3 weeks.  All pre-atezolizumab PK, ATA, and
PD sample collection will be just prior to study treatment administration on the 
specified day.  
a For each specified visit, samples should be collected on Day 1 of each cycle.
b Post-atezolizumab dose samples should be collected 30 10 minutes after the end 
of atezolizumab infusion.
c PK, ATA, Plasma PD biomarker samples, urine biomarker, whole blood PBMC, 
and whole blood FACS will be obtained from patients at the time of atezolizumab 
treatment completion or discontinuation.
d A sample will be obtained 120 days (30 days) after the final dose of 
atezolizumab, unless the patients has withdrawn consent of is lost to follow-up.


Atezolizumab—F. Hoffmann-La Roche Ltd
158/Protocol WO29635, Version 6
Appendix 5
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments:  Cohorts 1B, 2 and 3
Visit a
Timepoint
Sample Type
BCG Induction
Study Week 0/
Atezolizumab Cycle 1
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood TruCulture
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Post-atezolizumab dose b
Serum atezolizumab PK
Study Week 3/
Atezolizumab Cycle 2
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Study Week 6/
Atezolizumab Cycle 3
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Study Week 9/
Atezolizumab Cycle 4
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD Biomarker
Whole blood TruCulture
Whole blood PBMC
Urine Biomarker
Whole blood FACS
BCG Maintenance Course 1
Study Week 21/
Atezolizumab Cycle 8
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA


Appendix 5
Schedule of Pharmacodynamic and Pharmacokinetic 
Assessments:  Cohorts 1B, 2 and 3 (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
159/Protocol WO29635, Version 6
Visit a
Timepoint
Sample Type
BCG Maintenance Courses 25
Study Weeks 45 and 69/
Atezolizumab Cycles 16
and 24
Pre-atezolizumab dose
Serum atezolizumab PK
Serum atezolizumab ATA
Disease Progression
NA
Plasma PD Biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS
Atezolizumab treatment 
completion/discontinuation 
visit c
NA
Serum atezolizumab PK
Serum atezolizumab ATA
Plasma PD biomarker
Whole blood PBMC
Urine Biomarker
Whole blood FACS
120 days 30 days after 
last Atezolizumab dose d
NA
Serum atezolizumab PK
Serum atezolizumab ATA
ATAanti-therapeutic antibody; BCG bacille Calmette-Guérin; 
FACSfluorescence-activated cell sorting; NAnot applicable; PDpharmacodynamic; 
PKpharmacokinetic; PBMCperipheral blood mononuclear cells.
Note:  Each atezolizumab cycle is 3 weeks.  All pre-atezolizumab PK, ATA, and PD sample 
collection will be just prior to study treatment administration on the specified day.  
a For each specified visit, samples should be collected on Day1 of each cycle.
b
Post-Atezolizumab dose samples should be collected 3010 minutes after the end of 
atezolizumab infusion.
c PK, ATA, Plasma PD biomarker samples, Urine biomarker, Whole Blood PBMC, and 
Whole Blood FACS will be obtained from patients at the time of atezolizumab treatment 
completion or discontinuation.
d A sample will be obtained 120 days (30 days) after the final dose of atezolizumab, 
unless the patients has withdrawn consent or is lost to follow-up.


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Appendix 6
Preexisting Autoimmune Diseases
Acute disseminated 
encephalomyelitis
Addison’s disease
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune 
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic
purpura
Behcet’s disease
Bullous pemphigold
Chronic fatigue syndrome
Chronic inflammatory
demyelinating polyneuropathy
Chung-Strauss syndrome
Crohn’s disease 
Dermatomyositis
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease – chronic
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus 
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodusa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vitiligo
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis
Note:  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.


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161/Protocol WO29635, Version 6
Appendix 7
Eastern Cooperative Oncology Group 
Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature; e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead


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162/Protocol WO29635, Version 6
Appendix 8
Anaphylaxis Precautions
EQUIPMENT NEEDED

Oxygen

Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the 
following procedures should be performed:
1.
Stop the study drug infusion.
2.
Maintain an adequate airway.
3.
Administer antihistamines, epinephrine, or other medications as required by patient
status and directed by the physician in charge.
4.
Continue to observe the patient and document observations.


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163/Protocol WO29635, Version 6
Appendix 9
EORTC QLQ-C30 Questionnaire


Appendix 9
EORTC QLQ-C30 Questionnaire (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
164/Protocol WO29635, Version 6


Atezolizumab—F. Hoffmann-La Roche Ltd
165/Protocol WO29635, Version 6
Appendix 10
EORTC QLQ-NMIBC24 Questionnaire


Atezolizumab—F. Hoffmann-La Roche Ltd
166/Protocol WO29635, Version 6
Appendix 11
Bladder Map


Atezolizumab—F. Hoffmann-La Roche Ltd
167/Protocol WO29635, Version 6
Appendix 12
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have 
met the criteria for permanent discontinuation, resumption of atezolizumab 
may be considered if the patient is deriving benefit and has fully recovered from the 
immune-mediated event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 12 weeks if the 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 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
168/Protocol WO29635, Version 6
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 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
169/Protocol WO29635, Version 6
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
170/Protocol WO29635, Version 6
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
171/Protocol WO29635, Version 6
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function test.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
172/Protocol WO29635, Version 6
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
173/Protocol WO29635, Version 6
Table 3
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., TSH, 
growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
174/Protocol WO29635, Version 6
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH 0.1 mU/L and 0.5 mU/L:

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated hyperthyroidism.
c
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
175/Protocol WO29635, Version 6
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical 
Monitor. c
Hyperglycemia, 
Grade 1 or 2 

Continue atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume atezolizumab when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
176/Protocol WO29635, Version 6
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
177/Protocol WO29635, Version 6
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue atezolizumab.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Ocular event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator 
(or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
178/Protocol WO29635, Version 6
IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis has been associated with the administration of 
atezolizumab.  Immune-mediated myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, 
chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-
mediated myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI 
as appropriate per institutional guidelines.  A cardiologist should be consulted.  
An endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
179/Protocol WO29635, Version 6
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 1

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines.
Immune-mediated
myocarditis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Consider treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-mediated
myocarditis, Grade 34

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
ECMOextracorporeal membrane oxygenation; VADventricular assist device.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.  
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
180/Protocol WO29635, Version 6
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE
SYNDROME
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines,
anti-pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis.
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab.  These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity.
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells 
and/or other immune effector cells.  Symptoms can be progressive, always include fever 
at the onset, and may include hypotension, capillary leak (hypoxia), and end-organ 
dysfunction (Lee et al. 2019).  CRS has been well documented with chimeric antigen 
receptor T-cell therapies and bispecific T-cell engager antibody therapies but has also 
been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; 
Adashek and Feldman 2019), including atezolizumab.
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
181/Protocol WO29635, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome
Event
Management
Grade 1 a
Fever b with or 
without 
constitutional 
symptoms

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment, c including maintenance of 
IV fluids for hydration.

In case of rapid decline or prolonged CRS (2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
182/Protocol WO29635, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 2 a
Fever b with 
hypotension not 
requiring 
vasopressors
and/or
Hypoxia requiring 
low-flow oxygen d
by nasal cannula or 
blow-by

Immediately interrupt infusion.

Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset.

If symptoms recur, discontinue infusion of this dose.

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus as needed.

Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, and 
manage constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact Medical Monitor.

If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered.  

For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics and monitor closely 
for IRRs and/or CRS.

If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
183/Protocol WO29635, Version 6
Table 7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
Grade 3 a
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
and/or
Hypoxia requiring 
high-flow oxygen d
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor as needed.

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e

Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.
Grade 4 a
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
and/or
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue atezolizumab and contact Medical Monitor. f

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix.

Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. e  For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor.

Hospitalize patient until complete resolution of symptoms.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
184/Protocol WO29635, Version 6
Table7
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome (cont.)
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive airway 
pressure; CRS cytokine-release syndrome; CTCAE Common Terminology Criteria for 
Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRRinfusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive Network; 
NCI National Cancer Institute.
Note:  The management guidelines have been adapted from NCCN guidelines for management 
of CAR T-cellrelated toxicities (Version 2.2019).
a Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE v4.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading.
b Fever is defined as temperature 38C not attributable to any other cause.  In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia.
c
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice.
d Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min.
e
There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established.
f
Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  
Premedication with corticosteroids and extending the infusion time may also be considered 
after consulting the Medical Monitor and considering the benefitrisk ratio.
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
185/Protocol WO29635, Version 6
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-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
186/Protocol WO29635, Version 6
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
187/Protocol WO29635, Version 6
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limited, with or without pruritus.  
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in Table 9.
Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
188/Protocol WO29635, Version 6
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Immune-mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré 
syndrome 
(any grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
189/Protocol WO29635, Version 6
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function. Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
190/Protocol WO29635, Version 6
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
191/Protocol WO29635, Version 6
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among 
the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase 
increase), and imaging (electromyography/MRI) features, and is confirmed with a 
muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
192/Protocol WO29635, Version 6
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of 10 mg/day oral prednisone before atezolizumab can be resumed.
c
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
193/Protocol WO29635, Version 6
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS), which are considered to be potential risks for atezolizumab.  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of 
the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100 109/L (100,000/L)
–
ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should 
be classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


Appendix 12
Risks Associated with Atezolizumab and Guidelines for Management 
of Adverse Events Associated with Atezolizumab (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
194/Protocol WO29635, Version 6
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH 
or MAS

Permanently discontinue atezolizumab and contact Medical 
Monitor.

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
HLH hemophagocytic lymphohistiocytosis; MAS macrophage activation syndrome.
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McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
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29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:4819.
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther 
Clin Risk Manag 2019;15:32335.
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
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