Phase II Study of Neoadjuvant Atezolizumab-based Immunotherapy for Patients With Urothelial Carcinoma (NEBULA)
Phase: PHASE2
Conditions: Carcinoma, Transitional Cell
Sponsor: Lawrence Fong

Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
Phase II Study of Neoadjuvant Atezolizumab-based 
Immunotherapy for Patients with Urothelial Carcinoma 
(NEBULA) 
Protocol Number:  CC #14524
Investigational Products:  Atezolizumab and Tiragolumab
Version Number:  4.4
Version Date:  March 29, 2021
IND Number:  124,928
NCT Number: NCT02451423
Principal Investigator (Sponsor-Investigator)
Lawrence Fong, MD 
University of California San Francisco
 
 
Statistician
Li Zhang, PhD 
Revision History
Version 1.0
May 9, 2014
Version 1.1
October 16, 2014
Version 1.2
December 23, 2014
Version 1.3
February 1, 2015
Version 1.4
March 21, 2016
Version 2.0
July 10, 2017
Version 3.0
January 15, 2019
Version 4.0
September 5, 2019
Version 4.1
October 15, 2019
Version 4.2
March 12, 2020
Version 4.3
October 19, 2020
Version 4.4
March 29, 2021

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
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Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data and Safety Monitoring Committee 
(DSMC). 
2.
I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date

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Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
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Protocol Signature Page – Participating Sites 
Participating Site(s)
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, and local regulatory 
requirements.  
Signature of Principal Investigator
Date
Name of Principal Investigator (Printed)
Name of Facility
Mamta Parikh, MD
University of California-Davis
Instructions to the investigator: Please SIGN and DATE this 
signature page. PRINT your name and the name of the facility in which 
the study will be conducted. Scan and email the completed form to 
UCSF Helen Diller Family Comprehensive Cancer Center and keep a 
record for your files.

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Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
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Abstract
Title
Phase II Study of Neoadjuvant Atezolizumab-based Immunotherapy 
for Patients with Urothelial Carcinoma (NEBULA)
Phase of Study
Phase II
Study Drugs
Atezolizumab, an anti-PD-L1 antibody. Dose will be 1200mg IV given 
on Day 1 of a 21-day cycle x 3 doses. 
Tiragolumab, an anti-TIGIT antibody (Cohort B only). Dose will be 
600mg IV on Day 1 of a 21-day cycle x for up to 3 doses
Study Population
Subjects with muscle-invasive urothelial cell carcinoma of the bladder
Study Design
This is a single arm, open label multiple-cohort phase II study of 
atezolizumab, an anti-PD-L1 antibody, alone or in combination with 
tiragolumab, an anti-TIGIT antibody, administered as neoadjuvant 
therapy to patients with muscle-invasive urothelial carcinoma 
appropriate for cystectomy and either refusing or ineligible for 
neoadjuvant cisplatin-based chemotherapy. Enrolled patients will 
receive atezolizumab (1200mg IV on Day 1 of a 21 day cycle) and, in 
the combination cohort, tiragolumab (600mg IV on Day 1 of a 21 day 
cycle) as neoadjuvant treatment for an intended total of three 
treatment cycles. 
As of October 2020 the atezolizumab monotherapy cohort (Cohort A) 
has completed dose escalation and is in dose expansion, and will 
accrue up to 27 total patients. Once amendment 4.3 (October 19th, 
2020) is approved patients will only be accrued to the combination 
cohort (Cohort B). 
For Cohort B there will be an initial safety lead in phase for 
combination treatment, detailed in Section 3.1. Once the intended 
treatment regimen is established following completion of the safety 
assessment, an additional 15 patients will be enrolled at the same 
regimen for a total of 21 patients in Cohort B at the established 
regimen. Consequently, a minimum of 21 and a maximum of 33 
patients will be enrolled in Cohort B.
After all neoadjuvant study therapy is administered, each patient will 
undergo radical cystectomy with pelvic lymph node dissection to 
evaluate pathologic response to treatment and for immunologic 
characterization in the resected tissue. 
All patients will undergo radical cystectomy within 12 weeks of the 
start of neoadjuvant treatment. Any delays in surgery beyond 12 
weeks from the start of neoadjuvant treatment that are thought to be 
treatment related will be considered an adverse event. Serum and 
urine will be obtained as well to characterize circulating immune 

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Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
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responses. Following completion of radical cystectomy all patients will 
be followed clinically for up to 2 years with regular visits and imaging 
to assess for disease recurrence.
Primary Objectives
Cohort A (Atezolizumab Monotherapy): 
Multi-dose cohorts: To assess the intratumoral immune response 
associated with increasing numbers of Atezolizumab treatments. 
Expansion cohort: To assess the anti-tumor activity of Atezolizumab 
as determined by the pathologic T0 rate (pT0N0) at the time of 
cystectomy.
Cohort B (Atezolizumab + Tiragolumab): 
Multi-dose cohorts: To assess the safety of neoadjuvant combination 
treatment with atezolizumab and tiragolumab according to CTCAE 
v5.0 in cisplatin-ineligible patients with MIBC undergoing radical 
cystectomy.
Expansion cohort: To assess the anti-tumor activity of Atezolizumab + 
Tiragolumab as determined by the pathologic T0 rate (pT0N0) at the 
time of cystectomy.
Secondary 
Objectives
Cohorts A & B
Multi-dose cohorts: 
1.
To evaluate the safety and feasibility of administering up to 3 
cycles of Atezolizumab pre-operatively to patients with resectable 
urothelial bladder cancer. Note this is the coprimary objective for 
Cohort B.
Expansion cohort:
1.
To assess the anti-tumor activity of neoadjuvant treatment as 
determined by pathologic pathologic partial response (<pT2N0) 
assessed at the time of radical cystectomy
2.
To determine the 2-year relapse-free survival (RFS) rate and 
median RFS from time of radical cystectomy in patients treated 
with neoadjuvant therapy
3.
To determine the 2-year overall survival (OS) and median OS from 
time of radical cystectomy in patients treated with neoadjuvant 
therapy

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Phase II – atezolizumab and tiragolumab
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4.
To assess the intratumoral immune response of neoadjuvant by 
comparing pre-treatment TURBT with post-treatment cystectomy 
tumor specimens
Exploratory 
Objectives
Cohorts A & B
1.
To define the immunologic infiltration within bladder tissue 
following administration of neoadjuvant combination treatment with 
atezolizumab and tiragolumab when compared to pre-treatment 
TURBT biopsies
2.
To assess the immunologic impact of combined tiragolumab and 
atezolizumab regimen in the urothelial cancer tumor 
microenvironment (Cohort B) in comparison to the impact on the 
tumor microenvironment of atezolizumab monotherapy in a similar 
cohort of patients treated with neoadjuvant atezolizumab for MIBC 
at UCSF (Cohort A)
3.
To assess for tumor-based biomarkers of response and resistance 
to this combination therapy using single-cell RNA sequencing 
(scRNA-seq) and high-dimensional flow cytometry
4.
To define the treatment-induced effects on circulating immune 
cells with this combination therapy
5.
To assess the presence of antigen-specific immune responses to a 
broad panel of candidate tumor antigens
Sample Size
Cohort A Safety Lead-In: 18 participants (already accrued as of 
October 2020)
Cohort A Expansion: Up to 9 additional participants may be accrued 
so that Cohort A expansion group = up to 15 total participants treated 
at established regimen (6 participants treated at highest administered 
dose from multi-dose portion + up to 9 additional participants).
Cohort B Safety Lead-In: 6-18 patients will be included.
Cohort B Expansion: 15 additional patients treated with the regimen 
established during the safety lead-in phase (21 total treated with 
established regimen)
Total Cohort A accrual: Up to 27 patients
Total Cohort B accrual: 21-33 patients
Duration of Study 
Treatment
9 weeks 

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Phase II – atezolizumab and tiragolumab
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Duration of Follow 
up
2 years
Safety 
Assessments
For Cohort A: Frequency of all grade treatment-related toxicities 
according to NCI CTCAE v4.0
For Cohort B: Frequency of all grade treatment-related toxicities 
according to NCI CTCAE v5.0
Efficacy 
Assessments
Pathologic complete response rate (pT0N0), pathologic partial 
response rate (<pT2N0), median relapse-free survival and overall 
survival, 2 year relapse-free survival rate and overall survival rate
Unique Aspects of 
this Study
This is the first study to evaluate the safety and efficacy of 
atezolizumab-based neoadjuvant therapy prior to radical cystectomy in 
patients with muscle-invasive urothelial carcinoma who are either 
ineligible for or refusing cisplatin-based chemotherapy. Similarly it is 
the first study to provide a comprehensive characterization of the 
immunologic effects in the bladder tumor microenvironment of the 
neoadjuvant atezolizumab-based regimen      prior to radical 
cystectomy.

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Phase II – atezolizumab and tiragolumab
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1
List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATA
anti-therapeutic antibody
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CHO
Chinese hamster ovary
CI
Confidence interval
CIS
carcinoma in situ
CK
creatine kinase
CR
complete response
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DFS
disease-free survival
DLT
dose limiting toxicity
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
EBV
Epstein-Barr virus
ECG/EKG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLH
hemophagocytic lymphohistiocytosis
HR
hazard ratio
IB
Investigator’s Brochure

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Phase II – atezolizumab and tiragolumab
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ICF
informed consent form
ICH
International Conference on Harmonization
IRR
infusion-related reaction
IND
investigational new drug application
IRB
Institutional Review Board
IV
intravenous
ITT
intent-to-treat
LDH
lactate dehydrogenase
LFT
liver function test
MIBC
muscle-invasive bladder cancer 
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NK
natural killer
ORR
overall response rate
pCR
pathologic complete response 
PD
disease progression
PD-1
programmed death-1 receptor 
PD-L1
programmed death-1 ligand 
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PRC
Protocol Review Committee (UCSF)
PVR
poliovirus receptor
RFS
relapse-free survival
SD
stable disease
TBNK
T, B, and NK cells
TCC
transitional cell carcinoma
TIGIT
T cell immunoreceptor with Ig and ITIM domains
TSH
thyroid-stimulating hormone
UC
urothelial cancer
ULN
upper limit of normal 

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3
Table of Contents
Protocol Signature Page ............................................................................................................2
Protocol Signature Page – Participating Sites ...........................................................................3
Abstract
4
1
List of Abbreviations.......................................................................................................8
3
Table of Contents.........................................................................................................10
1
Introduction...................................................................................................................15
1.1
Background on Bladder Cancer...............................................................15
1.2
Treatment of Muscle Invasive Bladder Cancer (MIBC) .........................15
1.3
PD-L1 Immune Checkpoint Blockade.....................................................15
1.4
Background on Atezolizumab .................................................................16
1.4.1
Non-Clinical Pharmacokinetics and Metabolism and Toxicology ...............16
1.4.2
Toxicology and Safety Pharmacology..........................................................17
1.5
Clinical Studies of Atezolizumab ............................................................18
1.6
Background and Clinical Studies of Tiragolumab...................................19
1.7
Rationale for this Study ...........................................................................21
1.8
Rationale for the Study Design................................................................21
1.9
Correlative Studies...................................................................................23
2
Study Objectives ..........................................................................................................23
2.1
Primary Objectives and Endpoints ..........................................................23
2.2
Secondary Objective(s) and Endpoint(s).................................................24
2.3
Exploratory (Correlative) Objectives.......................................................25
3
Study Design................................................................................................................26
3.1
Characteristics..........................................................................................26
Cohort B Safety Lead-in Schema.............................................................................................28
3.2
Number of Participants............................................................................28
3.3
Eligibility Criteria....................................................................................29
3.3.1
Inclusion Criteria ..........................................................................................29
3.3.2
Exclusion Criteria .........................................................................................30
3.4
Duration of Treatment .............................................................................32
3.5
Duration of Follow Up.............................................................................33
3.6
Primary Completion.................................................................................33
3.7
Study Completion ....................................................................................33
4
Study Drugs..................................................................................................................33
4.1
Description, Supply and Storage .............................................................33
4.1.1
Atezolizumab ................................................................................................33
4.1.2
Tiragolumab..................................................................................................35
4.2
Accountability Records for Study Drug ..................................................36
4.3
Ordering Study Drugs..............................................................................36
5
Treatment Plan.............................................................................................................36
5.1
Dosage and Administration .....................................................................36

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5.1.1
Other Modalities or Procedures ....................................................................38
5.2
Cohort A Multi-dose Schedule ................................................................38
5.3
Cohort B Safety Lead-in Schedule ..........................................................39
5.4
Dose Limiting Toxicities (DLTs) ............................................................39
5.5
Interim Safety Analysis ...........................................................................39
5.6
Dose Modifications and Dosing Delays ..................................................40
5.7
Monitoring and Toxicity Management....................................................40
5.7.1
Eligibility ......................................................................................................40
5.7.2
Monitoring ....................................................................................................40
5.7.3
Management of General and Immune Related Adverse Events (irAEs) ......41
5.7.4
Management of Atezolizumab and Tiragolumab - Specific Adverse Events.41
5.7.4.1
Pulmonary Events........................................................................................................42
5.7.4.2
Hepatic Events.............................................................................................................43
5.7.4.3
Gastrointestinal Events ...............................................................................................45
5.7.4.4
Endocrine Events.........................................................................................................46
5.7.4.5
Ocular Events...............................................................................................................49
5.7.4.6
Immune-Related Myocarditis......................................................................................50
5.7.4.7
Infusion Related Reactions..........................................................................................51
5.7.4.8
Cytokine Release Syndrome........................................................................................52
5.7.4.9
Pancreatic Events ........................................................................................................55
5.7.4.10
Dermatologic Events ...............................................................................................57
5.7.4.11
Neurologic Disorders...............................................................................................58
5.7.4.12
Immune-Related Meningoencephalitis...................................................................59
5.7.4.13
Immune-Related Nephritis......................................................................................60
5.7.4.14
Immune-Related Myositis.......................................................................................62
5.7.4.15
Hemophagocytic lymphohistiocytosis and Macrophage Activation Syndrome......64
5.8
Concomitant Therapy ..............................................................................65
5.9
Excluded Therapy....................................................................................66
6
Study Schedule, Procedures and Observations ..........................................................67
6.1
Informed Consent Forms and Screening Log..........................................67
6.2
Medical History and Demographic Data .................................................68
6.3
Physical Examinations.............................................................................68
6.4
Vital Signs and Weight............................................................................68
6.5
Tumor Evaluation Methods .....................................................................69
6.6
Laboratory, Biomarker, and Other Biological Samples ..........................69
6.6.1
Local laboratory assessments........................................................................69
6.6.2
Central laboratory assessments.....................................................................70
6.7
Cardiac Tests: Electrocardiograms (ECGs).............................................72

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6.8
Anti-Therapeutic Antibody and atezolizumab and tiragolumab Testing.72
6.9
Study Schedule ........................................................................................73
6.9.1
Screening.......................................................................................................73
6.9.2
Treatment Period...........................................................................................74
6.9.3
End of Treatment (prior to cystectomy)........................................................75
6.9.4
Post-cystectomy/Follow Up Visits ...............................................................76
6.9.5
End of Study Visit.........................................................................................77
6.9.6
Long Term/Survival Follow-up Procedures .................................................79
6.9.7
Discontinuation of Therapy ..........................................................................79
6.9.8
Study Treatment Discontinuation .................................................................79
6.10
Study Calendar.........................................................................................81
7
Reporting and Documentation of Results ....................................................................85
7.1
Evaluation of Efficacy .............................................................................85
7.1.1
Pathologic Response .....................................................................................85
7.1.2
Antitumor Effect – Solid Tumors .................................................................85
7.1.2.1
Definitions ...................................................................................................................86
7.1.2.2
Disease Parameters.....................................................................................................86
7.1.2.3
Methods for Evaluation of Measurable Disease .........................................................87
7.1.2.4
Response Criteria ........................................................................................................87
7.2
Evaluation of Safety.................................................................................89
7.2.1
Specification of Safety Variables..................................................................89
7.2.2
Definitions of Adverse Events......................................................................89
7.2.2.1
Adverse Event..............................................................................................................89
7.2.2.2
Adverse reaction .........................................................................................................90
7.2.2.3
Suspected....................................................................................................................90
7.2.2.4
Unexpected .................................................................................................................90
7.2.2.5
Serious.........................................................................................................................91
7.3
Methods and Timing for Assessing AND Recording Safety variables ...91
7.4
Adverse Event Reporting Period .............................................................91
7.5
Procedures for Eliciting, Recording, and Reporting Adverse Events......92
7.5.1
Eliciting Adverse Events...............................................................................92
7.5.2
Specific Instructions for Recording Adverse Events....................................92
7.5.2.1
Diagnosis vs. Signs and Symptoms ..............................................................................92
7.5.2.2
Deaths .........................................................................................................................92
7.5.2.3
Preexisting Medical Conditions...................................................................................92
7.5.2.4
Hospitalizations for Medical or Surgical Procedures...................................................92
7.5.2.5
Pregnancy....................................................................................................................93
7.5.2.6
Post-Study Adverse Events..........................................................................................93

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7.5.2.7
Adverse Events of Special Interest (AESIs) ..................................................................93
7.5.2.8
Other Special Situations Reports.................................................................................94
7.5.2.9
Recording of an Adverse Event ...................................................................................95
7.6
Follow-up of Adverse Events ..................................................................95
7.7
Reporting Requirements for Pregnancies ................................................95
7.7.1
Pregnancies in Female Patients.....................................................................95
7.7.2
Pregnancies in Female Partners of Male Patients.........................................95
7.7.3
Congenital Anomalies/Birth Defects and Abortions ....................................96
7.8
Adverse Events Monitoring.....................................................................96
7.9
Expedited Reporting ................................................................................96
7.9.1
Reporting to the Data and Safety Monitoring Committee............................96
7.9.2
Reporting to UCSF Institutional Review Board ...........................................96
7.9.3
Expedited Reporting to the Food and Drug Administration.........................96
7.9.4
Expedited Reporting to Genentech ...............................................................97
7.9.5
Case Transmission Verification of Single Case Reports ..............................97
7.9.6
MedWatch 3500A Reporting Guidelines......................................................98
7.9.7
Follow-up Information..................................................................................98
7.9.8
7.9.8  Aggregate Reports ..............................................................................99
7.9.9
7.9.9 Study Close-Out           ........................................................................99
7.9.10
7.9.10 Queries..............................................................................................99
7.9.11
7.9.11 Safety Crisis Management................................................................99
7.9.12
7.9.12 Compliance with Pharmacovigilance Agreement/Audit ................100
8
Statistical Considerations and Evaluation of Results .................................................100
8.1
Determination of Sample Size and Power Calculation..........................100
8.2
Interim Analyses and Stopping Rules....................................................101
8.3
Analysis Plans........................................................................................101
8.3.1
Analysis Population ....................................................................................101
8.3.2
Analysis of Primary Endpoints ...................................................................101
8.3.2.1
pT0 rate .....................................................................................................................102
8.3.2.2
Safety.........................................................................................................................102
8.3.3
Analysis of Secondary Endpoints ...............................................................102
8.3.3.1
Near complete pathologic response rate, 2 year relapse-free survival, 2 year overall 
survival
102
8.3.3.2
PD-1/PD-L1 expression and response .......................................................................102
8.3.4
Analysis of Exploratory Endpoints: Tissue based endpoints......................103
8.3.4.1
Tumor PD-L1 assessment ..........................................................................................103
8.3.4.2
Tissue immune subset quantification and localization .............................................103
8.3.4.3
Immune cell mRNA signatures of response ..............................................................103
8.3.4.4
T cell receptor (TCR) deep sequencing......................................................................103
8.3.4.5
Genomic signatures of response...............................................................................103

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8.3.5
Analysis of Exploratory Endpoints: Immune endpoints.............................104
8.3.5.1
Immune cell activation..............................................................................................104
8.3.5.2
Circulating antibody detection and characterization ................................................104
9
Study Management ....................................................................................................104
9.1
Pre-study Documentation ......................................................................104
9.2
Institutional Review Board Approval....................................................105
9.3
Informed Consent ..................................................................................105
9.4
Changes in the Protocol.........................................................................105
9.5
Handling and Documentation of Clinical Supplies ...............................105
9.6
Case Report Forms (CRFs)....................................................................106
9.7
Oversight and Monitoring Plan..............................................................106
9.8
Multicenter communication...................................................................106
9.9
Record Keeping and Record Retention .................................................107
9.10
Coordinating Center Documentation of Distribution ............................107
9.11
Regulatory Documentation....................................................................108
10
Protection of Human Subjects....................................................................................108
10.1
Protection from Unnecessary Harm.......................................................108
10.2
Protection of Privacy .............................................................................108
11
References.................................................................................................................109

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1
Introduction
1.1
Background on Bladder Cancer
Urothelial cancer (UC) is the most common cancer of the urinary system worldwide with 
transitional cell carcinoma (TCC) being the predominant histologic type. It was estimated that in 
2013, there would be 72,570 new cases of bladder cancer and 15,210 deaths in the United 
States.1 Non-muscle invasive disease (stages Ta, T1, or carcinoma in situ (CIS)) accounts for 
approximately half of new diagnoses, muscle-invasive disease (stages T2-4) accounts for 
approximately 35% of new diagnoses, and metastatic disease accounts for the remainder. 
When confined to the bladder itself UC is a curable disease, although treatment approaches 
differ depending on the presence of muscle invasion as discussed below.
1.2
Treatment of Muscle Invasive Bladder Cancer (MIBC)
Although bladder tumors that are non-muscle invasive are treated with intravesical treatments 
such as BCG; due to the depth of invasion, intravesical treatments are inadequate for patients 
with muscle-invasive disease. Therefore, more definitive therapy is needed. Although 
concurrent chemoradiation may be used for patients who are not surgical candidates or for 
those desiring bladder preservation, radical cystectomy and bilateral pelvic lymphadenectomy is 
considered the standard of care. The addition of neoadjuvant cisplatin-based chemotherapy has 
been associated with both improved overall survival as well as a lower risk of recurrence.2 This 
was illustrated in a randomized Phase III study in which 3 cycles of neoadjuvant MVAC 
(methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy increased the pathologic T0 
rate from 15% to 38% (p<0.001) and was associated with a trend toward increased median 
survival (46 vs. 77 months, p=0.06) when compared to surgery alone.3 Importantly, in this study 
a pathologic complete response (pCR) to neoadjuvant therapy was associated with both a 
disease-free and an overall- survival benefit, suggesting that downstaging tumors prior to 
surgery may confer long term benefit. An analysis of 11 randomized trials of cisplatin-based 
neoadjuvant chemotherapy concluded neoadjuvant therapy confers a modest survival benefit 
(OS, hazard ratio [HR] for mortality 0.87, 95% CI 0.78-0.98) corresponding to an absolute 
survival benefit of 5%, and a modest reduction in the risk of recurrence (HR for recurrence 0.81, 
95% CI 0.74- 0.90), corresponding to an absolute disease-free survival benefit of 7%.2
Despite these benefits associated with chemotherapy prior to cystectomy, nationally less than 
20% of patients undergoing radical cystectomy for MIBC actually receive neoadjuvant therapy.4, 
5  Among concerns include advanced patient age, comorbidities, concerns over chemotherapy 
toxicity, and the modest nature of benefit from chemotherapy.6 Similarly there is no neoadjuvant 
standard of care for patients with marginal renal function, advanced hearing loss, or significant 
peripheral neuropathy that makes them ineligible for cisplatin therapy. Therefore, novel 
approaches for these patients are needed.
1.3
PD-L1 Immune Checkpoint Blockade
Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a significant 
survival benefit, and in recent years immunotherapeutic have been approved for multiple solid 
tumors including prostate cancer and melanoma.7-9
PD-L1 is an extracellular protein expressed on multiple tissues that downregulates immune 
responses primarily in peripheral tissues through binding to its two receptors PD-1 and B7.1. 
PD-1 is an inhibitory receptor expressed on T-cells following T-cell activation, which is

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sustained in states of chronic stimulation such as in chronic infection or cancer.10, 11  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.12, 13 
In cancer PD-L1 expression is prevalent in many human tumors, and overexpression of PD-L1 
on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion.10 
In UC elevated PD-L1 expression on tumor cells is associated with a increased pathologic 
stage, and PD-L1 expression predicts all causes-mortality after cystectomy for patients with 
organ-confined tumors.14, 15 
1.4
Background on Atezolizumab
Atezolizumab is a human immunoglobulin (IgG1) monoclonal antibody that is produced in 
Chinese hamster ovary (CHO) cells. It targets programmed death-ligand 1 (PD-L1) on antigen-
presenting cells or tumor cells and prevents interaction with programmed death−1 (PD-1) 
receptor, which is an inhibitory receptor expressed on T cells. Atezolizumab also blocks the 
interaction between PD-L1 and B7.1. Interference of the PD-L1:PD-1 and PD-L1:B7.1 
interactions may enhance the magnitude and quality of the tumor-specific T-cell response 
through increased T-cell priming, expansion, and/or effector function.
Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution at position 298 on the heavy chain, which results in a non-glycosylated antibody that 
has minimal binding to Fc receptors and, consequently, eliminates detectable Fc‑effector 
function.
1.4.1 Non-Clinical Pharmacokinetics and Metabolism and Toxicology
The pharmacology, pharmacokinetics, and toxicology of atezolizumab have been investigated in 
several nonclinical studies.  Atezolizumab binds to recombinant human and murine PD-L1 with 
subnanomolar affinity (Kd = 0.433 nM and 0.134 nM, respectively) and with comparable affinity 
to PD-L1 on cynomolgus monkey (Macaca fascicularis) T cells (50% effective concentration 
[EC50] = 0.704 nM).  Atezolizumab does not induce cytokine release from human peripheral 
blood mononuclear cells (PBMCs) following in vitro culture with immobilized or soluble 
atezolizumab. Two chimeric derivatives of atezolizumab (PRO304397, PRO314483) were 
generated to assess efficacy in mouse models with minimal interference of murine antibodies 
directed to human IgG.
Studies were conducted to assess the potential of PD-L1 blockade to enhance anti-tumor 
immunity when administered to mice with established tumors of colorectal and melanoma origin 
in three different genetic strains of mice. Anti−PD-L1 induced complete regression of 
immunogenic MC38 colorectal tumors and up to 60% overall responses in mice with unmodified 
established MC38 tumors. Tumor growth inhibition rates from 76% to 119% were observed and 
time to progression was increased by 1.75- to 3-fold in response to anti−PD-L1. Therefore, 
blockade of PD-L1 represents a compelling strategy for enhancing anti-tumor T-cell responses 
for the treatment of solid tumors.
In addition to the nonclinical tumor efficacy studies described above, the activity of anti−PD-L1 
was also evaluated in mouse infection models. Initial in vivo studies assessed the efficacy of 
atezolizumab in mice infected with lymphocytic choriomeningitis virus (LCMV). When anti−PD-

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L1 was administered during the chronic phase of LCMV CL-13 infection, the antibody was 
effective in enhancing T-cell function and reducing viral load without evidence of toxicity. 
However, blockade of PD-L1 at the peak of the acute T-cell response and concomitant peak 
viremia following LCMV CL-13 infection resulted in a mortality rate of 80%−100%. Published 
and internal data show that these mortalities are not unique to this molecule or pathway since 
similar mortalities are observed in this model with other PD-1 and PD-L1 inhibitors, as well as 
with IL-216. Rather, the data suggest that the mortalities observed in the acute CL-13 infection 
model are mediated by enhanced CD8+ T-cell function in the presence of extremely high viral 
burden in multiple organs thereby compromising vascular integrity leading to circulatory system 
collapse.17 The unique features of the murine CL-13 infection model contribute significantly to 
these deaths, and these features are not representative of the vast majority of viral infections 
that affect humans.
1.4.2 Toxicology and Safety Pharmacology
The toxicology program was designed to support clinical administration of Atezolizumab for up 
to 2 months when administered intravenously or subcutaneously to patients and consisted of 
the following:
●
A 15-day pilot study in mice
●
An 8-week repeat-dose study in cynomolgus monkeys
●
An in vitro hemolytic potential assay
●
A tissue cross-reactivity analysis of human and cynomolgus monkey 
tissues.
The mouse was considered the preferred rodent species in which to test the toxicity of 
Atezolizumab because the PD-L1/PD-1 pathway has been characterized more extensively in 
mice than in rats. The nonclinical efficacy studies were conducted in mice, as the known biology 
is more comparable to that in humans. Additionally, the availability of murine- specific reagents 
enabled an extensive immune response characterization. The pilot study demonstrated a high 
level of immunogenicity in mice. The immune response to Atezolizumab resulted in rapid drug 
clearance in a pilot mouse study in C57BL/6 and CD-1 mice, which would confound 
interpretation of immune system consequences of blocking PD-L1/PD-1 in a study of longer 
than 2 weeks; thus, the use of this species was precluded in studies of > 2 weeks for 
assessment of general toxicity. Because Atezolizumab binds to PD-L1 in cynomolgus monkeys 
and humans with comparable affinity, the cynomolgus monkey was chosen as the most 
appropriate species to assess the systemic toxicity of Atezolizumab. At necropsy, arteritis was 
observed in 3 animals at the 50 mg/kg dose and 1 animal at the 15 mg/kg dose. These 
histological findings were not associated with any clinical signs or symptoms. As no arteritis was 
found in animals treated with 5 mg/kg, this dose level was identified as the NOAEL. All other 
findings were considered incidental and not drug related. Overall, Atezolizumab was clinically 
well tolerated by cynomolgus monkeys at doses up to 50 mg/kg for 8 weeks (total of nine doses) 
(Study 08-1148).
The Phase I starting dose of 0.01 mg/kg was based on nonclinical PK/PD data that projected 
~80% receptor occupancy at the Cmax of this dose (unpublished data) and was supported by 
the toxicology data. On the basis of this starting dose, a safety factor of 160-fold based on BSA 
was determined as it relates to the NOAEL of 5 mg/kg in the 8-week, repeat dose GLP toxicity 
study in cynomolgus monkeys.

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1.5
Clinical Studies of Atezolizumab
There are multiple ongoing studies of Atezolizumab, and it has received accelerated FDA 
approval for the treatment of urothelial cancer. Details of all studies may be found in the 
Atezolizumab Investigator’s Brochure (IB). Briefly, in patients with metastatic disease, the 
IMvigor 210 study18 enrolled 310 subjects with inoperable locally advanced or metastatic 
urothelial carcinoma whose disease had progressed after previous platinum-based 
chemotherapy. These patients received atezolizumab 1200mg IV every 3 weeks. The PD-L1 
expression status on infiltrating immune cells (ICs) in the tumor microenvironment was defined 
by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 
(≥5%). The primary analysis showed that compared with a historical control overall response 
rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 
objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19–37], 
p<0·0001; IC1/2/3: 18% [13–24], p=0·0004) and in all patients (15% [11–20], p=0·0058). With 
longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates 
were 26% (95% CI 18–36) in the IC2/3 group, 18% (13–24) in the IC1/2/3 group, and 15% (11–
19) overall in all 310 patients. With a median follow-up of 11.7 months (95% CI 11·4–12·2), 
ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed 
The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive 
for response to atezolizumab. Grade 3–4 treatment-related adverse events, of which fatigue 
was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 
3–4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with 
pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, 
and dyspnea being the most common. No treatment-related deaths occurred during the study. 
Similar studies including IMvigor 211 and SAUL have demonstrated comparable results. 
In the neoadjuvant setting one study in addition to this trial explored the value of atezolizumab 
as monotherapy. The ABACUS study19 was an open-label, international, multicenter, single-
arm, neoadjuvant phase 2 trial evaluating the effects of two cycles (1,200 mg, three times 
weekly) of preoperative atezolizumab in patients with histologically confirmed (T2–T4aN0M0) 
transitional cell UC of the bladder, awaiting planned radical cystectomy. Additional eligibility 
criteria included residual disease after TURBT, adequate fitness for planned cystectomy 
(according to local guidelines), ineligibility for or refusal of cisplatin-based neoadjuvant 
chemotherapy, no evidence of nodal or metastatic disease on cross-sectional imaging, ECOG 
performance status of 0 or 1, and adequate hematologic and end-organ function within 4 weeks 
of the first study treatment. Major exclusion criteria included evidence of significant uncontrolled 
concomitant disease that could affect compliance with the protocol or interpretation of results, 
previous autoimmune disease, ongoing active infections or prior use of immune checkpoint 
inhibitors. Pathological complete response was the primary endpoint. Secondary endpoints 
focused on safety, relapse-free survival and biomarker analysis. The pathological complete 
response rate was 31% (95% confidence interval: 21–41%). Baseline biomarkers showed that 
the presence of preexisting activated T cells was more prominent than expected and correlated 
with outcome. Other established biomarkers, such as tumor mutational burden, did not predict 
outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression 
signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations 
with treatment were uncommon. Responding tumors showed predominant expression of genes 
related to tissue repair after treatment, making tumor biomarker interpretation challenging in this 
group. Stromal factors such as transforming growth factor-β and fibroblast activation protein 
were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

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A similarly designed study, the PURE-01 trial20, also accrued patients with MIBC to receive 
neoadjuvant PD-1 checkpoint inhibition. Patients had a predominant urothelial carcinoma 
histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab (a 
PD-1 inhibitor) 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat 
population was pathologic complete response (pT0). Biomarker analyses included programmed 
death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 
pharmDx assay), genomic sequencing, and an immune gene expression assay. Fifty patients 
were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 
21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 
transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 
21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to 
<pT2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with 
PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of 
those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation 
burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several 
genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. 
Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune 
resistance were observed in residual tumors.
1.6
Background and Clinical Studies of Tiragolumab
Tiragolumab is a fully human immunoglobulin G1 (IgG1)/kappa mAb derived in Open 
Monoclonal Technology (OMT) rats that binds T-cell Immunoreceptor with Immunoglobulin and 
Immunoreceptor Tyrosine-Based Inhibition Motif [ITIM] domains (TIGIT) and prevents its 
interaction with the poliovirus receptor (PVR). The recombinant antibody is produced in Chinese 
hamster ovary (CHO) cells and consists of two heavy chains (456 amino acid residues each) 
and two light chains (220 amino acid residues each). 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of tumor-
associated lymphocytes. TIGIT is an immunoglobulin (Ig) super family member expressed on 
subsets of activated T cells and natural killer (NK) cells, and found highly expressed in tumor 
tissue and in tumor-infiltrating immune cells in many human cancers, including, but not limited to 
NSCLC, breast cancer, multiple myeloma, and non-Hodgkin lymphoma. In multiple tumor types, 
TIGIT is coordinately expressed with PD-121-23. Genetic ablation or antibody blockade of TIGIT 
has been shown to enhance NK cell killing, CD4 and CD8 T-cell activation, and effector 
function in vitro and in vivo in nonclinical models.21, 22, 24, 25 In the nonclinical tumor models, 
TIGIT interacted with high affinity to CD155 (also known as PVR), which also has an activating 
counter-receptor CD226. Activation of TIGIT on T cells and NK cells was demonstrated to limit 
proliferation, effector cytokine production, and killing of target tumor cells.21, 22, 24
Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for cancer 
therapy and is expected to enhance the magnitude and quality of the tumor-specific T-cell 
responses, which may result in improved meaningful anti-tumor activity when tiragolumab is 
used in combination with other cancer immunotherapies and administered with chemotherapy. 
The available nonclinical and clinical data provide a strong rationale for evaluating the potential 
clinical benefit of tiragolumab in cancer patients. Refer to the tiragolumab Investigator’s 
Brochure for details on nonclinical studies. 
Clinically study GO3010326 is a first-in-human, open-label, multicenter, global, dose-
escalation/dose-expansion Phase I study designed to evaluate the safety, tolerability, and 
pharmacokinetics of tiragolumab as a single agent (Phase Ia) and in combination with 

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atezolizumab (Phase Ib) in patients with locally advanced, recurrent, or metastatic incurable 
tumors, including urothelial cancer, renal cell cancer, NSCLC, head and neck squamous cell 
carcinoma, esophageal cancer, colorectal cancer (CRC), gastric cancer, cholangiocarcinoma, 
and triple-negative breast cancer. 
As of the data cutoff date of 3 December 2018, 42 patients had received tiragolumab 
monotherapy at doses of 2−1200 mg, and 164 patients had received tiragolumab at doses of 
2−600 mg in combination with 1200-mg atezolizumab. The best observed response with 
tiragolumab monotherapy was prolonged stable disease in 8 of 42 patients, with some patients 
(including 1 patient with CRC) experiencing a decrease in tumor size. Among 164 patients 
receiving tiragolumab in combination with atezolizumab, a complete response was observed in 
3 patients (including 1 patient with esophageal cancer), a partial response was observed in 22 
patients (including patients with esophageal cancer), and stable disease was observed in 38 
patients. Among 4 patients with urothelial cancer receiving tiragolumab in combination with 
atezolizumab, a confirmed partial response was observed in 3 patients. 
No maximum tolerated dose, dose-limiting toxicities (DLTs), or clear dose-related trends in the 
incidence or severity of adverse events have been determined for tiragolumab as a single agent 
or in combination with atezolizumab. A fatal case of hepatic toxicity culminating in fulminant liver 
failure occurred in a patient with metastatic head and neck cancer receiving single-agent 
tiragolumab at the highest dose cleared for enrollment (1200 mg) (see the tiragolumab IB for 
details). No other fatal cases of fulminant liver failure have been observed. 
Overall, tiragolumab as a single agent or in combination with atezolizumab has been well 
tolerated, adverse events have been manageable, and the safety profile is observed to be 
consistent across different solid tumor indications. 
A second study GO4029027 is a global, multicenter, randomized, blinded, placebo-controlled 
Phase II study designed to evaluate the safety and efficacy of tiragolumab plus atezolizumab 
compared with placebo plus atezolizumab in patients with previously untreated, locally 
advanced unresectable, or metastatic PD-L1−selected NSCLC. 
As of the primary clinical cutoff date of 30 June 2019, a total of 135 patients with a PD-L1 TPS ≥ 
1% were included in the intent-to-treat (ITT) population and were randomly assigned to receive 
tiragolumab plus atezolizumab (n  67) or placebo plus atezolizumab (n  68). Of the enrolled 
patients, 43.0% of patients had a TPS ≥ 50% relative to 57.0% of patients with a TPS 1%−49%, 
59.3% had non-squamous histology compared with 40.7% of patients who had squamous 
histology, and 10.4% of patients were never- smokers versus 89.6% who had smoked. These 
three stratification factors were well balanced between treatment groups. Demographics were 
also generally well balanced between treatment groups, with a median age of 68 years in both 
the tiragolumab plus atezolizumab and placebo plus atezolizumab arms. There were more 
females (41.8% vs. 29.4%) and more White patients (62.7% vs. 58.8%) in the tiragolumab plus 
atezolizumab arm compared with the placebo plus atezolizumab arm. 
In the ITT population, the confirmed ORR was higher in the tiragolumab plus atezolizumab arm 
(31.3%) than in the placebo plus atezolizumab arm (16.2%). In the subgroup of patients with 
TPS ≥ 50%, the confirmed ORR was higher in the tiragolumab plus atezolizumab arm (n  29; 
55.2% [95% CI: 35.4%, 75.0%]) than the placebo plus atezolizumab arm (n  29; 17.2% [95% 
CI: 1.8%, 32.7%]). Of note, responders in the tiragolumab plus atezolizumab arm included 
patients with both squamous and non-squamous histology. 

 U C S F H el e n Dill er F a mil y C o m pr e h e n si v e C a n c er C e nt er
V er si o n d at e: 0 3- 2 9- 2 0 2 1
Pr ot o c ol C C #: 1 4 5 2 4
P h a s e II – at e z oli z u m a b a n d tir a g ol u m a b
 P a g e 2 1 of 1 2 1
I n t h e I T T p o p ul ati o n, i n v e sti g at or- a s s e s s e d P F S w a s i m pr o v e d i n t h e tir a g ol u m a b pl u s 
at e z oli z u m a b gr o u p o v er t h e pl a c e b o pl u s at e z oli z u m a b gr o u p ( str atifi e d H R 0. 5 7  [ 9 5 % CI: 
0. 3 7, 0. 9 0]; m e di a n P F S 5. 4 v s. 3. 6 m o nt h s, r e s p e cti v el y). I n t h e s u b gr o u p of p ati e nt s wit h T P S 
≥ 5 0 %, i n v e sti g at or- a s s e s s e d P F S w a s i m pr o v e d i n t h e tir a g ol u m a b pl u s at e z oli z u m a b gr o u p 
o v er t h e pl a c e b o pl u s at e z oli z u m a b gr o u p ( u n str atifi e d H R  0. 3 3 [ 9 5 % CI: 0. 1 5, 0. 7 2]; m e di a n 
P F S n ot e sti m a bl e ( N E) v s. 3. 9 m o nt h s, r e s p e cti v el y) ( R o c h e u n p u bli s h e d d at a o n fil e). 
T o d at e, m o st a d v er s e e v e nt s h a v e b e e n Gr a d e 1 or Gr a d e 2. S eri o u s a d v er s e e v e nt s, Gr a d e 
3 −5  a d v er s e e v e nt s, a d v er s e e v e nt s l e a di n g t o di s c o nti n u ati o n, a n d a d v er s e e v e nt s l e a di n g t o 
d e at h h a v e b e e n b al a n c e d b et w e e n t h e t w o tr e at m e nt ar m s. S eri o u s a n d hi g h- gr a d e tr e at m e nt-
r el at e d a d v er s e e v e nt s h a v e al s o b e e n b al a n c e d b et w e e n t h e t w o tr e at m e nt ar m s. I m m u n e-
m e di at e d a d v er s e e v e nt s w er e b al a n c e d b et w e e n t h e t w o tr e at m e nt ar m s, wit h t h e e x c e pti o n of 
a hi g h er fr e q u e n c y of i nf u si o n-r el at e d r e a cti o n a n d r a s h r e p ort e d i n t h e at e z oli z u m a b pl u s 
tir a g ol u m a b ar m. Di s c o nti n u ati o n d u e t o a d v er s e e v e nt s w a s l o w ( a p pr o xi m at el y 6 % i n b ot h 
ar m s). A f at al c a s e of E p st ei n- B arr vir u s ( E B V) r e a cti v ati o n a n d p o s si bl e s e c o n d ar y 
h e m o p h a g o c yti c l y m p h o hi sti o c yt o si s ( H L H) w a s r e p ort e d i n St u d y G O 4 0 2 9 0 i n a 6 9- y e ar- ol d 
m al e i n T ai w a n wit h m et a st ati c l y m p h o e pit h eli o m a-li k e c ar ci n o m a s u bt y p e of N S C L C ( P D- L 1 
p o siti v e), w hi c h c a n b e a s s o ci at e d wit h E B V i nf e cti o n i n A si a n p ati e nt s. 
O v er all, tir a g ol u m a b i n c o m bi n ati o n wit h at e z oli z u m a b h a s b e e n w ell t ol er at e d, a d v er s e e v e nt s 
h a v e b e e n m a n a g e a bl e, a n d t h e s af et y pr ofil e s e e m s t o b e c o n si st e nt a s r e p ort e d a cr o s s 
diff er e nt s oli d t u m or i n di c ati o n s. 
R ef er t o t h e tir a g ol u m a b I n v e sti g at or’ s Br o c h ur e f or a d diti o n al d et ail s o n all o n g oi n g a n d 
pl a n n e d cli ni c al st u di e s. 
1. 7
R ati o n al e f or t hi s St u d y
B a s e d o n t h e r e s ult s of t h e A B A C U S, P U R E- 0 1, CI T Y S C A P E tri al s a n d o ur u n p u bli s h e d d at a 
o n cli ni c al o ut c o m e s fr o m t h e i niti al m o n ot h er a p y tr e at m e nt c o h ort, it a p p e ar s t h at t h er e i s 
si g nifi c a nt cli ni c al a cti vit y of b ot h of t h e s e a g e nt s, i n cl u di n g i n di c ati o n s of p ot e nti al s y n er g y, wit h 
a c c e pt a bl e ri s k s. Gi v e n t h e n e e d f or n o v el t h er a pi e s t o i m pr o v e o ut c o m e s f or p ati e nt s wit h 
MI B C i n eli gi bl e f or ci s pl ati n- b a s e d c h e m ot h er a p y, t hi s st u d y off er s a p ot e nti all y t h er a p e uti c 
o pti o n. It will a d diti o n all y pr o vi d e a w e alt h of c orr el ati v e bi ol o gi c a n d i m m u n ol o gi c d at a t o b ett er 
u n d er st a n d t h e m e c h a ni s m( s) b y w hi c h t h e s e t h er a pi e s w or k a n d i d e ntif y pr o g n o sti c a n d 
pr e di cti v e bi o m ar k er s. 
1. 8
R ati o n al e f or t h e St u d y D e si g n 
T hi s st u d y will e v al u at e t h e p at h ol o gi c a n d i m m u n ol o gi c c h a n g e s i n d u c e d b y at e z oli z u m a b-
b a s e d t h er a p y i n bl a d d er ti s s u e s c o m p ar e d t o pr etr e at m e nt bi o p si e s. T hi s st u d y h a s t w o c o h ort s 
( C o h ort A a n d C o h ort B) a n d will a c cr u e e a c h c o h ort s e q u e nti all y (i. e., C o h ort A will f ull y a c cr u e, 
t h e n C o h ort B).
C o h ort A: At e z oli z u m a b M o n ot h er a p y 
I n t h e i niti al m o n ot h er a p y m ulti- d o s e p h a s e ( C o h ort A), t h e eff e ct s of i n cr e a si n g n u m b er s of 
d o s e s of at e z oli z u m a b will b e e x pl or e d. Si mil arl y, t h e s af et y, f e a si bilit y, a n d effi c a c y of 
a d mi ni st eri n g u p t o 3 d o s e s of at e z oli z u m a b i n p ati e nt s s c h e d ul e d f or c y st e ct o m y will al s o b e 
e x a mi n e d. 

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●
Multi-dose phase (fully accrued as of October 2020): A fixed number of 6 
patients will be accrued at each dose level in the multi-dose portion of the 
study to allow for investigation into the immunologic impact of different 
cumulative doses of atezolizumab prior to cystectomy. It is unknown 
whether multiple doses of atezolizumab are necessary to achieve a 
complete response or a durable remission as opposed to a single dose, 
and accrual of 6 patients at each dose level will allow for a preliminary 
estimate of the efficacy of each cumulative dose level. The safety profile 
of atezolizumab is well established from multiple Phase I - III studies, and 
treatment related Grade 3 or 4 toxicities were rare. The multi- dose 
portion may better inform future studies of neoadjuvant atezolizumab and 
potentially allow for shorter neoadjuvant courses to be administered.
●
Cohort A expansion phase opened after the multi-dose portion of Cohort 
A completed, consisting of up to 27 total patients in Cohort A. In order to 
reduce the number of subjects needed for this study and allow for faster 
study completion, the 6 subjects treated at the highest dose from the 
multi-dose phase of the study will be included as part of the expansion 
cohorts, therefore the total accrual to the expansion cohort after the multi-
dose portion of Cohort A will be up to 9 subjects. The highest dose level 
is chosen for the expansion cohorts as it is expected that administration 
of multiple doses of atezolizumab will best enhance immune responses 
and lead to better clinical responses. These expansion cohorts will allow 
for a better estimate that treatment-related grade 3 or 4 events, or delays 
in cystectomy >12 weeks, are observed at a frequency of less than 
<33%. It will also allow for an exploratory estimation of efficacy of 
atezolizumab in this setting, and for further characterization of the 
immunologic effects of atezolizumab in this patient population.
Cohort B: Atezolizumab + Tiragolumab
After completion of enrollment into Cohort A, and upon approval of Amendment 4.3 (October 19, 
2020) the study will begin accrual into Cohort B, where participants will receive combination 
neoadjuvant therapy with atezolizumab (1200mg IV on Day 1 of a 21 day cycle) and 
tiragolumab (600mg IV on Day 1 of a 21 day cycle) as neoadjuvant treatment for an intended 
total of three treatment cycles prior to an intended radical cystectomy. Similar to Cohort A, the 
safety and efficacy of administering up to 3 doses of atezolizumab in combination with 
tiragolumab preoperatively in patients scheduled for cystectomy will be examined. No adjuvant 
therapy will be offered as no study to date has shown benefit for adjuvant PD-1 therapy in 
urothelial cancer patients who had received prior immunotherapy.28 Recently Checkmate-274 
study had a press release indicating a DFS benefit for nivolumab over placebo for high-risk 
patients with urothelial cancer following radical cystectomy however none of these patients have 
had prior neoadjuvant immunotherapy.
●
Safety Lead-in: As adding tiragolumab together with atezolizumab in 
patients with NSCLC generates only minimal additive toxicity, this study 
will start with an initial safety lead-in of 6 patients at which time enrollment 
will pause to assess the safety of this combination treatment. If dose 
limiting toxicities are met (certain AEs or surgery delay, as defined in 
Section 5.4) then fewer doses of tiragolumab will be evaluated (See 
Cohort B Safety Lead-in Schema). 

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●
Expansion: Once the intended treatment regimen is established following 
completion of the safety assessment, an additional 15 patients will be 
enrolled at the same regimen for a total of 21 patients on that treatment 
regimen.
1.9
Correlative Studies
In addition to evaluating the change in immunologic infiltration in tumor tissues induced by study 
therapy, the safety, toxicity, and efficacy of neoadjuvant atezolizumab-based therapy, this study 
aims to more thoroughly characterize the immunologic response induced by treatment with 
study therapy.
More specifically, bladder tissue taken at the time of surgery and peripheral blood will be 
analyzed immunohistochemically and genomically in order to:
1.
Characterize the tumor and immune cell subsets
2.
Explore the location of tumor infiltration lymphocytes (e.g. within tumors, at tumor 
periphery)
3.
Characterize T cell receptor diversity
4.
Explore the correlation of tumor PD-L1 expression across different grades and stages of 
disease with response to therapy.
In addition, serum and blood will be analyzed to determine whether antigen-specific immune 
responses are modulated and to quantify and characterize circulating immune cell subsets.
2
Study Objectives 
2.1
Primary Objectives and Endpoints
Cohort A (Atezolizumab monotherapy):
1.
Multi-dose cohorts: To assess the intratumoral immune response associated with 
increasing numbers of Atezolizumab treatments. 
●
Endpoint: CD3+ T cell count/µm2 between the pretreatment biopsy and 
the cystectomy tissue following single and multiple neoadjuvant 
Atezolizumab infusions.
2.
Expansion cohort: To assess the anti-tumor activity of Atezolizumab as determined by the 
pathologic T0 rate (pT0N0) at the time of cystectomy.
●
Endpoint: Pathologic T0 rate at the time of cystectomy, defined as the 
pathologic absence of disease in the bladder after resection (See section 
7.1.1).
Cohort B (Atezolizumab + tiragolumab)

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1.
To assess the safety of neoadjuvant combination treatment with atezolizumab and 
tiragolumab according to CTCAE v5.0 in a curative intent treatment population of 
urothelial carcinoma patients undergoing radical cystectomy.
●
Endpoint: The percentage of patients in Cohort B with treatment-related 
adverse events according to CTCAE v5.0 or treatment-related delays in 
surgery beyond 12 weeks following administration of neoadjuvant 
treatment with atezolizumab and tiragolumab.  
2.
To assess the anti-tumor activity of Atezolizumab + Tiragolumab as determined by the 
pathologic T0 rate (pT0N0) at the time of cystectomy.
●
Endpoint: Pathologic T0 rate at the time of cystectomy, defined as the 
pathologic absence of disease in the bladder after resection (See section 
7.1.1).
2.2
Secondary Objective(s) and Endpoint(s)
Cohorts A and B
Multi-Dose Cohorts
1.
To evaluate the safety and feasibility of administering up to 3 cycles of Atezolizumab pre-
operatively to patients with resectable urothelial bladder cancer. Note this is the coprimary 
objective for Cohort B.
●
Endpoint: The percentage of patients with treatment-related adverse 
events according to CTCAE v5.0 or treatment-related delays in surgery 
beyond 12 weeks following administration of neoadjuvant treatment with 
atezolizumab with or without tiragolumab. Note for Cohort A CTCAE v4.0 
was used.   
Expansion Cohorts
1.
To assess the anti-tumor activity of neoadjuvant treatment as determined by pathologic 
partial response (<pT2N0) assessed at the time of radical cystectomy
●
Endpoint: Percentage of patients with pathologic downstaging (<pT2N0) 
at the time of radical cystectomy
2.
To determine the 2-year relapse-free survival (RFS) rate and median RFS from time of 
radical cystectomy in patients treated with neoadjuvant therapy
●
Endpoint: 2-year RFS rate and median RFS in ITT population
3.
To determine the 2-year overall survival (OS) and median OS from time of radical 
cystectomy in patients treated with neoadjuvant therapy
●
Endpoint: 2-year OS rate and median OS in ITT population
4.
To assess the intratumoral immune response of neoadjuvant by comparing pre-treatment 
TURBT with post-treatment cystectomy tumor specimens

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●
Endpoint: Association of tumor and T-cell PD-L1/PD-1 
immunohistochemical expression with disease response
2.3
Exploratory (Correlative) Objectives
1.
To define the immunologic infiltration within bladder tissue following administration of 
neoadjuvant combination treatment with atezolizumab and tiragolumab when compared to 
pre-treatment TURBT biopsies
2.
To assess the immunologic impact of combined tiragolumab and atezolizumab regimen in 
the urothelial cancer tumor microenvironment (Cohort B) in comparison to the impact on 
the tumor microenvironment of atezolizumab monotherapy in a similar cohort of patients 
treated with neoadjuvant atezolizumab for MIBC at UCSF (Cohort A)
3.
To assess for tumor-based biomarkers of response and resistance to this combination 
therapy using single-cell RNA sequencing (scRNA-seq) and high-dimensional flow 
cytometry
4.
To define the treatment-induced effects on circulating immune cells with this combination 
therapy
5.
To assess the presence of antigen-specific immune responses to a broad panel of 
candidate tumor antigens
Endpoints: 
●
Immunohistochemistry and gene expression analysis for immune cell 
subset quantification and localization within resected tumors, in particular 
through the comparison of intratumoral environment of post-treatment 
cystectomies to pre-treatment TURBTs
●
Flow cytometry to evaluate changes in intratumoral and circulating 
immune cells
●
T cell receptor (TCR) deep sequencing of tissue samples from pre-
treatment biopsies and post-treatment resected tissues, and post-
cystectomy circulating T cells.
●
Immune response mRNA expression analysis to derive signatures 
associated with tumor response
●
Identification of genomic mutations and gene copy aberrations associated 
with response and resistance to therapy
●
Antigen array-base detection of circulating antibody responses
●
Flow cytometry to evaluate changes in intratumoral and circulating 
immune cells
●
T cell receptor (TCR) deep sequencing of tissue samples from pre-
treatment biopsies and post-treatment resected tissues, and post-
cystectomy circulating T cells.
●
Immune response mRNA expression analysis to derive signatures 
associated with tumor response (expansion only)

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●
Identification of genomic mutations and gene copy aberrations associated 
with response and resistance to therapy (expansion only)
●
Antigen array-base detection of circulating antibody responses 
(expansion only)
3
Study Design
3.1
Characteristics
This is a single arm, open-label multiple-cohort Phase II study of atezolizumab-based 
neoadjuvant therapy in subjects with muscle-invasive bladder cancer appropriate for cystectomy 
and refusing or ineligible for neoadjuvant cisplatin-based chemotherapy. This study has two 
cohorts (Cohort A and Cohort B) and will accrue each cohort sequentially (i.e., Cohort A will fully 
accrue, then Cohort B). Cohort A participants will receive neoadjuvant atezolizumab 
monotherapy and Cohort B participants will receive combination neoadjuvant treatment with 
atezolizumab and tiragolumab. As of October 2020, Cohort A has finished dose escalation and 
is in dose-expansion. 
Following the administration of all intended neoadjuvant treatment regimen, participants will 
undergo cystectomy to evaluate pathologic response to treatment and for immunologic 
characterization in the resected tissue. Surgery should be performed within 12 weeks from the 
start of neoadjuvant treatment. Any treatment-related delays that put the surgery outside of this 
window will be considered an adverse event.
Serum and urine will be obtained as well to characterize circulating immune responses. Patients 
will be followed clinically for up to 2 years to assess for disease recurrence.
While adjuvant Atezolizumab was initially offered to patients in Cohort A who had pT3/pT4 or 
pN+ disease, given the lack of efficacy of adjuvant atezolizumab observed in the IMvigor 010 
trial, no further adjuvant therapy will be offered to patients.
Cohort A (Atezolizumab monotherapy) 
●
Multi-dose phase (fully accrued): Enrolled patients will be assigned sequentially to 
atezolizumab dose levels in cohorts of 6 patients per dose level. The starting dose level 
is 1200mg x 1 dose and will be escalated in subsequent cohorts to 1200mg q 3 weeks x 
2 doses, and finally 1200mg q 3 weeks x 3 doses.
●
Expansion phase: After completion of the multi-dose phase, Cohort A expansion will 
open and up to 27 enrolled participants will receive atezolizumab 1200mg q 3 weeks x 3 
doses prior to cystectomy.

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Cohort B (Atezolizumab + tiragolumab)
After completion of Cohort A, Cohort B will open and enrolled patients will receive atezolizumab 
(1200mg IV on Day 1 of a 21 day cycle) and tiragolumab (600mg IV on Day 1 of a 21 day cycle) 
as neoadjuvant treatment for an intended total of three treatment cycles prior to an intended 
radical cystectomy. 
●
Safety Lead-in (see schema below): 
o
Dose Level 1 (Atezolizumab 1200 mg x 3 cycles, Tiragolumab 600 mg x 3 
cycles): There will be an initial safety lead in of 6 patients treated with this 
regimen, at which time enrollment will pause to assess the safety of this 
combination treatment. As long as no more than 1 out of the initial 6 patients 
experience dose limiting toxicities (DLTs) or a delay in the time to radical 
cystectomy, the remaining patients will enroll at the same dose and regimen. 
▪
If two or more patients out of the initial six experience DLTs within the 
first  cycle (3 weeks), accrual will be halted and the combination 
reevaluated.
▪
If two or more patients out of the initial six experience DLTs within the 
first 2 cycles (6 weeks), accrual to this dose level will be halted and 
we will move to dose level 3.
▪
If two or more patients out of the initial six experience DLTs or delay 
in the time to radical cystectomy, and no more than 1 patient 
experienced DLTs during the first 2 cycles (6 weeks), the next six 
patients will be treated at dose level 2
o
Dose Level 2 (Atezolizumab 1200 mg x 3 cycles, Tiragolumab 600 mg x 2 
cycles): As long as no more than 1 out of 6 patients experience DLTs or a 
delay in the time to radical cystectomy with this treatment, the remaining 
patients will enroll at the same dose and regimen. 
▪
If two or more patients out of the six patients experience DLTs within 
the first cycle (3 weeks), accrual will be halted and the combination 
reevaluated.
▪
If two or more patients out of the six experience DLTs or delay in the 
time to radical cystectomy, and no more than 1 patient experienced 
DLTs during the first cycle (3 weeks),  the next six patients will be 
treated at dose level 3 
o
Dose Level 3 (Atezolizumab 1200 mg x 3 cycles, Tiragolumab 600 mg x 1 
cycle): This will be the selected regimen if no more than 1 out of 6 patients 
experience DLTs or a delay in the time to radical cystectomy. However if 2 or 
more patients experience DLTs or a delay in the time to radical cystectomy 
with this combination regimen, then accrual will be halted and the 
combination reevaluated. 
●
Expansion: Once the intended treatment regimen is established following completion of 
the safety assessment, an additional 15 patients will be enrolled at the same regimen for 
a total of 21 patients on that treatment regimen.

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Cohort B Safety Lead-in Schema
3.2
Number of Participants
Total Cohort A accrual: Up to 27 participants
●
Cohort A Safety Lead-In: 18 participants (already accrued as of October 2020)
●
Cohort A Expansion: Up to 9 additional participants may be accrued so that Cohort A 
expansion group = up to 15 total participants treated at established regimen (6 
participants treated at highest administered dose from multi-dose portion + up to 9 
additional participants).
Total Cohort B accrual: 21-33 patients
●
Cohort B Safety Lead-In: 6-18 patients will be included.
●
Cohort B Expansion: 15 additional patients treated with the regimen established during 
the safety lead-in phase (21 total treated with established regimen)
Enroll 6 patients at Dose Level 1
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 3 cycles
≤1 pt has DLT or 
surgery delay
Enroll 15 pts at Dose Level 1
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 3 cycles
≥2 pts have DLT (≤ 1 within 
first 2 cycles) or surgery delay
Enroll 6 pts at Dose Level 2
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 2 cycles
≥2 pts have DLT (≤ 1 within 
first cycle) 
≤1 pt has DLT or 
surgery delay
Enroll 15 pts at Dose Level 2
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 2 cycles
Enroll 6 pts at Dose Level 3
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 1 cycle
≥2 pts have DLT or 
surgery delay
≤1 pt has DLT or 
surgery delay
Enroll 15 pts at Dose Level 3
Atezo 1200 mg x 3 cycles
Tiragolumab 600 mg x 1 cycle
Halt accrual and 
reevaluate combination 
treatment
Halt accrual and 
reevaluate 
combination treatment
Halt accrual and 
reevaluate 
combination treatment
≥2 pts have DLT within first 
cycle 
≥2 pts have DLT within 
first cycle or surgery delay 
≥2 pts have DLT within first 
2 cycles 

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3.3
Eligibility Criteria
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.
3.3.1 Inclusion Criteria
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1.
18 years of age or older
2.
ECOG performance status 0-1
3.
Histologically documented transitional cell carcinoma with the presence of any of the 
following stages: grade cT2-T4a, considered appropriate for radical cystectomy. Subjects 
with mixed histology are required to have a dominant TCC pattern.
4.
Patients not suitable for neoadjuvant cisplatin-based chemotherapy as determined by the 
following:
a.
Creatinine clearance less than 60ml/min. GFR should be assessed by calculation 
from serum/plasma creatinine (Cockcroft-Gault formula)
b.
CTCAE Gr >/= 2 hearing loss
c.
CTCAE Gr >/= 2 neuropathy
5.
Subjects with MIBC not meeting the above criteria are still eligible provided the patient 
declines neoadjuvant cisplatin-based chemotherapy, after specific informed consent 
describing the known benefits of cisplatin-based chemotherapy. The reason for declining 
must be documented.
6.
Adequate bone marrow function defined as:
a.
WBC > 2500 cells/mm3
b.
ANC > 1500 cells/mm3
c.
Hemoglobin > 9 g/dL. Patients may be transfused or receive erythropoietic 
treatment to meet this criterion.
d.
Platelet count > 100,000 cells/mm3
7.
Adequate renal function: Calculated CrCl > 30ml/min
8.
Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert’s disease)

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9.
AST and ALT < 2.5 x ULN
10. Ability to understand and willingness to sign a written informed consent.
11. Have available evaluable archival tumor tissue for PD-L1 biomarker assessment. 
Presence of PD-L1 antigen on tumors is NOT required for study entry.
12. The effects of atezolizumab or tiragolumab on the developing human fetus are unknown. 
For this reason women of child-bearing potential and men must agree to use adequate 
contraception prior to study entry, during study participation, and for 5 months after study 
treatment discontinuation. Should a woman become pregnant or suspect she is pregnant 
while she or her partner is participating in this study, she should inform her treating 
physician immediately. Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study participation, and for 90 
days after completion of study drug administration.
3.3.2 Exclusion Criteria
Individuals who meet any of the following criteria are not eligible to participate in this study:
1.
Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the 
bladder are not allowed.
2.
Known distant metastatic disease (e.g. pulmonary or hepatic metastases).
a.
Subjects with malignant lymphadenopathy in the abdomen or pelvis considered 
appropriate for radical cystectomy and lymphadenectomy with the goal of complete 
resection of all malignant disease are allowed.
3.
Intravesical chemo- or biologic therapy within 6 weeks of first treatment.
4.
Prior systemic chemotherapy, immunotherapy or radiation therapy for transitional cell 
carcinoma of the bladder.
a.
Subjects who have received prior intravesical chemotherapy or intravesical 
immunotherapy (e.g., interferon) are allowed.
5.
Prior treatment with, anti-TIGIT antibodies, CD137 agonists or immune checkpoint 
blockade therapies, including anti CTLA-4, anti-PD1 and anti-PD-L1 therapeutic 
antibodies.
6.
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner’s 
granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, 
vacuities, or glomerulonephritis.
a.
Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible for this study.
b.
Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen 
are eligible for this study.

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7.
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.
a.
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
8.
HIV or active hepatitis B (HBV; chronic or acute; defined below) or active hepatitis C
a.
Patients with resolved HBV infection (defined as the presence of hepatitis B core 
antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA must be 
obtained in these patients prior to Cycle 1, Day 1, but detection of HBV DNA in 
these patients will not exclude study participation.
b.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA.
9.
Active tuberculosis
10. Positive Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening 
a.
An EBV polymerase chain reaction (PCR) test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection. 
Patients with a positive EBV PCR test are excluded.
11. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia
12. Prior allogeneic stem cell or solid organ transplant
13. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study. 
Inactivated vaccines (such as hepatitis A or polio vaccines) are permitted during the study.
a.
Influenza vaccination should be given during influenza season only (approximately 
September to March). Patients must not receive live attenuated influenza vaccine 
(e.g., FluMist) within 4 weeks prior to Cycle 1, Day 1 and for at least 12 weeks after 
the last dose.
14. Clinically significant active infection or uncontrolled medical condition based on the 
discretion of the treating physician
15. Uncontrolled cystitis, significant bladder pain or spasms, or gross hematuria that in the 
opinion of the treating investigator, should preclude study entry.
16. 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
a.
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction < 50% must be on a stable 
medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate.

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17. Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or 
anticipation of need for a major surgical procedure other than cystectomy during the 
course of the study
18. Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) 
within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic 
immunosuppressive medications during the trial
a.
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 Study Chair.
b.
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for 
adrenal insufficiency) is allowed.
19. Pregnant or nursing women are excluded
20. Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component 
of the atezolizumab or tiragolumab formulation
21. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins
22. Malignancies other than UC within 3 years prior to Cycle 1, Day 1, with the exception of 
those with a low risk of metastasis or death treated with expected curative outcome (such 
as, but not limited to, adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated with curative intent and 
absence of PSA relapse, or ductal carcinoma in situ of the breast treated surgically with 
curative intent) or incidental prostate cancer (T1a, Gleason score ≤ 6 and PSA < 0.5 
ng/mL).
3.4
Duration of Treatment
In the absence of treatment delays due to adverse events (AEs), neoadjuvant study treatment 
may continue (up to 3 cycles depending on cohort) until:
●
Disease progression which requires discontinuation of the study 
treatment;
●
Inter-current illness that prevents further administration of treatment;
●
Unacceptable adverse event(s);
●
Participant decides to withdraw from the study;
●
Significant participant non-compliance with protocol;
●
If the participant meets an exclusion criterion (either newly developed or 
not previously; or, recognized) that precludes further study participation
●
General or specific changes in the participant’s condition render the 
participant unacceptable for further treatment in the judgment of the 
investigator.

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3.5
Duration of Follow Up
Participants will be followed for 2 years after cystectomy, removal from study, or until death, 
whichever occurs first. Participants removed from study for unacceptable treatment related 
adverse event(s) will be followed until resolution or stabilization of all treatment related adverse 
events to Grade 2 or lower.
3.6
Primary Completion 
It is expected that the study will reach primary completion about 14-19 months from the time 
Cohort B opens to accrual, accounting for 11-16 months to accrue all subjects to Cohort B, and 
another 3 months from enrollment of last patient to cystectomy.
3.7
Study Completion
It is expected that the study will reach full completion 41-46 months from the time Cohort B 
opens to accrual.
4
Study Drugs
4.1
Description, Supply and Storage 
4.1.1 Atezolizumab
Classification
Atezolizumab is a human monoclonal antibody based on a human IgG1 framework containing 
heavy chain VHIII and light chain VκI subgroup sequences. The recombinant antibody consists 
of two heavy chains (448 amino acid residues each) and two light chains (214 amino acid 
residues each) with inter- and intra-chain disulfide bonds that are typical of IgG1 antibodies.
Atezolizumab incorporates an amino acid substitution (asparagine to alanine) at position 298 in 
the CH2 domain of each heavy chain resulting in a non-glycosylated antibody that has minimal 
binding to Fcγ receptors and, consequently, prevents Fc-effector function and depletion of cells 
expressing PD-L1 at expected concentrations in humans. Therefore, atezolizumab lacks the N- 
linked oligosaccharides typically observed on other CHO-derived monoclonal antibodies.
Mechanism of Action
Atezolizumab targets programmed death-ligand 1 (PD-L1) on antigen-presenting cells or tumor 
cells and prevents interaction with programmed death−1 (PD-1) receptor, which is an inhibitory 
receptor expressed on T cells. Atezolizumab also blocks the interaction between PD-L1 and 
B7.1. Interference of the PD-L1:PD-1 and PD-L1:B7.1 interactions may enhance the magnitude 
and quality of the tumor-specific T-cell response through increased T-cell priming, expansion, 
and/or effector function.
Pharmacokinetics and Metabolism
Serum Atezolizumab concentrations exhibited a biphasic disposition with an initial rapid 
distribution phase followed by a slow elimination phase. Atezolizumab exhibited nonlinear 
pharmacokinetics at doses < 1 mg/kg (i.e., 0.03−0.3 mg/kg), likely due to target-mediated CL at 
lower concentrations. Atezolizumab exhibited linear pharmacokinetics at doses ≥ 1 mg/kg. At 

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doses ≥ 1 mg/kg, the mean Cmax increased in a dose-proportional manner and was 26.0 μg/mL 
for the 1-mg/kg dose group and 486 μg/mL for the 20-mg/kg dose group. Similarly, at doses ≥ 1 
mg/kg, the group mean AUC0-∞ had a range of 340−6050 day × μg/mL for 1-mg/kg and 20- 
mg/kg dose group and was approximately dose proportional, as evidenced by similar CL across 
the dose range. The observed CL and Vss for Atezolizumab at doses ≥ 1 mg/kg are consistent 
with these of a typical IgG1 antibody in humans. The development of anti-therapeutic antibodies 
(ATAs) has been observed in patients in all dose cohorts and was associated with changes in 
pharmacokinetics for some patients in the lower dose cohorts (0.3, 1, and 3 mg/kg). Patients 
dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected target trough 
levels of drug despite the detection of ATAs. Accordingly, the development of detectable ATAs 
does not appear to have a clinically significant impact on pharmacokinetics for doses from 10 to 
20 mg/kg. To date, no relationship between the development of measurable ATAs and safety or 
efficacy has been observed.
The expected metabolic products of proteins and peptides, including IgG1 monoclonal 
antibodies such as atezolizumab, are small peptides and individual amino acids. Cytochrome 
P450 enzymes as well as conjugation/glucuronidation reactions are not involved in the 
metabolism of Atezolizumab.
Contraindications
Atezolizumab is contraindicated for patients with the following:

History of severe allergic anaphylactic reactions to chimeric, human or humanized 
antibodies, or fusion proteins

Known hypersensitivity to CHO cell products or any component of the atezolizumab 
formulation.
As with all investigational products, unknown side effects may occur. Patients should be 
monitored closely throughout their participation in clinical studies of Atezolizumab.
Availability
The atezolizumab drug product is provided in a single-use, 20-mL USP/Ph. Eur. Type 1 glass 
vial as a colorless to slightly yellow, sterile, preservative-free clear liquid solution intended for IV 
administration. The vial is designed to deliver 20 mL (1200 mg) of Atezolizumab solution but 
may contain more than the stated volume to enable delivery of the entire 20 mL volume. The  
Atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine acetate, 
120 mM sucrose, 0.04% polysorbate 20, pH 5.8.
Atezolizumab will be delivered in infusion bags with IV infusion lines with product contacting 
surfaces of polyvinylchloride (PVC) and polyolefin and 0.2 μm in-line filters (filter membrane of 
polyethersulfone [PES]). No incompatibilities have been observed between v and PVC or 
polyolefin infusion materials (bags and infusion lines).
For further details, see the Atezolizumab Pharmacy Manual and IB. 
Storage and handling
Atezolizumab must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use.  Atezolizumab 
vials should not be used beyond the expiration date provided by the manufacturer. No 
preservative is used in the Atezolizumab drug product; therefore, each vial is intended for single 

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use only. Vial contents should not be frozen or shaken and should be protected from direct 
sunlight.
Side Effects
Potential risks associated with Atezolizumab described here are based on observed nonclinical 
toxicities and adverse events observed in ongoing clinical trial(s) of Atezolizumab, as well as 
clinical toxicities related to monoclonal antibodies targeting the PD-L1/PD-1 pathway. Adverse 
events that have occurred within 24 hours after infusion include: infusion reactions, 
hypertension, fatigue, decreased appetite and headache.
Therapy with Atezolizumab may increase the risk of immune-related adverse events (IRAEs), 
including rash, hypothyroidism, hepatitis/transaminitis and colitis. Subjects should therefore be 
carefully monitored for evidence of clinically significant systemic IRAEs (e.g., SLE−like 
diseases) or organ-specific IRAEs (e.g., rash, colitis, uveitis, hepatitis, or thyroid disease).
Suggested workup for suspected IRAEs includes evaluation of the gastrointestinal tract, lung, 
liver, skin, eye, and pituitary and adrenal glands. Specific management of IRAEs is provided 
later in the protocol.
In addition, specific management for the toxicities occurring in the following organ systems is 
provided in this protocol: gastrointestinal tract (diarrhea, colitis), pulmonary (pneumonitis), 
hepato-biliary (hepatitis, pancreatitis), and dermatologic (rash, pruritus, severe cutaneous 
adverse reactions (SCARs)).
4.1.2 Tiragolumab
Classification
Tiragolumab is a fully human IgG1 monoclonal antibody. The recombinant antibody is produced 
in CHO cells, and consists of two heavy chains (456 amino acid residues each) and two light 
chains (220 amino acid residues each). There are two N-linked glycosylation sites (Asn306) in 
the Fc domain.
Mechanism of Action
Tiragolumab binds to TIGIT and prevents its interaction with Poliovirus receptor (PVR). The 
inhibitory immunoreceptor TIGIT has been shown to limit the effector function of tumor-
associated lymphocytes.
Pharmacokinetics and Metabolism
Preliminary population-PK analyses show that tiragolumab exposures increased approximately 
dose-proportionally following IV administration at doses ranging from 100 to 1200 mg Q3W as 
monotherapy or in combination with 1200 mg Q3W atezolizumab. Preliminary population-PK 
analysis estimated tiragolumab clearance at 0.28 L/day with a linear drug elimination half-life of 
approximately 15 days.
Contraindications

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Tiragolumab is contraindicated for patients with a history of severe allergic anaphylactic 
reactions to chimeric, human, humanized antibodies, or fusion proteins because of the potential 
for severe reactions.
Availability
The tiragolumab drug product will be supplied in single-use, 15-mL glass vials. The vials contain 
10 mL of tiragolumab drug product and are buffered in histidine solution containing polysorbate 
20, sucrose, L-methionine, and WFI. The approximate concentration of tiragolumab antibody in 
the vials is 60 mg/mL. 
Storage and handling
The recommended storage condition for the tiragolumab drug product is 2°C-8°C (36°F–46°F). 
Do not shake or freeze IV bags containing dose solution. Protect from direct sunlight (exposure 
to indoor ambient light is acceptable).
Tiragolumab must be prepared for dosing under appropriate aseptic conditions as it does not 
contain antimicrobial preservatives. The dose solution should be used immediately. If not used 
immediately, the total storage time of the dose solution prior to administration should not exceed 
24 hours to limit the risk of microbial growth in case of accidental contamination. 
Side Effects
IRRs have been reported in patients treated with tiragolumab, with or without atezolizumab.  
The majority of events were mild to moderate and manageable.      As an antagonist of TIGIT, 
tiragolumab is anticipated to enhance T-cell and NK cell proliferation, survival, and function. 
Therefore, tiragolumab may increase the risk of autoimmune inflammation (also described as 
immune-mediated AEs [imAEs]). In addition, due to the intact Fc-effector function of 
tiragolumab, lymphopenia via ADCC is a theoretical risk.      For information on the 
pharmacokinetics, metabolism, formulation and handling of tiragolumab, see the pharmacy 
manual and the Tiragolumab Investigator's Brochure.
4.2
Accountability Records for Study Drug
The Investigational Pharmacist at each site will manage drug accountability records.
4.3
Ordering Study Drugs
UCSF will obtain Atezolizumab and Tiragolumab directly from Genentech as study supply. Drug 
will be shipped directly to subsites if required to ensure drug stability.
5
Treatment Plan
5.1
Dosage and Administration
Cohort A: The starting dose level of atezolizumab for Cohort A was 1200 mg administered by 
IV infusion on an outpatient basis for one dose, and was escalated in subsequent cohorts to 
1200 mg administered by IV infusion every 3 weeks for a maximum of 3 neoadjuvant doses. 
Prior to Amendment 4.3 (October 19, 2020) subjects with adverse histology at the time of 
cystectomy (pT3, pT4, or N+) and no metastatic disease could elect to receive adjuvant 
MPDL3280A will receive 1200mg by IV infusion on an outpatient basis every 3 weeks for up to 
16 doses cumulative doses.

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Cohort B: The starting combination regimen will be atezolizumab 1200 mg administered by IV 
infusion on an outpatient basis every 3 weeks and tiragolumab 600 mg administered by IV 
infusion every 3 weeks for a total intended 3 neoadjuvant doses. As previously detailed, there 
will be a safety lead in of 6 initial patients at which time trial accrual will temporarily pause to 
assess the safety of combination treatment. 
Administration of atezolizumab and tiragolumab will be performed in a setting with emergency 
medical facilities and staff who are trained to monitor for and respond to medical emergencies.
Atezolizumab and Tiragolumab will be delivered in infusion bags with IV infusion lines with 
product contacting surfaces of polyvinylchloride (PVC) and polyolefin and 0.2 μm in-line filters 
(filter membrane of polyethersulfone [PES]). No incompatibilities have been observed between 
atezolizumab and PVC or polyolefin infusion materials (bags and infusion lines). 
The compatibility of tiragolumab with diluents other than described is unknown. Tiragolumab 
must not be infused into the same line or cannula concomitantly with other drug infusions, 
including parenteral nutrition. Infusions of blood products and any electrolyte supplementation 
must not occur simultaneously with infusion of tiragolumab. 
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 (for 
subjects receiving more than 2 doses) 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 during or after the infusion if clinically indicated or if 
symptoms occurred in the prior infusion. Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed to contact their study physician if they develop 
such symptoms.
No premedication will be allowed for the first dose of atezolizumab. Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician after consultation with the 
Study Chair.
Tiragolumab dose will be administered following the dose of atezolizumab and 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 (for subjects receiving more than 2 doses) 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 during or after the infusion if clinically indicated or if 
symptoms occurred in the prior 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.

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No premedication will be allowed for the first dose of tiragolumab. Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician after consultation with the 
Study Chair.
Table 5.1
Regimen Description
Study Drug
Premedication;
precautions
Dose
Route
Schedule
Cycle 
Length
Atezolizumab
None for 1st 
dose
1200mg
Intravenous
Day 1 each 
cycle
21 days
Tiragolumab 
(Cohort B 
only)
None for 1st 
dose
600mg
Intravenous
Day 1 each cycle
21 days
5.1.1 Other Modalities or Procedures
A radical cystectomy per institutional standard of care is planned for all patients enrolling in this 
study. No other procedures following initiation of systemic treatment (e.g., TURBT) are required 
for subjects while on study. Cystectomy may be performed beginning 3 weeks after the last 
planned dose of study therapy is administered. See study calendar (Section 6.10) for schedule 
of evaluations.
5.2
Cohort A Multi-dose Schedule
Three successive cohorts were enrolled to evaluate immunologic impact of escalating 
neoadjuvant doses of atezolizumab prior to cystectomy as outlined in the table below. A fixed 
dose of atezolizumab 1200mg was given with each cycle. For individual subjects there was no 
dose modifications above or reductions below the assigned dose allowed. 
Table 5.2
Cohort A Multi-Dose Cohort Schedule
Dose Level
Dose of Atezolizumab
Number of Patients Accrued 
Before Accrual of Next Cohort
1
1200 mg x 1 dose
6
2
1200 mg q3 weeks x 2 doses
6
3
1200 mg q3 weeks x 3 doses
6
Multi-dose cohort accrual then proceeded according to the following: Dosing began in the first 
cohort (Dosing Level 1) with atezolizumab 1200mg IV x 1 dose. Beginning with this starting 
dose level, six patients were treated at each cumulative dose level. Accrual to the next higher 

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dose cohort began after 6 subjects in the lower cohort completed treatment and underwent 
cystectomy.
18 patients were treated in this multi-dose phase. 
Cohort A Dose-expansion occurred at dose level 3 given no unacceptable treatment-related 
toxicity (as defined in Section 5.4) was observed. The rationale for expansion at this dose level 
is discussed in Section 1.8.
5.3
Cohort B Safety Lead-in Schedule
The Cohort B safety lead-in is described in section 3.1. Dosing for the Cohort B safety lead-in is 
detailed below. Once the intended treatment regimen is established following completion of the 
safety assessment, an additional 15 patients will be enrolled at the same regimen for a total of 
21 patients on that treatment regimen.
Table 5.3
Cohort B Safety Lead-in Dosing
Dose Level
Atezolizumab 
Tiragolumab
1
1200 mg q3 weeks x 3 doses
600mg x 3 doses
2
1200 mg q3 weeks x 3 doses
600mg x 2 doses
3
1200 mg q3 weeks x 3 doses
600mg x 1 dose
5.4
Dose Limiting Toxicities (DLTs)
Dose Limiting Toxicity (DLT) is an unacceptable treatment-related toxicity that occurs between 
time of first dose and time of cystectomy, defined as:
●
any Grade 4 toxicity, or
●
any recurrent Grade 3 toxicity, or
●
any Grade 3 toxicity persisting more than 2 weeks, or
●
any toxicity that results in delay of cystectomy beyond 12 weeks from the 
first dose of study drug
5.5
Interim Safety Analysis
A stopping rule for safety will halt accrual to the study and prompt reevaluation of the treatment 
regimen if unacceptable treatment-related toxicity (defined as any Grade 4 toxicity, any 
recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 2 weeks), or treatment-
related delay in cystectomy beyond 12 weeks (12 week window starts at time of first dose to 
time of cystectomy), is observed at a frequency of ≥ 33.3%.      
Because of the known excellent safety profile of atezolizumab, this safety review will occur after 
all 6 subjects have been accrued to each individual dosing cohort in the Cohort A multi-dose 
phase and Cohort B safety lead-in and treated with at least one dose of study treatment, as well 
as on an ongoing basis should serious treatment-related toxicities or treatment-related delays in 
cystectomy be observed at any point in the study.

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5.6
Dose Modifications and Dosing Delays
There will be no dose reduction for atezolizumab or tiragolumab for individual subjects in this 
study. Treatment delays are allowed for subjects who experience toxicity, as long as the 
following treatment occurs within the 12 week window between the first dose of study therapy 
and cystectomy. If any toxicity will delay cystectomy beyond 12 weeks from the time that patient 
begins study therapy, then no further study therapy should be given and the subject should 
proceed to cystectomy.
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed with Study Chair approval. The acceptable length of interruption will depend on 
agreement between the investigator and the Study Chair and should conform with guidelines for 
delay of cystectomy above.
Treatment or visit delays for public holidays or weather conditions do not constitute a DLT or 
protocol violation.
5.7
Monitoring and Toxicity Management
5.7.1 Eligibility
Eligibility criteria were selected to guard the safety of patients in this trial. Results from the 
nonclinical toxicology studies with atezolizumab and tiragolumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were taken into account. Specifically, 
patients at risk for study- emergent autoimmune conditions or with a prior diagnosis of 
autoimmune disease, patients with evidence of acute infections, and patients who have 
received a live-attenuated viral vaccine within 4 weeks before Day 1 are excluded from the 
study.
5.7.2 Monitoring
Each patient receiving atezolizumab, with or without tiragolumab, will be evaluable for safety. 
The safety parameters include but are not limited to all laboratory tests and hematological 
abnormalities, physical findings, and spontaneous reports of adverse events reported to the 
investigator by patients. Safety will be evaluated in this study through the monitoring of all 
serious and non-serious adverse events. For Cohort A, toxicity will be assessed according to 
CTCAE v4.0 and for Cohort B, toxicity will be assessed according to the CTCAE v5.0. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6-Study Schedule, Procedures and Observations. General safety assessments will 
include serial interval histories, physical examinations, and specific laboratory studies, including 
serum chemistries and blood counts (see section 6 for the list and timing of study assessments). 
Laboratory values must be reviewed prior to each infusion.
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 Section 7.5.2.7) 
will be reported in an expedited fashion. In addition, observed adverse events will be monitored 
on a regular basis.

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Patients will be followed for safety for 30 days following their last dose of study treatment and 
for 2 years of follow up after cystectomy, 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.
Interim Analyses for Safety are outlined in Section 5.5.
5.7.3 Management of General and Immune Related Adverse Events (irAEs)
Toxicities associated or possibly associated with atezolizumab or tiragolumab treatment should 
be managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to determine a possible immunogenic etiology.
Although most irAEs 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 or tiragolumab may not have an immediate 
therapeutic effect, and there is no available antidote for either drug. In severe cases, immune-
related toxicities may be acutely managed with topical corticosteroids, systemic corticosteroids, 
mycophenolate,      TNF-α inhibitors, or other immunosuppressants.
The primary approach to Grade 1-2 irAEs is supportive and symptomatic care; for higher grade 
irAEs, steroids by mouth or parenterally are given, and either delaying a dose or stopping 
therapy is appropriate. Recurrent Grade 2 irAEs may also mandate delaying a dose of 
atezolizumab and tiragolumab or the use of steroids. If the patient is being managed with 
corticosteroids, treatment should not be restarted until the steroids have been tapered 
off. Consideration for benefit/risk balance should be made by the investigator, with 
consideration of the totality of information as it pertains to the nature of the toxicity and the 
degree of clinical benefit a given patient may be experiencing prior to further administration of 
atezolizumab and tiragolumab. Atezolizumab and tiragolumab should be permanently 
discontinued in patients with life-threatening immune-related adverse events.
5.7.4 Management of Atezolizumab and Tiragolumab - Specific Adverse Events
Toxicities associated or possibly associated with atezolizumab and tiragolumab 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.
Because of the expected pharmacologic activity of tiragolumab, the adverse event management 
guidelines described here, including those for continuing, withholding, resuming, and 
discontinuing atezolizumab, as outlined below, are applicable to tiragolumab as well as 
atezolizumab where noted.
Although most immune-related AEs 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 and/or tiragolumab may not have an 
immediate therapeutic effect, and in severe cases, immune-related toxicities may require acute 

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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 and/or tiragolumab may be considered 
if the patient is deriving benefit and has fully recovered from the immune-related event. Patients 
can be rechallenged with atezolizumab and/or tiragolumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical Monitor.
5.7.4.1
Pulmonary Events
Immune-mediated pulmonary events are a potential risk with tiragolumab.
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 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 the table below.
Management Guidelines for Pulmonary Events, Including Pneumonitis
Event
Management
Pulmonary event, 
Grade 1
●
Continue tiragolumab and atezolizumab and monitor closely.
●
Re-evaluate on serial imaging.
●
Consider patient referral to pulmonary specialist.
Pulmonary event, 
Grade 2
●
Withhold tiragolumab and 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 tiragolumab and atezolizumab. 
b
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and 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 tiragolumab and 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.

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BAL= bronchoscopic alveolar lavage; IVIG= intravenous immunoglobulin
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Tiragolumab and 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. Protocol defined 
windows for treatment discontinuation may differ and should be followed 
accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before tiragolumab and atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event. Patients can 
be re-challenged with tiragolumab and atezolizumab only after approval has 
been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.
5.7.4.2
Hepatic Events
Immune-mediated hepatic events are a potential risk with tiragolumab.  
Immune-related hepatitis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin 
and hepatic transaminases, and liver function will be monitored throughout study treatment.
Management guidelines for hepatic events are provided in the table below.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have 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.

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Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1
●
Continue tiragolumab and 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 tiragolumab and 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 
tiragolumab and atezolizumab. b
●
If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab, permanently 
discontinue tiragolumab and atezolizumab and contact 
Medical Monitor. c
Hepatic event, 
Grade 3 or 4
●
Permanently discontinue tiragolumab and 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.
LFTs = liver function tests.
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Tiragolumab and 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. Protocol defined windows for treatment 
discontinuation may differ and should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to
≤ 10 mg/day oral prednisone or equivalent before tiragolumab and atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be rechallenged with 
tiragolumab and atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.

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5.7.4.3
Gastrointestinal Events
Immune-mediated gastrointestinal events are a potential risk with tiragolumab. 
Immune-related colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in the table below.
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 CRP, platelet count, or 
bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 3 
to 5 specimens for standard paraffin block to check for inflammation and lymphocytic infiltrates 
to confirm colitis diagnosis.
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)
Event
Management
Diarrhea or colitis, 
Grade 1
●
Continue tiragolumab and atezolizumab.
●
Initiate symptomatic treatment.
●
Endoscopy is recommended if symptoms persist for > 7 days.
●
Monitor closely.
Diarrhea or colitis, 
Grade 2
●
Withhold tiragolumab and 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 tiragolumab and 
atezolizumab. b
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact Medical Monitor. c
Diarrhea or colitis, 
Grade 3
●
Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a
●
Refer patient to gastrointestinal 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 tiragolumab and 
atezolizumab. b
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact Medical Monitor. c

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Diarrhea or colitis, 
Grade 4
●
Permanently discontinue tiragolumab and atezolizumab and contact 
Medical Monitor.
c
●
Refer patient to gastrointestinal 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.
IV=intravenous
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Atezolizumab and tiragolumab  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. Protocol defined windows for treatment 
discontinuation may differ and should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone 
or equivalent before tiragolumab and atezolizumab can be resumed.
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can be 
rechallenged with tiragolumab and atezolizumab only after approval has been documented 
by both the investigator (or an appropriate delegate) and the Medical Monitor.
5.7.4.4
Endocrine Events
Immune-related endocrine events are a potential risk with tiragolumab. 
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 the table below.
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 T3 and T4 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.

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Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism
●
Continue tiragolumab and atezolizumab.
●
Initiate treatment with thyroid replacement hormone.
●
Monitor TSH weekly.
Symptomatic 
hypothyroidism
●
Withhold tiragolumab and 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 tiragolumab and atezolizumab.
●
Monitor TSH every 4 weeks. 
TSH < 0.1 mU/L:
●
Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism
●
Withhold tiragolumab and 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 tiragolumab and atezolizumab and 
contact Medical Monitor for life-threatening immune-related 
hyperthyroidism.c
Symptomatic adrenal 
insufficiency,
Grade 2−4
●
Withhold tiragolumab and 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 tiragolumab 
and atezolizumab, permanently discontinue tiragolumab and 
atezolizumab and contact Medical Monitor. c
Hyperglycemia Grade 1 or 
2
●
Continue tiragolumab and atezolizumab.
●
Initiate treatment with insulin if needed.
●
Monitor for glucose control.

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Hyperglycemia, Grade 
3 or 4
●
Withhold tiragolumab and atezolizumab.
●
Initiate treatment with insulin.
●
Monitor for glucose control.
●
Resume tiragolumab and atezolizumab when symptoms resolve 
and glucose levels are stable.
Hypophysitis
(pan-hypopituitarism), 
Grade 2-3
●
Withhold tiragolumab and 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.a
●
Initiate hormone replacement therapy if clinically indicated.
●
If event resolves to Grade 1 or better, resume 
tiragolumab and atezolizumab. b
●
If event does not resolve to Grade 1 or better while 
withholding tiragolumab and atezolizumab, permanently 
discontinue tiragolumab and atezolizumab and contact 
Medical Monitor. c
●
For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis
(pan-hypopituitarism), 
Grade 4
●
Permanently discontinue tiragolumab and 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.a
●
Initiate hormone replacement therapy if clinically indicated.
MRI= magnetic resonance imaging; TSH =thyroid-stimulating hormone, IV= intravenous
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Atezolizumab and tiragolumab 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. Protocol defined windows for treatment discontinuation may differ 
and should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before tiragolumab and atezolizumab can be resumed.
c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event. Patients can be rechallenged 
with tiragolumab and atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.

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5.7.4.5
Ocular Events
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in the table below.
Management Guidelines for Ocular Events
Event
Management
Ocular event, Grade 
1
●
Continue tiragolumab and 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 tiragolumab and 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 tiragolumab and 
atezolizumab. b
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Ocular event, Grade 
3 or 4
●
Permanently discontinue tiragolumab and 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.
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
A Atezolizumab and tiragolumab           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. Protocol defined windows for treatment 
discontinuation may differ and should be followed accordingly.
B If corticosteroids have been initiated, they must be tapered over ≥ 1 month to
≤ 10 mg/day oral prednisone or equivalent before tiragolumab and atezolizumab can be resumed.
C Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event. Patients can be rechallenged 
with tiragolumab and atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.

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5.7.4.6
Immune-Related Myocarditis
Immune-related myocarditis is a potential risk with tiragolumab and has been associated with 
the administration of atezolizumab.
Immune-related myocarditis should be suspected in any patient
presenting with signs or symptoms suggestive of myocarditis, including, but not limited to, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.
Immune-related myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g. in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of pre-existing 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 the table below.
Management Guidelines for Immune-Related Myocarditis
Event
Management
Immune-related 
myocarditis, Grade 1
●Refer patient to cardiologist
●Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2
●Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor.
●Refer patient to cardiologist
●Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate.
●Consider treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement.a
●If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab. B
●If event does not resolve to Grade 1 or better while withholding tiragolumab 
and atezolizumab, permanently discontinue atezolizumab and contact Medical 
Monitor. C

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Immune-related 
myocarditis, Grade 3-
4
●Permanently discontinue tiragolumab and atezolizumab and contact Medical 
Monitor. C
●Refer patient to cardiologist
●Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate.
●Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. A,b
●If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.
●If event resolves to Grade 1 or better, taper corticosteroids over≥ 1 month.
ECMO= extracorporeal membrane oxygenation; VAD= ventricular assist device; IV= intravenous.
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Atezolizumab and tiragolumab 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. Protocol defined windows for treatment discontinuation may differ and 
should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral 
prednisone or equivalent before tiragolumab and atezolizumab can be resumed.
c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be rechallenged with 
tiragolumab and atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor.
5.7.4.7
Infusion Related Reactions 
No premedication is indicated for the administration of Cycle 1 of tiragolumab and atezolizumab. 
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 tiragolumab 
and atezolizumab may receive premedication with antihistamines, antipyretics, 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 tiragolumab and atezolizumab. These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of tiragolumab and 
atezolizumab administration and are generally mild to moderate in severity.
Guidelines for medical management of IRRs during Cycle 1 are provided in the table below.  For 
subsequent cycles, IRRs should be managed according to institutional guidelines.
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 

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event onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids).

Permanently discontinue tiragolumab or atezolizumab and contact 
Medical Monitor. a
IRR  infusion-related reaction.
a Resumption of tiragolumab or atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the event.  Patients can be re-challenged 
with tiragolumab or atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.
5.7.4.8
Cytokine Release Syndrome
No premedication is indicated for the administration of Cycle 1 of tiragolumab or atezolizumab.  
However, patients who experience cytokine-release syndrome (CRS) with tiragolumab or 
atezolizumab may receive premedication with antihistamines, anti pyretics, and/or analgesics 
(e.g., acetaminophen) for subsequent infusions.
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 dysfunction29. 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-
L130, 31, including atezolizumab.
Guidelines for medical management of CRS are provided below.
Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
interleukin (IL)-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, which 
should be confirmed or refuted through assessment of exposure history, appropriate laboratory 

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testing, and clinical or radiologic evaluations per investigator judgment.  If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or institutional guidelines.
Management Guidelines for 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 CRS.
Grade 2 a
Fever b with at least 
one of the following:
Hypotension not 
requiring 
vasopressors
Hypoxia requiring 
low-flow oxygen d by 
nasal cannula or 
blow-by
Immediately interrupt infusion.
Upon symptom resolution, wait for 30 minutes and then 
restart infusion at half the rate being given at the time of 
event onset.
If symptoms recur, discontinue infusion of this dose.
Administer symptomatic treatment. c
For hypotension, administer IV fluid bolus as needed.
Monitor cardiopulmonary and other organ function closely (in 
the ICU, if appropriate).  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ 
toxicities as per institutional practice.
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS 
as described in this appendix.
Consider IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy. 
Consider hospitalization until complete resolution of 
symptoms.  If no improvement within 24 hours, manage as 
per Grade 3, that is, hospitalize patient (monitoring in the ICU 
is recommended), permanently discontinue tiragolumab or 
atezolizumab, and contact Medical Monitor.
If symptoms resolve to Grade 1 or better for 3 consecutive 
days, the next dose of tiragolumab or atezolizumab may be 
administered.  For subsequent infusions, consider 

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administration of oral premedication with antihistamines, anti-
pyretics, and/or analgesics and monitor closely for CRS.
If symptoms do not resolve to Grade 1 or better for 
3 consecutive days, contact Medical Monitor.
Management Guidelines for Cytokine-Release Syndrome (cont.)
Event
Management
Grade 3 a
Fever b with at least 
one of the following:
Hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin)
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask

Permanently discontinue tiragolumab or atezolizumab and 
contact Medical Monitor. e

Administer symptomatic treatment. c

For hypotension, administer IV fluid bolus and vasopressor 
as needed.

Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended.  Administer IV fluids 
as clinically indicated, and manage constitutional symptoms 
and organ toxicities as per institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS 
as described in this appendix.

Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy. 

Hospitalize patient until complete resolution of symptoms.  If 
no improvement within 24 hours, manage as per Grade 4, 
that is, admit patient to ICU and initiate hemodynamic 
monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to 
anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator and in 
consultation with the Medical Monitor.

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Grade 4 a
Fever b with at least 
one of the following:
Hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin)
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation)

Permanently discontinue tiragolumab or atezolizumab and 
contact Medical Monitor. e

Administer symptomatic treatment. c

Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per 
institutional practice.

Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS 
as described in this appendix.

Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours).

Consider anti-cytokine therapy.   For patients who are 
refractory to anti-cytokine therapy, experimental treatments f 
may be considered at the discretion of the investigator and 
in consultation with the Medical Monitor.

Hospitalize patient until complete resolution of symptoms.
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).
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for 
continuing, withholding, resuming, and discontinuing atezolizumab are also applicable to 
tiragolumab.
a.
Grading system for management guidelines is based on ASTCT consensus 
grading for CRS. NCI CTCAE (version as specified in the protocol) should be 
used when reporting severity of IRRs, CRS, or organ toxicities associated with 
CRS on the Adverse Event eCRF. Organ toxicities associated with CRS should 
not influence overall CRS grading.
b.
Fever is defined as temperature ≥38°C not attributable to any other cause. In 
patients who develop CRS and then receive anti-pyretic, anti-cytokine, or 
corticosteroid therapy, fever is no longer required when subsequently 
determining event severity (grade). In this case, the grade is driven by the 
presence of hypotension and/or hypoxia.
c.
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, 
analgesics, bronchodilators, and/or oxygen. For bronchospasm, urticaria, or 

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dyspnea, additional treatment may be administered as per institutional 
practice.
d.
Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined 
as oxygen delivered at > 6 L/min.
e.
Resumption of tiragolumab and 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.
f.
Refer to Riegler et al.32 for information on experimental treatments for CRS.
5.7.4.9
Pancreatic Events
Immune-related pancreatic events are a potential risk with tiragolumab.
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 the table below.
Management Guidelines for Pancreatic Events, Including Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2
●Continue tiragolumab and atezolizumab.
●Monitor amylase and lipase weekly.
●For prolonged elevation (e.g., > 3 weeks), consider treatment with 10 mg/day oral 
prednisone or equivalent.

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Amylase and/or lipase 
elevation, Grade 3 or 4
●Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a
●Refer patient to gastrointestinal 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 tiragolumab and 
atezolizumab. b
●If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab and 
atezolizumab and contact Medical Monitor. c
●For recurrent events, permanently discontinue tiragolumab and atezolizumab 
and contact Medical Monitor. c
Immune-related 
pancreatitis, Grade 2 or 3
●
Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset. a
●
Refer patient to gastrointestinal 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 tiragolumab and  
atezolizumab.
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact Medical Monitor. C
●
For recurrent events, permanently discontinue tiragolumab and 
atezolizumab and contact Medical Monitor. c
Immune-related 
pancreatitis, Grade 4
●Permanently discontinue tiragolumab and atezolizumab and contact Medical 
Monitor. c
●Refer patient to gastrointestinal 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.
IV=intravenous
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Atezolizumab and tiragolumab 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. Protocol defined windows for treatment discontinuation may differ 
and should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day 
oral prednisone or equivalent before tiragolumab and atezolizumab can be resumed.

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c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can be 
rechallenged with tiragolumab and atezolizumab only after approval has been documented 
by both the investigator (or an appropriate delegate) and the Medical Monitor.
5.7.4.10 Dermatologic Events
Immune-related dermatologic events are a potential risk with tiragolumab.  
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. Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis have been reported with atezolizumab A dermatologist should 
evaluate persistent and/or severe rash or pruritus. A biopsy should be considered unless 
contraindicated. Management guidelines for dermatologic events are provided in the table 
below.
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic event, 
Grade 1
●
Continue tiragolumab and atezolizumab.
●
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic event, 
Grade 2
●
Continue tiragolumab and 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 tiragolumab and  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, resumetiragolumab and      
atezolizumab. b
●
If event does not resolve to Grade 1 or better while 
withholding tiragolumab and  atezolizumab, 
permanently discontinue tiragolumab and atezolizumab 
and contact Medical Monitor. c
Dermatologic event, 
Grade 4
●
Permanently discontinue tiragolumab and atezolizumab and 
contact Medical Monitor.c
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis (any 
grade)
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis:
●
Withhold tiragolumab and atezolizumab for suspected 
Stevens-Johnson syndrome or toxic epidermal necrolysis.

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Event
Management
●
Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if 
indicated, biopsy.
●
Follow the applicable treatment and management guidelines above.
●If Stevens-Johnson syndrome or toxic epidermal necrolysis, 
permanently discontinue tiragolumab and  atezolizumab.
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
A Atezolizumab and tiragolumab      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. Protocol defined windows for treatment 
discontinuation may differ and should be followed accordingly.
B If corticosteroids have been initiated, they must be tapered over  ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before tiragolumab and atezolizumab can be 
resumed.
C Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can 
be rechallenged with tiragolumab and atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.
5.7.4.11 Neurologic Disorders
Immune-related neurologic events are a potential risk with tiragolumab.  
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 
the table below.

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Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, Grade 
1
●
Continue tiragolumab and  atezolizumab.
●
Investigate etiology.
Immune-related 
neuropathy, Grade 
2
●
Withhold tiragolumab and 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 tiragolumab and  
atezolizumab. B
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact Medical Monitor. C
Immune-related 
neuropathy, Grade 
3 or 4
●
Permanently discontinue tiragolumab and  atezolizumab and 
contact Medical Monitor. C
●
Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade)
●
Permanently discontinue tiragolumab and 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.
IV=intravenous. Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for 
continuing, withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Atezolizumab and tiragolumab 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. Protocol defined windows for treatment 
discontinuation may differ and should be followed accordingly.
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before tiragolumab and atezolizumab can 
be resumed.
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can be 
rechallenged with tiragolumab and atezolizumab only after approval has been documented 
by both the investigator (or an appropriate delegate) and the Medical Monitor.
5.7.4.12 Immune-Related Meningoencephalitis
Immune-mediated meningoencephalitis is a potential risk with tiragolumab.  
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any patient 

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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 the table below.
Management Guidelines for Immune-Related Meningoencephalitis
Event
Management
Immune-related 
meningoencephalitis, 
all grades
●
Permanently discontinue tiragolumab and 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.
IV = intravenous. Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for 
continuing, withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
a Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can 
be rechallenged with tiragolumab and atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.
5.7.4.13 Immune-Related Nephritis
Immune-related nephritis is a potential risk with tiragolumab has been associated with the 
administration of atezolizumab. Eligible patients must have adequate renal function, and renal 
function, including serum creatinine, should be monitored throughout study treatment. Patients 
with abnormal renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non- steroidal 
anti- inflammatory drugs). Refer the patient to a renal specialist if clinically indicated. A renal 
biopsy may be required to enable a definitive diagnosis and appropriate treatment. If no 
alternative cause of acute kidney injury is identified, patients with signs and symptoms of acute 

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kidney injury, in the absence of an identified alternate etiology, should be treated according to 
the management guidelines for immune-related renal events in the table below.
Management Guidelines for Renal Events
Event
Management
Renal event, Grade 
1
●Continue tiragolumab and atezolizumab.
●Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values.
Renal event, Grade 
2
●Withhold tiragolumab and 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 tiragolumab and 
atezolizumab. b
●If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue 
tiragolumab and atezolizumab and contact Medical Monitor. c
Renal event, Grade 
3 or 4
●Permanently discontinue tiragolumab and 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.
Note: Management guidelines are presented by adverse event severity based on NCI 
CTCAE and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0.
Note: Because of the expected pharmacologic activity of tiragolumab, guidelines for continuing, 
withholding, resuming, and discontinuing atezolizumab are also applicable to tiragolumab. 
 a Atezolizumab and tiragolumab 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 tiragolumab and atezolizumab can be 
resumed.
c Resumption of tiragolumab and atezolizumab may be considered in patients who are 
deriving benefit and have fully recovered from the immune-related event. Patients can 
be re-challenged with tiragolumab and atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor.

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5.7.4.14 Immune-Related Myositis
Immune-mediated myositis is a potential risk with tiragolumab and 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 the table below.
Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune- mediated 
myositis, Grade 1
●
Continue tiragolumab and atezolizumab.
●
Refer patient to rheumatologist or neurologist.
●
Initiate treatment as per institutional guidelines.
Immune- mediated 
myositis, Grade 2
●
Withhold tiragolumab and atezolizumab for up to 12 weeks after event 
onset a and contact Sponsor-Investigator.
●
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 tiragolumab and 
atezolizumab. b
●
If event does not resolve to Grade 1 or better while withholding 
tiragolumab and atezolizumab, permanently discontinue tiragolumab 
and atezolizumab and contact Sponsor-Investigator. c

 U C S F H el e n Dill er F a mil y C o m pr e h e n si v e C a n c er C e nt er
V er si o n d at e: 0 3- 2 9- 2 0 2 1
Pr ot o c ol C C #: 1 4 5 2 4
P h a s e II – at e z oli z u m a b a n d tir a g ol u m a b
 P a g e 6 4 of 1 2 1
E ve nt
M a n a ge me nt
I m m u ne- me diate d 
m y ositis, Gra de 3
●
Wit h h ol d tira g ol u ma b a n d atez oliz u ma b f or u p t o 1 2 wee ks after e ve nt 
o nset a a n d
c o ntact S p o ns or-I n vesti gat or.
●
Refer patie nt t o r he u mat ol o gist or ne ur ol o gist.
●
I nitiate treat me nt as per i nstit uti o nal g ui deli nes.
●
Res pirat or y s u p p ort ma y be re q uire d i n m ore se vere cases.
●
I nitiate treat me nt wit h c ortic oster oi ds e q ui vale nt t o
●
1- 2 m g/ k g/ da y I V met h yl pre d nis ol o ne, or hi g her- d ose b ol us if patie nt 
is se verel y c o m pr o mise d (e. g., car diac or res pirat or y s y m pt o ms, 
d ys p ha gia, or wea k ness t hat se verel y li mits m o bilit y); c o n vert t o 1- 2 
m g/ k g/ da y oral pre d nis o ne or e q ui vale nt u p o n i m pr o ve me nt.
●
If e ve nt d oes n ot i m pr o ve wit hi n 4 8 h o urs after i nitiati n g 
c ortic oster oi ds, c o nsi der a d di n g a n i m m u n os u p pressi ve a ge nt.
●
If e ve nt res ol ves t o Gra de 1 or better, res u me tira g ol u ma b a n d 
atez oliz u ma b. b
●
If e ve nt d oes n ot res ol ve t o Gra de 1 or better w hile wit h h ol di n g
atez oliz u ma b, per ma ne ntl y disc o nti n ue tira g ol u ma b a n d atez oliz u ma b 
a n d c o ntact
S p o ns or-I n vesti gat or. c
●
F or rec urre nt e ve nts, treat as a Gra de 4 e ve nt.
I m m u ne- me diate d 
m y ositis, Gra de 4
●
Per ma ne ntl y disc o nti n ue tira g ol u ma b a n d atez oliz u ma b a n d c o ntact 
S p o ns or-
I n vesti gat or. c
●
Refer patie nt t o r he u mat ol o gist or ne ur ol o gist.
●
I nitiate treat me nt as per i nstit uti o nal g ui deli nes.
●
Res pirat or y s u p p ort ma y be re q uire d i n m ore se vere cases.
●
I nitiate treat me nt wit h c ortic oster oi ds e q ui vale nt t o
●
1 2  m g/ k g/ da y I V met h yl pre d nis ol o ne, or hi g her- d ose b ol us if patie nt 
is se verel y c o m pr o mise d (e. g., car diac or res pirat or y s y m pt o ms, 
d ys p ha gia, or wea k ness t hat se verel y li mits m o bilit y); c o n vert t o 1- 2 
m g/ k g/ da y oral pre d nis o ne or e q ui vale nt u p o n i m pr o ve me nt.
●
If e ve nt d oes n ot i m pr o ve wit hi n 4 8 h o urs after i nitiati n g 
c ortic oster oi ds, c o nsi der a d di n g a n i m m u n os u p pressi ve a ge nt.
●
If e ve nt res ol ves t o Gra de 1 or better, ta per c ortic oster oi ds o ver 
1 m o nt h.
N ote: Beca use of t he e x pecte d p har mac ol o gic acti vit y of tira g ol u ma b, g ui deli nes f or c o nti n ui n g, 
wit h h ol di n g, res u mi n g, a n d disc o nti n ui n g atez oliz u ma b are als o a p plica ble t o tira g ol u ma b. 
a Atez oliz u ma b a n d tira g ol u ma b ma y be wit h hel d f or a l o n ger peri o d of ti me (i.e., > 1 2 
wee ks after e ve nt o nset) t o all o w f or c ortic oster oi ds (if i nitiate d) t o be re d uce d t o t he 
e q ui vale nt of  1 0 m g/ da y oral pre d nis o ne. T he acce pta ble le n gt h of t he e xte n de d peri o d of 
ti me m ust be a gree d u p o n b y t he i n vesti gat or a n d t he S p o ns or-I n vesti gat or.

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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 tiragolumab and 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 tiragolumab and atezolizumab only after approval has been documented 
by both the investigator (or an appropriate delegate) and the Sponsor-Investigator.
5.7.4.15 Hemophagocytic lymphohistiocytosis and Macrophage Activation 
Syndrome
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be considered 
when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2014).  A patient should be classified as having HLH if five of the following eight criteria 
are met:

Fever ≥ 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
o
 Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [< 10 g/dL] for infants < 4 weeks old)
o
 Platelet count < 100 x 109/L (< 100,000/mL)
o
ANC < 1.0  109/L (< 1000/mL)
o
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (< 
150 mg/dL)
o
Hemophagocytosis in bone marrow, spleen, lymph node, or liver
o
Low or absent natural killer cell activity
o
Ferritin > 500 mg/L ( > 500 ng/mL)
o
Soluble interleukin-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:
o
 Ferritin > 684 mg/L (684 ng/mL)
o
At least two of the following:

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
Platelet count ≤ 181 x 109/L (≤ 181,000/mL)

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 
below:
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome
Event
Management
Suspected HLH or 
MAS
·     Permanently discontinue tiragolumab and 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 and/or anti-cytokine therapy.
·    If event does not respond to treatment within 24 hours, contact Medical 
Monitor and initiate treatment as appropriate according to published 
guidelines (La Rosée 2015; Schram and Berliner 2015; La Rosée et al. 
2019).
·     If event resolves to Grade 1 or better, taper corticosteroids over  1 
month.
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome.
5.8
Concomitant Therapy
Concomitant therapy includes any prescription medications or over-the-counter preparations 
used by a patient between the 7 days preceding the screening evaluation and the treatment 
discontinuation visit. At subsequent visits, changes to current medications or medications used 
since the last documentation of medications will be recorded.

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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. Serious infusion-associated events manifested by 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or 
respiratory distress should be managed with supportive therapies as clinically indicated (e.g., 
supplemental oxygen and β2-adrenergic agonists; see Appendix 5).
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab and tiragolumab but may be administered at the 
discretion of the treating physician after consultation with the Study Chair. If feasible, 
alternatives to corticosteroids should be considered. Premedication may be administered for 
Cycles ≥ 2 at the discretion of the treating physician after consultation with the Study Chair.
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with 
orthostatic hypotension, adrenocortical insufficiency, or for obstructive lung disease 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 September 
to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 
weeks prior to Cycle 1, Day 1 or at any time during the study but may receive inactivated 
vaccine.
Patients who use hormonal therapy with gonadotropin-releasing hormone agonists or 
antagonists for prostate cancer, oral contraceptives, hormone-replacement therapy, prophylactic 
or therapeutic anticoagulation therapy (such as low molecular weight heparin or warfarin at a 
stable dose level), or other allowed maintenance therapy (see section 3.3 Eligibility Criteria) 
should continue their use.
Males and females of reproductive potential should use highly effective means of contraception.
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF.
5.9
Excluded Therapy
Any concomitant therapy intended for the treatment of cancer, whether health 
authority−approved or experimental, is prohibited. This includes but is not limited to the 
following:
●
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, 
investigational agents, or herbal therapy (except for maintenance 
therapies outlined in section 5.8).
●
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
●
Patients who are receiving a receptor activator of nuclear factor kappa B 
ligand (RANK- ligand) inhibitor (denosumab) prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while on study; 

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denosumab could potentially alter the activity and the safety of the study 
drugs.
●
Initiation or increased dose of granulocyte colony-stimulating factors (e.g. 
granulocyte colony-stimulating factor, granulocyte/macrophage colony-
stimulating factor, and/or pegfilgrastim) is strongly discouraged.
●
Patients are not allowed to receive immunostimulatory agents, including 
but not limited to interferon (IFN)-α, IFN-γ, IL-2, or ipilumumab during the 
entire study. These agents, in combination with the study drugs, 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 the study drugs. Systemic corticosteroids and 
anti−TNF-α agents may attenuate potential beneficial immunologic effects 
of treatment with the study drugs but may be administered at the 
discretion of the treating physician after consultation with the Study Chair. 
If feasible, alternatives to these agents should be considered.
●
In addition, all patients (including those who discontinue the study early) 
should not receive any other immunostimulatory agents for 10 weeks 
after the last dose of the study drugs.
●
Patients who receive local therapy directed at the bladder (i.e., repeat 
TURBT, radiation therapy) after study treatment initiation but prior to 
cystectomy will be considered ineligible for response evaluation, but will 
remain eligible for safety and correlative evaluation. Such cases must be 
discussed with and approved by the Study Chair.
6
Study Schedule, Procedures and Observations
The study-specific assessments are detailed in this section. Screening assessments must be 
performed within 28 days prior to the first dose of investigational product. Any results falling 
outside of the reference ranges may be repeated at the discretion of the investigator. All on- 
study visit procedures are allowed a window of ± 3 days unless otherwise noted. Treatment or 
visit delays for public holidays or weather conditions do not constitute a protocol violation.
Patients will be closely monitored for safety and tolerability throughout the study. All 
assessments must be performed and documented for each patient.
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable.
The following apply to both screening assessments as well as to on study visits:
6.1
Informed Consent Forms and Screening Log
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records. Informed 

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Consent Forms for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is 
password protected and meets HIPAA requirements.
Each participating site is responsible for OnCore® registration of study participants consented at 
the 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.
6.2
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, ECOG performance status, sex, and self-reported 
race/ethnicity.
Cancer history will include an assessment of prior treatment with BCG.
6.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, nose, 
and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
and neurological systems. Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. Height (baseline only) and weight 
should be measured and recorded in the eCRF.
6.4
Vital Signs and Weight
Vital signs will include measurements of pulse rate, respiratory rate, systolic and diastolic blood 
pressures while the patient is in a seated position, weight, oxygen saturation, and temperature. 
Patient height should be recorded once during the study either in the screening period or on 
cycle 1 day 1 prior to the first study treatment.
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 15 [± 5] minutes), 
and 30 (± 10) minutes. 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.
Blood oxygen saturation will be measured at timepoints indicated in the study calendar using 
pulse oximetry.

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6.5
Tumor Evaluation Methods
All subjects must have undergone cystoscopy or TURBT prior to study screening to document 
the presence of urothelial carcinoma.
Screening assessments must include CT scans of the chest, abdomen, and pelvis (with oral/IV 
contrast unless contraindicated) or magnetic resonance imaging (MRI) of the chest, abdomen, 
and pelvis.
Screening bone imaging with either a technetium bone scan or a sodium-fluoride PET/CT is 
required only for subjects with an elevated alkaline phosphatase or symptoms to suggest bony 
metastasis. If bony metastases are detected at screening then the subject will be ineligible for 
study participation. Further bone-specific imaging should be performed as clinically indicated.
Imaging of the brain, head, and/or neck is not required for study entry but should also be 
performed if clinically indicated. If a CT scan for tumor assessment is performed using an FDG 
positron emission tomography (PET) /CT scanner, the CT acquisition must be consistent with 
the standards for a full-contrast diagnostic CT scan. At the investigator’s discretion, other 
methods of assessment of measurable disease as per RECIST v1.1 may be used.
Results of standard of care tests or examinations performed prior to obtaining Informed Consent 
and ≤28 days prior to study entry may be used for the purposes of Screening rather than 
repeating such tests. Radiographic imaging assessments performed up to 45 days prior to study 
entry (i.e., available) may be used for the purposes of Screening.
For subsequent tumor assessments, procedures for tumor assessment should be performed as 
per the study calendar (see section 6.10) and clinically indicated. The same radiographic 
procedure used to assess disease sites at screening should be used throughout the study (e.g., 
the same contrast protocol for CT scans). All known sites of disease (i.e., local lymph nodes) 
must be documented at screening and reassessed at each subsequent tumor evaluation. 
Relapse will be assessed by the investigator using RECIST v1.1 and modified RECIST criteria. 
The same evaluator should perform assessments if possible to ensure internal consistency 
across visits.
At the investigator’s discretion, CT scans or bone-specific imaging should be repeated at any 
time if recurrent disease is suspected.
6.6
Laboratory, Biomarker, and Other Biological Samples
“Local” laboratory tests may be performed either at a local certified laboratory or at the study 
site. “Central” laboratory tests should be drawn at the study site and may be analyzed at the 
coordinating center or sent to Roche.
6.6.1 Local laboratory assessments
Local laboratory assessments may 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)

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●
Serum chemistries including: sodium, potassium, chloride, bicarbonate, 
BUN, creatinine, glucose, calcium, magnesium, phosphorus, total 
bilirubin, ALT, AST,
●
alkaline phosphatase, total protein, albumin and LDH
●
C-reactive protein (CRP)
●
Serum pregnancy test (only for women of childbearing potential, including 
premenopausal women who have had a tubal ligation)
●
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood)
●
Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free 
T4)
●
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core 
antigen)
●
HBV DNA should be obtained prior to Cycle 1, Day 1 if patient has 
positive serology for anti-HBc Ab.
●
HCV serology (anti-HCV antibody)
●
HIV testing (if in accordance with national and/or institutional guidelines)
●
The following laboratory tests will be performed only if there is clinical 
suspicion of acute immune-related toxicity. These should be performed at 
any point during the study if immune-related toxicity is suspected:
●
Auto-antibody testing
●
Anti-nuclear antibody (ANA)
●
Anti−double-stranded DNA (Anti-dsDNA)
●
Circulating anti-neutrophil cytoplasmic antibody (C-ANCA)
●
Perinuclear anti-neutrophil cytoplasmic antibody (P-ANCA)
●
Epstein-Barr virus (EBV) serology
●
Creatine kinase (CK) level
6.6.2 Central laboratory assessments
Central laboratories will coordinate the collection of archival tumor, fresh tumor, and leftover 
tumor tissue and blood samples for the assessment of atezolizumab and tiragolumab 
biomarkers, ATA assays, and auto-antibody testing. Instruction manuals and supply kits will be 
provided for all central laboratory assessments.
The following assessments will be performed at a central laboratory or Genentech:
●
Anti-Therapeutic Antibody (ATA) assays and atezolizumab and 
tiragolumab levels (only in case of clinical suspicion of serious acute 
immune or inflammatory toxicity, related to atezolizumab and/or 
tiragolumab)
o
Serum samples will be assayed for the presence of ATAs to anti-
atezolizumab and tiragolumab with use of validated 

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immunoassays. Atezolizumab and tiragolumab levels will be 
assessed using validated assays.
●
T, B, and NK cell (TBNK) assays
●
PD-L1 testing by IHC
o
Archival tissue blocks are slides will be shipped to a central lab for 
analysis of PD- L1 expression by IHC
●
Biomarkers in tumor tissues
●
RNA and DNA will be extracted from ~ 5 7μ sections for the analysis of 
genes associated with tumor immune biology as well as genomic 
mutations.
●
Biomarker and immunologic assays in blood samples
o
Blood samples will be obtained for biomarker evaluation from all 
eligible patients at screening, before treatment, on treatment, at 
the treatment discontinuation visit, and in the follow-up period. 
Samples will be processed to obtain blood cells (and their 
derivatives), plasma, and serum for the determination of changes 
in surrogate biomarkers and immunologic assays that may be 
altered in UC or biomarkers that are related to UC and tumor 
immune biology (including but not limited to IFN-gamma and other 
exploratory biomarkers).
●
Biomarker immunologic assays in urine samples
o
Urine samples will be obtained for biomarker evaluation from all 
eligible patients before study treatment, on treatment, and at the 
treatment discontinuation visit. Samples will be processed to 
obtain tumor cells (and their derivatives) and immune cells, for the 
determination of changes in surrogate biomarkers that may be 
altered in UC or biomarkers that are related to UC and tumor 
immune biology (including but not limited to IFN-gamma and other 
exploratory biomarkers).
Any remaining samples collected for biomarker assays, may be used for exploratory biomarker 
profiling and identification purposes as appropriate. In addition, exploratory biomarkers 
(including but not limited to markers related to immune or UBC biology) may be evaluated in 
tissue samples.
●
Archival and fresh tumor tissue sample
o
Representative tumor specimens in paraffin blocks (preferred) or 
at least 15 unstained slides, with an associated pathology report, 
should be submitted prior to study enrollment.
o
Tumor tissue should be of good quality based on total and viable 
tumor content (sites will be informed if the quality of the submitted 
specimen is inadequate to determine tumor PD-L1 status). Fine-
needle aspiration, brushing, cell pellets, and lavage samples are 
not acceptable. For any core needle biopsy specimens, at least 
three cores should be submitted for evaluation.

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o
Additional archival tumor specimens should be submitted if 
available.
o
Any fresh and/or paraffin embedded TURBT specimens (prior to 
study therapy or while on study therapy) or cystectomy specimens 
(after study therapy) will be made available for assessment of 
tumor response, and characterization of PD-1 and PD-L1 
expression and of immunologic infiltrate.
o
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 4 weeks after eligibility 
determination.
●
Tumor biopsy at the time of initial radiographic recurrence
o
All patients will undergo a mandatory tumor biopsy sample 
collection, if clinically feasible as determined by the study 
investigator in consenting patients, at the first evidence of 
radiographic disease recurrence. Subjects may opt-out of this 
biopsy.
o
Acceptable samples include core needle biopsies for deep tumor 
tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions. For 
core needle biopsy specimens, at least three cores should be 
submitted for evaluation. A fine needle aspirate is not acceptable.
●
Use and storage of remaining samples from study-related procedures
o
The remainder of 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.
Please refer to the laboratory manual for additional details on laboratory assessments and 
sample handling.
6.7
Cardiac Tests: Electrocardiograms (ECGs)
Twelve-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 safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at the 
site. Any morphologic waveform changes or other ECG abnormalities must be documented on 
the eCRF.
6.8
Anti-Therapeutic Antibody and atezolizumab and tiragolumab Testing
Atezolizumab and/or tiragolumab may elicit an immune response. Patients with signs of any 
potential immune response to atezolizumab and/or tiragolumab will be closely monitored. 

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Validated assays will be employed to detect ATAs and atezolizumab and/or tiragolumab levels if 
warranted based on clinical suspicion of ATA development.
6.9
Study Schedule
6.9.1 Screening
 The Screening procedures and assessments must be completed within 28 days of the Day 1 
Visit. Local and Central laboratory assessments done within 14 days of beginning treatment do 
not need to be repeated for Cycle 1 Day 1.
●
Physical examination
●
Vital signs
●
Complete medical history
●
Baseline conditions assessment
●
Documentation of disease
●
Performance status
●
History of prior treatments and any residual toxicity relating to prior 
treatment
●
Baseline medications taken within 7 days of Day 1
●
Archival sample of tumor tissue acquisition. Acquisition of representative 
formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin 
blocks (blocks preferred) or at least 15 unstained slides, with an 
associated pathology report, for central testing for tumor PD-L1 
expression and immune characterization.
●
Laboratory assessments:
o
Hematology (CBC, including RBC count, hemoglobin, hematocrit, 
WBC count with differential [neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells], and platelet 
count)
o
Serum chemistries including: sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, glucose, calcium, magnesium, 
phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, total 
protein, albumin and LDH
o
C-reactive protein (CRP)
o
Serum pregnancy test (only for women of childbearing potential, 
including premenopausal women who have had a tubal ligation) 
must be performed within 14 days of cycle 1 day 1.
o
Urinalysis (specific gravity, pH, glucose, protein, ketones, and 
blood)
o
Thyroid function testing (thyroid-stimulating hormone [TSH], free 
T3, free T4)
o
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core 
antigen)

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o
HBV DNA should be obtained prior to Cycle 1, Day 1 if patient has 
positive serology for anti-HBc Ab.
o
HCV serology (anti-HCV antibody)
o
HIV testing (if in accordance with national and/or institutional 
guidelines)
o
Serum will be banked and frozen during screening for the 
following assays in all patients, however these assays will only be 
run to establish baseline values if there is clinical suspicion of 
acute immune-related toxicity related to atezolizumab and/or 
tiragolumab:
▪
Auto-antibody testing, including ANA, Anti-dsDNA, C-
ANCA, P-ANCA
o
EBV serology (See Section 3.3.2 Exclusion Criteria) 
o
Creatine kinase (CK) level
●
Central laboratory assessments
o
TBNK blood sample
o
Urine sample for cytokine assessment.
●
Imaging (CT or MRI) of the chest, abdomen, and pelvis for tumor/lesion 
assessment. These assessments may be performed up to 45 days prior 
to study entry. Imaging of the upper tracts with an intravenous pyelogram, 
CT urography, renal ultrasound with retrograde pyelogram, ureteroscopy, 
or MRI urogram should be performed if clinically indicated.
●
Electrocardiogram (ECG)
●
Bone scan (technetium OR sodium-fluoride PET/CT) (only for subjects 
with an elevated alkaline phosphatase or clinical suspicion of bony 
metastatic disease)
6.9.2 Treatment Period
Day 1 of all cycles (+/- 3 days for cycles ≥2)
●
Physical examination
●
Vital signs
●
Performance status
●
Evaluation of adverse events
●
Concomitant medications
●
Local laboratory assessments. Unless otherwise noted, they may be 
obtained up to 96 hours prior to day 1 of each cycle:
o
CBC with differential and platelet count

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o
Blood chemistry assessment, including: sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
magnesium, phosphorus, total bilirubin, ALT,
o
AST, alkaline phosphatase, total protein, albumin and LDH
o
C-reactive protein
o
Urinalysis
●
Central laboratory assessments
o
Immunologic and pharmacodynamic evaluations
o
TBNK blood sample
o
Plasma, serum, and blood sample for PD biomarkers
o
Urine sample for cytokine assessment.
●
Atezolizumab/tiragolumab infusion. See section 5.1 for dosing and 
administration requirement.
6.9.3 End of Treatment (prior to cystectomy)
To be completed within 30 days of the last dose of study drug and prior to cystectomy.
●
Physical examination
●
Vital signs
●
Performance Status
●
Evaluation of adverse events
●
Concomitant medications
●
Local Laboratory Assessments. Unless otherwise noted, they may be 
obtained up to 96 hours prior to the visit:
o
Hematology assessment, including CBC with differential and 
platelet count
o
Blood chemistry assessment, including: glucose, BUN, creatinine, 
sodium, potassium, magnesium, chloride, bicarbonate, calcium, 
phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, 
total protein, and albumin
o
C-reactive protein
o
Urinalysis
o
TSH, T3 and T4
●
Central laboratory assessments
o
Immunologic and pharmacodynamic evaluations
o
TBNK blood sample
o
Plasma, serum, and blood sample for PD biomarkers
o
Urine sample for cytokine assessment.
●
Imaging (CT or MRI) of the abdomen, and pelvis for tumor/lesion 
assessment, and if clinically indicated, imaging of the chest (CXR or CT). 

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Imaging of the upper tracts with an intravenous pyelogram, CT 
urography, renal ultrasound with retrograde pyelogram, ureteroscopy, or 
MRI urogram should be performed if clinically indicated.
●
No repeat TURBT is required after the initiation of study therapy, however 
if performed per institutional standard of care then any tissue or other 
tumor biopsy should be obtained for analysis.
6.9.4 Post-cystectomy/Follow Up Visits
Patients will be followed every 4 weeks (+/- 1 weeks) from the time of cystectomy for 12 weeks, 
and thereafter every 12 weeks for up to 2 years after cystectomy or until disease progression, 
death, study termination, or withdrawal from study, whichever occurs first. 
●
Radiographic imaging should occur every 12 weeks and at end of 
treatment as outlined in the study calendar.
●
The following Central Laboratory tests should be obtained every 12 
weeks
o
TBNK blood sample
o
Plasma, serum, and blood sample for PD biomarkers
o
Urine sample for cytokine assessment.
Once all therapy is completed patients should be followed every 12 weeks until the completion 
of 2 years after cystectomy or until disease progression, death, study termination, or withdrawal 
from study, whichever occurs first.
Patients who discontinue study treatment prior to cystectomy for reasons other than disease 
progression (e.g., toxicity) should continue to undergo scheduled tumor assessments until the 
patient dies, experiences disease progression, withdraws consent, for 2 years from the last 
dose of study therapy or until the study closes, whichever occurs first.
Patients who start a new anti-cancer therapy (i.e. adjuvant chemotherapy) in the absence of 
disease progression should continue to be followed for progression according to the protocol 
schedule of response assessments unless they withdraw consent, experience disease 
progression, death, study termination, or withdrawal from study, whichever occurs first. 
In addition to tests performed per local standard of care, the following procedures will be 
performed at the Follow Up Visit(s):
●
Physical examination
●
Vital signs
●
Performance Status
●
Evaluation of adverse events
o
After initiation of study drug, all adverse events will be reported 
until 30 days after the last dose of study treatment. After this 
period, investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be 
related to prior treatment with study drug.
●
Concomitant medications

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●
Pathologic review of tumor response (first follow up visit only)
●
Local Laboratory Assessments. Unless otherwise noted, they may be 
obtained up to 96 hours prior to the visit:
o
Hematology assessment, including CBC with differential and 
platelet count
o
Blood chemistry assessment, including: glucose, BUN, creatinine, 
sodium, potassium, magnesium, chloride, bicarbonate, calcium, 
phosphorus, total bilirubin,
o
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin
o
C-reactive protein
o
Urinalysis including urine cytology
o
TSH, T3 and T4
●
Central laboratory assessments
o
Immunologic and pharmacodynamic evaluations
o
TBNK blood sample
o
Plasma, serum, and blood sample for PD biomarkers
o
Acquisition of cystectomy tissue (either fresh or paraffin 
embedded) for immunologic characterization.
●
Imaging
o
CT or MRI of the abdomen and pelvis for tumor recurrence to be 
performed every 12 weeks.
o
Imaging of the upper tracts with an intravenous pyelogram, CT 
urography, renal ultrasound with retrograde pyelogram, 
ureteroscopy, or MRI urogram should be performed per 
institutional standard of care.
o
Chest imaging (Chest X-ray or CT Chest) every 12 weeks.
●
Tumor tissue (only at the first evidence of radiographic disease 
recurrence)
o
Mandatory tumor biopsy sample collection, if clinically feasible as 
determined by the study investigator in consenting patients. 
Subjects may opt-out of this biopsy.
o
Acceptable samples include core needle biopsies for deep tumor 
tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions. For 
core needle biopsy specimens, at least three cores should be 
submitted for evaluation. A fine needle aspirate is not acceptable.
6.9.5 End of Study Visit
In addition to tests performed per local standard of care, at 1 month (allowed up to 2 months) off 
study the following procedures will be performed at the End of Study Visit:
●
Physical examination

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●
Vital signs
●
Performance Status
●
Evaluation of adverse events
o
After initiation of study drug, all adverse events will be reported 
until 30 days after the last dose of study treatment. After this 
period, investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be 
related to prior treatment with study drug.
●
Concomitant medications
●
Pathologic review of tumor response (if not already performed)
●
Local Laboratory Assessments. Unless otherwise noted, they may be 
obtained up to 96 hours prior to the visit:
o
Hematology assessment, including CBC with differential and 
platelet count
o
Blood chemistry assessment, including: glucose, BUN, creatinine, 
sodium, potassium, magnesium, chloride, bicarbonate, calcium, 
phosphorus, total bilirubin,
o
ALT, AST, alkaline phosphatase, LDH, total protein, and albumin
o
C-reactive protein
o
Urinalysis including urine cytology
●
Central laboratory assessments
o
Immunologic and pharmacodynamic evaluations
o
TBNK blood sample
o
Plasma, serum, and blood sample for PD biomarkers
o
Acquisition of cystectomy tissue (either fresh or paraffin 
embedded) for immunologic characterization (if not done already 
performed)
●
Imaging (only required if not performed within the last 8 weeks)
o
CT or MRI of the abdomen and pelvis
o
Imaging of the upper tracts with an intravenous pyelogram, CT 
urography, renal ultrasound with retrograde pyelogram, 
ureteroscopy, or MRI urogram should be performed per 
institutional standard of care.
o
Chest imaging (Chest X-ray or CT Chest)
●
Tumor tissue (only at the first evidence of radiographic disease 
recurrence, if not already performed)
o
Mandatory tumor biopsy sample collection, if clinically feasible as 
determined by the study investigator in consenting patients. 
Subjects may opt-out of this biopsy.
o
Acceptable samples include core needle biopsies for deep tumor 
tissue or lymph nodes or excisional, incisional, punch, or forceps 

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biopsies for cutaneous, subcutaneous, or mucosal lesions. For 
core needle biopsy specimens, at least three cores should be 
submitted for evaluation. A fine needle aspirate is not acceptable.
6.9.6 Long Term/Survival Follow-up Procedures
Following early discontinuation all patients will be followed for 2 year relapse free survival and 
subsequent anti-cancer therapy. Survival and subsequent anti-cancer therapy follow-up 
information will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study 
termination by the Sponsor, for up to 2 years after cystectomy. Subjects will not be followed for 
overall survival.
6.9.7 Discontinuation of Therapy
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. Reasons 
for withdrawal from the study may include but are not limited to the following:
●
Patient withdrawal of consent at any time
●
Any medical condition or adverse event 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
●
Any significant uncertainty on the part of the Investigator that continued 
participation is prudent.
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 after a dose of study therapy has been administered will 
not be replaced.
6.9.8 Study Treatment Discontinuation
Patients must discontinue study treatment if they experience any of the following:
●
Symptomatic deterioration (i.e., uncontrollable pain secondary to disease) 
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 and/or tiragolumab, including 
development of an immune-related adverse event (irAE) 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

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●
Use of another non-protocol anti-cancer therapy (see Section 5.9)
●
Pregnancy
●
The primary reason for study treatment discontinuation must be 
documented in the eCRF.

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6.10 Study Calendar
Screeninga
All 
Cycles
Treatment 
Discontinuationb
Post-
cystectomy
Follow-Up
Off 
Study
Assessment 
Window 
(Days)
Day -28 to 
Day -1
Day   1 
(± 3 Days 
for Cycles 
≥ 2)
≤ 30 Days after 
Last Dose, prior 
to cystectomy
Every 4 weeks
(+/- 1 week) x 
12 weeks 
totalz
Every 12
weeks (+/- 
2 weeks)
Informed Consent
x
Review of eligibility criteria
x
Medical, surgical, and 
cancer histories, 
including demographic 
information
x
Concomitant medicationc
x
x
x
x
x
x
Adverse eventsd
x
x
x
x
x
x
Tumor tissue acquisition 
or 15 unstained slides e
x
xk
xk
Treatment administration
Atezolizumab infusionf 
(Cohort A)
x
Atezolizumab and 
Tiragolumab infusionf,g 
(Cohort B) 
X
Clinical procedures
Complete 
physical 
examinationh
x
x
x
x
x
x
Performance statush
x
x
x
x
x
x
Vital signsi
x
x
x
x
x
x
Oxygen saturation 
(pulse oximetry)
x
x
x
x
x
x
Tumor assessmentsj
x
x
x
x
Survival and anti-
cancer therapy follow-
up l
x
x
Laboratory proceduresh
Hematologym
x
x
x
x
x
x
Serum chemistryn
x
x
x
x
x
x
Urinalysiso
x
x
x
x
x
x
Urine sample
x
x
x
x
x
x

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Screeninga
All 
Cycles
Treatment 
Discontinuationb
Post-
cystectomy
Follow-Up
Off 
Study
Assessment 
Window 
(Days)
Day -28 to 
Day -1
Day   1 
(± 3 Days 
for Cycles 
≥ 2)
≤ 30 Days after 
Last Dose, prior 
to cystectomy
Every 4 weeks
(+/- 1 week) x 
12 weeks 
totalz
Every 12
weeks (+/- 
2 weeks)
Pregnancy test (HCG)p
x
TSH, free T3, free T4
x
x
HIV, HBV, and HCV
Serologyq
x
CRP
x
x
x
x
x
x
Serum banking for 
baseline auto-antibody 
testingr
x
EBV serologys
x
CKt
x
TBNK blood sampleu
x
x
x
x
x
x
Plasma, serum, and 
blood sample for PD 
biomarkersu
x
x
x
x
x
Imaging procedures
ECGv
x
Chest imagingw
x
x x
x
x
Bone scanx
x
Abdominal imaging (CT 
or MRI)
x
x
x x
x
x
anti-HBc = hepatitis B core antigen; ATA = anti-therapeutic antibody; EBV = Epstein-Barr virus; HBV = hepatitis B virus, 
HCV = hepatitis C virus; MRI = magnetic resonance imaging; TBNK = T, B, and NK cells; TSH = thyroid-stimulating 
hormone; CK = creatine kinase.
Note: Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless 
otherwise noted.
a.
Examinations performed as standard of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 
1 may be used rather than repeating tests, and within 45 days for radiographic imaging. If patients are declining 
cisplatin-based chemotherapy the reason must be documented.
b.
All patients will return within 30 days for a follow up visit, including those who discontinue study therapy early.
c.
See Section 5.8.
d.
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a 
protocol-mandated intervention should be reported. After initiation of study drug, all adverse events will be reported 
until 30 days after the last dose of study treatment. After this period, investigators should report any deaths, serious 
adverse events, or other adverse events of concern that are believed to be related to prior treatment with study drug. The 
investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow up, or the patient withdraws consent. Every effort 
should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.

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e.
Only tumor tissue from initial TURBT and cystectomy are required per protocol. Tumor tissue 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). Fine-needle aspiration, brushing, and cytologic cell pellets are not 
acceptable. For core needle biopsy specimens, at least three cores should be submitted for evaluation. Ideally, a tumor 
specimen obtained after completion of the most recent therapy should be submitted. Any archival tumor specimen, if 
available, should also be submitted. Repeat TURBT or other tumor biopsies are not required after the start of 
therapy, prior to cystectomy, however if done at any point per local standard of care then all tissue available 
should be acquired.
f.
For both atezolizumab and tiragolumab, the initial dose of study drug 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. 
g.
Tiragolumab dose will be administered following the dose of atezolizumab. If one agent (either atezolizumab or 
tiragolumab is held then both study drugs should be held.
h.
ECOG performance status, physical examination, and local laboratory assessments (CBC, serum chemistries, urinalysis) 
may be obtained ≤ 96 hours before the scheduled visit. Laboratory procedures measured within 14 days of beginning 
treatment do not need to be repeated on Cycle 1 Day 1.
i.
Vital signs include heart rate, respiratory rate, blood pressures, temperature, weight, and oxygen saturation. Height 
should be recorded once during screening or prior to cycle 1 day 1. For first infusion of study treatment, 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. Patients will be informed about the possibility of delayed post-infusion symptoms and instructed to contact 
their study physician if they develop such symptoms.
j.
All measurable and evaluable lesions should be assessed and documented at the screening visit. The same radiographic 
procedure should be used throughout the study for each patient. Available results must be reviewed by the investigator 
before dosing at the next cycle. Pathologic review of tumor response should occur at the first follow up visit after 
cystectomy. Patients will undergo assessments for tumor recurrence every 12 weeks (+/- 2 weeks) for the first 2 years 
following cystectomy. Patients who discontinue from the initial treatment stage for reasons other than disease 
progression (e.g. toxicity) will continue scheduled tumor assessments until disease recurrence, withdrawal of consent, or 
death. Patients who start a new anti-cancer therapy in the absence of disease recurrence (e.g. adjuvant therapy) should 
be followed according to the protocol schedule unless they withdraw consent. Investigators may perform additional 
scans or more frequent assessments if clinically indicated.
k.
Tumor biopsy at recurrence, preferably at the time of radiographic progression. Patients may opt out of this biopsy. 
Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, 
or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. For core needle biopsy specimens, at least three 
cores should be submitted for evaluation.
l.
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately every 3 months until death, loss to follow-up, withdrawal of consent, or study termination by Sponsor. 
All patients will be followed for survival and new anti-cancer therapy information unless the patient requests to be 
withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator. If 
the patient 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.
m.
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential 
(neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), and platelet count. A manual differential 
can be done if clinically indicated. 
n.
Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, magnesium, 
phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, total protein, albumin and LDH
o.
Specific gravity, pH, glucose, protein, ketones, and hemoglobin.
p.
Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be 
performed and documented as negative within 14 days prior to Day 1.
q.
HIV testing to be performed in accordance with national and/or institutional guidelines. Hepatitis B surface antigen, 
anti-HBc antibody and anti-HBs antibody should be collected during screening. In patients who have positive serology 
for the anti-HBc antibody, HBV DNA should be collected prior to Cycle 1, Day 1.
r.
Serum will be banked and frozen during screening, however these assays will only be run to establish baseline values if, 
at a later point in the study, there is clinical suspicion of acute immune-related toxicity related to study drug.
s.
Perform Epstein-Barr virus (EBV) viral capsid antigen IgM test at screening (See Section 3.3.2 Exclusion Criteria)
t.
Perform creatine kinase (CK) testing at screening, and as clinically indicated as determined by the Investigator
u.
See Appendix 4 for details
v.
ECG recordings will be obtained during screening and as clinically indicated at other timepoints. Patients should be 
resting and in a supine position prior to ECG collection.

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w.
Chest CT is required for screening. Chest X-ray or Chest CT are acceptable in the follow-up phase for surveillance for 
tumor recurrence, per institutional guidelines. If clinical suspicion of recurrent disease in the chest a CT scan should be 
performed.
x.
Bone scan (Technetium or Sodium-fluoride PET/CT required at screening only for subjects with an elevated alkaline 
phosphatase or clinical suspicion of bony metastatic disease. Further imaging for subjects on study only as clinical 
indicated.
y.
Chest and abdominal imaging at the 12 week post cystectomy visit, does not need to be done earlier unless clinically 
warranted

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7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy
7.1.1 Pathologic Response
Treatment efficacy will be determined by the pathologic determination of tumor response at the 
time of cystectomy. This will include determination of tumor response in the bladder as well as 
in any resected lymph nodes.
Pathologic determination should be in accord with collaborative guidelines33 and should 
specifically proceed as follows:
For all cystectomy specimens the pathologist will cut the tissue at roughly 0.5cm intervals to 
look for a tumor mass. If no tumor mass is seen on gross examination then representative 
sections should be put in. If cystoscopic abnormalities are noted by the treating Urologist, then 
the treating Urologist will indicate location of cystoscopic abnormalities (up to 4 different ones) 
on the pathology requisition, and that pathologists will “block in” each of these areas (up to 4 
different areas) during pathologic evaluation of the bladder to cover at least 1 cm square area of 
each indicated location. This is in addition to any grossly-recognized residual tumor foci that are 
seen when opening the bladder for pathologic evaluation.
It is similarly recommended that prior surgical sites or mucosal ulcerations be sampled in their 
entirety for residual tumor and adequate mapping performed. Furthermore, areas that appear 
red and regions of mucosal induration should be sampled to rule out CIS. There is no need for 
complete embedding of the entire bladder wall. Communication between the urologic surgeon 
and pathologist is key in cases where prior surgical sites, mucosal ulcerations, or alterations are 
not evident to ensure that appropriate tissue sampling occurs.
The following definitions apply to determination of pathologic responses:
Evaluable for pathologic complete response
Only those patients who have received at least one cycle of therapy, and have had their disease 
evaluated pathologically at the time of resection will be considered evaluable for pathologic 
response. These patients will have their response classified according to the pathologic 
complete response definitions below:
●
Pathologic complete response (pCR): Defined as the presence of pT0 
disease. Similarly there must be no evidence of tumor in all resected 
lymph nodes (N0).
●
Near pathologic complete response (near pCR): Defined as the 
presence of Ta or Tis disease (or both) in the resection specimen, without 
evidence of any higher stage disease elsewhere or evidence of tumor in 
all resected lymph nodes (N0).
All patients will be followed for 2 years post-cystectomy to evaluate for tumor recurrence.
7.1.2 Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 

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92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria.
7.1.2.1
Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
Evaluable for objective response
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated prior to resection will be 
considered evaluable for response. These patients will have their response classified according 
to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of Cycle 1 will also be considered evaluable.)
7.1.2.2
Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. 
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.
Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response.
Non-target lesions
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. It is possible to record multiple non-target lesions involving the same organ as a single 
item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”).  Bone lesions may be measurable if ≥ 1 cm on MRI. Measurements of these 
lesions are not required, but the presence or absence of each will be noted throughout follow-
up.
Non-measurable disease (Tumor Markers)

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Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan). 
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non- 
measurable. (e.g. PSA, CA-125, CA19-9, CEA)
7.1.2.3
Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.
The same method of assessment (for example CT or MRI) and the same technique will be used 
to characterize each identified and reported lesion at baseline and during follow-up. Imaging- 
based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment.
7.1.2.4
Response Criteria
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart. Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD. There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis).

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Incomplete Response/Stable Disease (SD)
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
Table 7.1 Response Criteria
Target 
Lesions
Non-Target 
Lesions
New Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-CR/Non-PD
No
PR
PR
Non-PD
No
PR
≥4 wks. Confirmation**
SD
Non-PD
No
SD
Documented at least once ≥4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression
Duration of Response
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.
Progression-Free Survival

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Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression.
Disease-Free Survival
Disease-free survival (DFS) is defined as the duration of time from start of treatment to time of 
documented disease recurrence.
7.2
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use CTCAE v4.0 for Cohort A and will use CTCAE v5.0 for Cohort B for reporting of 
non-hematologic adverse events and modified criteria for hematologic adverse events, see 
section 5.7.
7.2.1 Specification of Safety Variables
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to study drug, all events of death, and any 
study specific issue of concern.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.
7.2.2 Definitions of Adverse Events
7.2.2.1
Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product (IMP) or other protocol-imposed intervention without any 
judgment about causality. An adverse event can arise from any use of the drug (e.g., off-label 
use, use in combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose.
This includes the following:
●
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms 
associated with transitional cell carcinoma of the bladder that were not 
present prior to the AE reporting period.
●
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations).
●
If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention.

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●
Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period.
7.2.2.2
Adverse reaction
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.2.2.3
Suspected
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:
Yes (definite, probably, possible, unlikely)
 
There is a plausible temporal relationship between the onset of the AE and administration of 
the {study drug}, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the {study drug} or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of the {study drug} or dose reduction and, if applicable, reappears upon re- 
challenge.
 
No (unrelated)
 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or 
the AE has no plausible temporal relationship to {study drug} administration (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.     
7.2.2.4
Unexpected
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.

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Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure. For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
7.2.2.5
Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:
●
Death
●
Life-threatening adverse event, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death
●
Inpatient hospitalization or prolongation of existing hospitalization
●
A persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life function
●
Congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP.
●
Significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above).
     
7.3
Methods and Timing for Assessing AND Recording Safety variables
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, 
Inc. in accordance with CFR 312.32 (IND Safety Reports). 
7.4
Adverse Event Reporting Period
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of any study procedures and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment.

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7.5
Procedures for Eliciting, Recording, and Reporting Adverse Events
7.5.1 Eliciting Adverse Events
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be 
adopted. Examples of non-directive questions include:
●
“How have you felt since your last clinical visit?”
●
“Have you had any new or changed health problems since you were last 
here?”
7.5.2 Specific Instructions for Recording Adverse Events
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations.
7.5.2.1
Diagnosis vs. Signs and Symptoms
If known at the time of reporting, a diagnosis should be reported 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, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information.
7.5.2.2
Deaths
All deaths that occur during the protocol-specified AE reporting period (see Section 7.3.3), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”.
7.5.2.3
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”).
7.5.2.4
Hospitalizations for Medical or Surgical Procedures
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE.
Hospitalizations for the following reasons do not require reporting:

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●
Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for preexisting conditions
●
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or
●
Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study.
7.5.2.5
Pregnancy
If a female subject or a female partner of a male subject becomes pregnant while receiving 
investigational therapy or within 5 months      of the last dose of study drug, a report should be 
completed and expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome 
of the pregnancy should also occur. Abortion, whether accidental, therapeutic, or spontaneous, 
should always be classified as serious, and expeditiously reported as an SAE. Similarly, any 
congenital anomaly/birth defect in a child born to a female subject exposed to atezolizumab 
and/or tiragolumab should be reported as an SAE.
7.5.2.6
Post-Study Adverse Events
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior atezolizumab and/or tiragolumab exposure. 
If the investigator should become aware of the development of cancer or a congenital anomaly 
in a subsequently conceived offspring of a female subject who participated in the study, this 
should be reported as an SAE.
7.5.2.7
Adverse Events of Special Interest (AESIs)
AEs of Special Interest (AESIs): AEs of Special Interest are a subset of Events to Monitor 
(EtMs) of scientific and medical concern specific to the product, for which ongoing monitoring 
and rapid communication by the Investigator to the Sponsor is required. Such an event might 
require further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial Sponsor to other parties (e.g., Regulatory 
Authorities) may also be warranted     
Adverse events of special interest for this study include the following:
●
Cases of potential drug-induced liver injury that include an elevated ALT 
or AST in combination with either elevated bilirubin or clinical jaundice, as 
defined by Hy's Law 
o
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN
o
Treatment-emergent ALT or AST  3  ULN in combination with 
clinical jaundice 
●
Suspected transmission of an infectious agent by the study treatment, 
defined as: 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 

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product. This term applies only when a contamination of study treatment 
is suspected.
●
Pneumonitis
●
Colitis
●
Endocrinopathies: Diabetes mellitus, Pancreatitis, or Adrenal 
Insufficiency, hyperthyroidism, and hypophysitis
●
Hepatitis, including AST or ALT > 10 × upper limit of normal
●
Systemic Lupus Erythematosus
●
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome 
or myasthenia gravis, and meningoencephalitis
●
Events suggestive of hypersensitivity, cytokine release, influenza like 
illness, SIRS, or infusion reaction syndromes, hemophagocytic 
lymphohistiocytosis (HLH), and macrophage activating syndrome (MAS)
●
Nephritis
●
Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis)
●
Myositis
●
Myopathies, including rhabdomyolysis
●
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, 
pericarditis)
●
Vasculitis
●
Autoimmune hemolytic anemia
●
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis 
bullous, or toxic epidermal necrolysis)
7.5.2.8
Other Special Situations Reports
The following other Special Situations Reports should be collected even in the absence of an 
Adverse Event and transmitted to Genentech:
Data related to the Product usage during breastfeeding
●
Data related to overdose, abuse, misuse or medication error (including potentially 
exposed or intercepted medication errors)
●
In addition, reasonable attempts should be made to obtain and submit the age or 
age group of the patient, in order to be able to identify potential safety signals 
specific to a particular population
●
Product complaints
•
A Product Complaint is defined as any written or oral information received from 
a complainant that alleges deficiencies related to identity, quality, safety, 
strength, purity, reliability, durability, effectiveness, or performance of a product 
after it has been released and distributed to the commercial market or clinical 
trial.

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7.5.2.9
Recording of an Adverse Event
Adverse Events will be recorded as described in the Data Safety Monitoring Plan (Appendix 2)
7.6
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator.
7.7
Reporting Requirements for Pregnancies
7.7.1 Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 5 months      after the last dose of study drug. 
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no more 
than 24 hours after learning of the pregnancy) and submitted to Genentech. A pregnancy report 
will automatically be generated and sent to Safety Risk Management. Pregnancy should not be 
recorded on the Adverse Event eCRF. The Sponsor-Investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until conclusion of the pregnancy. Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) should 
be reported on the Adverse Event eCRF.
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and Pregnancy 
Fax Coversheet should be completed and faxed to Safety Risk Management or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), using the fax numbers 
provided in Section 7.9.4).
7.7.2 Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 5 months      after the 
last dose of study drug. A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted via the 
EDC system. Attempts should be made to collect and report details of the course and outcome 
of any pregnancy in the partner of a male patient exposed to study drug. The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy. Once the authorization has been signed, the investigator 
will update the Pregnancy Report eCRF with additional information on the course and outcome 
of the pregnancy. An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the fetus to 
support an informed decision in cooperation with the treating physician and/or obstetrician.
In the event that the EDC system is unavailable, follow reporting instructions provided in Section 
7.7.1.

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7.7.3 Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study drug or 
the female partner of a male patient exposed to study drug should be classified as a serious 
adverse event, recorded on the Adverse Event eCRF, and reported to Genentech immediately 
(i.e., no more than 24 hours after learning of the event; see above). Abortion, whether 
accidental, therapeutic, or spontaneous should be reported in the same fashion (because 
Genentech considers spontaneous abortions to be medically significant events).
7.8
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2
7.9
Expedited Reporting
7.9.1 Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail.
7.9.2 Reporting to UCSF Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting adverse events: https://irb.ucsf.edu/adverse-event
The PI at each participating site is responsible for reporting events to the IRB of record 
according to IRB guidelines.
The sponsor (UCSF) will be responsible for the distribution of safety information to participating 
investigators, where relevant, in accordance with local regulations.
7.9.3 Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:
●
Suspected adverse reaction
●
Unexpected
●
Serious
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.

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The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).
7.9.4 Expedited Reporting to Genentech
Investigators will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious 
Adverse Events (SAEs), pregnancy reports (including pregnancy occurring in female partner of 
a male study subject), other Special Situation reports, AESIs and Product Complaints with an 
AE where the patient has been exposed to Genentech Product.      The completed Medwatch      
report should be sent via fax or email       to Genentech Drug Safety at:
Fax: 
Email: 
And all Product Complaints without an AE should be reported via:
PC Hotline Number: 
 (M-F: 5 am to 5 pm PST)
Investigators must report all the above mentioned single case reports adequately to Genentech 
on a MedWatch form within one (1) business day of the awareness date
     
●
Relevant follow-up information should be submitted to Genentech Drug Safety as soon 
as it becomes available.
●
                    All Non-serious Adverse Events originating from the Study will be 
forwarded in a quarterly report Genentech.
7.9.5 Case Transmission Verification of Single Case Reports
The Sponsor agrees to conduct the Case Transmission verification to ensure that all single case 
reports have been adequately received by Genentech via Sponsor-Investigator emailing 
Genentech a monthly line-listing documenting single case reports sent by Sponsor-Investigator 
to Genentech in the preceding time period. 
The monthly line-listing will be exchanged within seven (7) calendar days of the end of the 
agreed time period. Confirmation of receipt should be received within the time period mutually 
agreed upon.               
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution.  The sponsor shall receive reconciliation guidance 
documents within the ‘Activation Package’. 

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Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Sponsor-Investigator to Genentech within five (5) calendar 
days from request by Genentech.
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech.
 For questions related to safety reporting, please contact Genentech Drug Safety:
Tel: 
Fax: 
 or 
7.9.6 MedWatch 3500A Reporting Guidelines
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form:
●
Protocol description (and number, if assigned)
●
Description of event, severity, treatment, and outcome if known
●
Supportive laboratory results and diagnostics
●
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication
7.9.7 Follow-up Information
Additional information may be added to a previously submitted report by any of the following 
methods:
●
Adding to the original MedWatch 3500A report and submitting it as follow-
up
●
Adding supplemental summary information and submitting it as follow-up 
with the original MedWatch 3500A form
●
Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e. D.O.B. initial, patient number), protocol description 
and number, if assigned, brief adverse event description, and notation 
that additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the 
correct initial report)
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request.
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html
                                        

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7.9.8 7.9.8  Aggregate Reports
IND Annual Reports: All IND annual reports submitted to the FDA by the Sponsor-Investigator 
should be copied to Genentech. Copies of such reports should be emailed      to Genentech 
Drug Safety:
Genentech Drug Safety CTV mail box:
Other Reports: The Sponsor-Investigator will forward a copy of the Final Study Report to 
Genentech upon completion of the Study.
     
7.9.9 7.9.9 Study Close-Out           
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study:
And to Genentech Drug Safety CTV oversight mail box at:
 
7.9.10 7.9.10 Queries
Queries related to the Study will be answered by Sponsor-Investigator. However, responses to 
all safety  queries  from  regulatory  authorities  or  for publications will be discussed and 
coordinated between the Parties. The Parties agree that Genentech shall have the final say and 
control over safety queries relating to the Product. Sponsor-Investigator agrees that it shall not 
answer such queries from regulatory authorities and other sources relating to the Product 
independently but shall redirect such queries to Genentech.
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met. The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required.
 
7.9.11 7.9.11 Safety Crisis Management
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), 
on the conduct of the Study, may lead to labeling changes or regulatory actions that limit or 
restrict the way in which the Product is used, or where there is media involvement, the Party 
where the crisis originates will contact the other Party as soon as possible.
 
The Parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the Product. Sponsor-Investigator agrees that it shall not answer 
such queries from media and other sources relating to the Product but shall redirect such 
queries to Genentech.

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7.9.12 7.9.12 Compliance with Pharmacovigilance Agreement/Audit
The Parties shall follow their own procedures for adherence to AE reporting timelines.
 
Each Party shall monitor and, as applicable, request feedback from the other Party regarding 
AE report timeliness in accordance with its own procedures. The Parties agree to provide 
written responses in a timely manner to inquiries from the other Party regarding AE reports 
received outside the agreed upon Agreement timelines. If there is any detection of trends of 
increasing or persistent non-compliance to transmission timelines stipulated in this Agreement, 
both Parties agree to conduct ad hoc or institute a regular joint meeting to address the issue.
 
In case of concerns related to non-compliance of processes, other than exchange timelines, 
with this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving 
the issues causing non-compliance. Every effort will be made by the non-compliant Party to 
solve the non-compliance issues and inform the other Party of the corrective and preventative 
actions taken.
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit.
8
Statistical Considerations and Evaluation of Results
8.1
Determination of Sample Size and Power Calculation
Cohort A 
Multi-dose phase: With 6 patients in each cohort, there will be 80% of power to detect the 
effect size of 1.5 at significance level of 0.1. For the lowest dose level, a 2-fold increase from 
pre-treatment to post- treatment is expected, if at the higher dose level, there is more than 3-fold 
increase, assuming the standard deviation equals 1, then there will be 80% power to detect 
significant treatment effect on the intratumoral immune response.
Expansion phase: Data from a study of intravesical valrubicin chemotherapy in BCG refractory 
patients34 demonstrated that a 21% CR rate is achievable at 6 months. Assuming a 5% (null) 
CR rate for untreated patients at 6 months, 15 patients would be required to observe an 
improvement to a 36% CR rate at 6 months in response to-PD-L1 therapy (effect size = 0.642), 
at a significance level of 0.1 with 80% power.
Cohort B 
A pT0 rate at cystectomy was observed for ~30% of patients treated with immune checkpoint 
inhibitors monotherapy based on published Phase II clinical trials. In order to observe an 
improvement from a 30% CR rate (null hypothesis) to 60% CR rate (alternative hypothesis) with 
the combination of atezolizumab and tiragolumab a total of 21 patients are required in Cohort B 
assuming a significance level of 0.05 and 80% power.

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Using these assumptions, following a lead in safety phase of 6 patients at a combination 
regimen that is deemed to be safe based on the criteria outlined above, a further 15 patients will 
be enrolled at the same regimen. This will make a total of 21 patients to be treated in Cohort B 
with the intended regimen.
8.2
Interim Analyses and Stopping Rules
A stopping rule for safety will halt accrual to the study and prompt reevaluation of the regimen if 
unacceptable treatment-related toxicity (defined as any Grade 4 toxicity, any recurrent Grade 3 
toxicity, or any Grade 3 toxicity persisting more than 2 weeks), or treatment-related delay in 
cystectomy beyond 12 weeks (including both the treatment period and any delay due to an 
adverse event), is observed at a frequency of ≥33.3% 
No formal interim stopping rule for efficacy will be performed. This is due to the fact that immune 
therapies may require weeks to months to have efficacy, and therefore the true antitumor 
activity of atezolizumab and tiragolumab may not be apparent at the time of cystectomy. Rather, 
durable immune responses may be generated against the tumor and may prevent post-
cystectomy recurrence; this effect may not be detectable for months to years after study drug 
administration.
Furthermore, given the relatively small sample size of this study an interim stopping rule for 
futility based on longer-term clinical endpoints (i.e. relapse-free survival) is not considered 
feasible or warranted.
8.3
Analysis Plans
8.3.1 Analysis Population
All patients who receive any part of a dose of any study drug will be analyzed for safety and 
efficacy. Subjects who discontinue from study participation prior to receiving any dose of study 
therapy may be replaced after discussion with the Study Chair. Subjects who have received any 
dose of study therapy will not be replaced.
Demographic and baseline characteristics will be summarized. In general, frequency distribution 
and percentage will be used to summarize categorical measurements, while mean with 
standard deviation and median with range will be used to describe symmetric and skewed 
continuous measurements, respectively. Univariate analysis among variables will be assessed 
using the two-sample t-test, Wilcoxon-rank-sum test, Chi- square test, as appropriate.
8.3.2 Analysis of Primary Endpoints
The immunologic effect of activity study therapy within bladder tissue will be measured by a 
change in the CD3+ T cell count/µm2 between the pretreatment biopsy and the cystectomy 
tissue following study therapy administrations. Immunohistochemistry will be performed in the 
Fong lab at UCSF per established SOPs. Based on prior experience tissue will be designated 
into 3 distinct compartments: benign epithelium, tumor centers, and tumor interfaces. Tumor 
interfaces will be defined as fields where malignant and benign epithelium are present. 
Automatic cell counts for single- and double-stained cells will be determined for each field with 
color-specific algorithms.
The cell count for each compartment will be reported as the mean for each of the five 
quantitated fields. Cells of interest will include CD3+ T cells, CD3+ Ki67+ proliferative T cells, 

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CD4+ FoxP3- helper T cells, CD4+ FoxP3+ regulatory T cells, CD8+ cytotoxic T cells, as well as 
PD-1 expression on the different lymphocytes. In collaboration with Genentech, PD-L1 
expression on both tumor and immune cells within the microenvironment will be assessed.
For each cohort, the change of T cell counts from pre-treatment to post-treatment will be 
calculated for each compartment as log2 of the ratio of post-treatment vs. pre-treatment counts. 
If different regimens are used (for example atezolizumab x 3 doses and tiragolumab x 2 doses) 
two-sample Wilcoxon rank sum test will be used to compare the difference of the change from 
pretreatment to post-treatment between cohorts to assess if the intratumoral immune response 
associated with increasing numbers of  treatments. No multiple comparison adjustments will be 
performed.
8.3.2.1
pT0 rate
Point estimates and 95% confidence intervals of pathologic T0 rate at the time of cystectomy as 
defined in Section 7.1.1 will be obtained for subjects treated with atezolizumab and tiragolumab. 
Pathologic T0 rate at the time of cystectomy will be compared with the null hypothesis rate (see 
Section 8.1) separately by using one-sample proportion test.
8.3.2.2
Safety
Adverse events occurring prior to surgery will be summarized by maximum toxicity grade for all 
patients treated with the particular regimen. The toxicity grade for laboratory data will be 
calculated using NCI CTCAE-v4.0 for the (already accrued) Cohort A and using CTCAE-v5.0 for 
Cohort B, and the lab data will be summarized according to the subjects’ baseline grade and 
maximum grade for each cycle of therapy. The percentage of subjects requiring a treatment- 
related delay in surgery beyond 12 weeks from study start will be summarized using descriptive 
statistics. All treatment related adverse events that lead to delay in cystectomy will be graded 
using NCI CTAE-v4.0 or 5.0 as discussed above and will be recorded.
8.3.3 Analysis of Secondary Endpoints 
8.3.3.1
Near complete pathologic response rate, 2 year relapse-free survival, 2 year 
overall survival
Point estimates and 95% confidence intervals of the near complete pathologic response rate, 
defined as the presence of only pTa or pTis in patients with T2 of greater disease at baseline, 
the 2 year RFS rate defined from study start until recurrence of disease or death from any 
cause, and the 2 year overall survival (OS) rate defined from study start until death from any 
cause, will be obtained for patients enrolled in the study, and compared with the null hypothesis 
rate (see Section 8.1) separately by using one-sample proportion test. RFS and OS will be 
obtained by Kaplan Meier method for the ITT population.
8.3.3.2
PD-1/PD-L1 expression and response
For each dose level as well as for each individual expansion cohort, Fisher’s exact test will be 
used to test the association of baseline tumor and T-cell PD-L1/PD-1 immunohistochemical 
expression with disease response.
8.3.4 Analysis of Exploratory Endpoints: Tissue based endpoints
Note: Tissue will be used for multiple different exploratory assays. In the event that there is 
insufficient tissue to perform all assays for an individual subject, the tissue should be prioritized 

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for assays as follows, in which the first assay described is the highest priority. Also note that 
PD-L1 immunohistochemistry and immune cell mRNA signature assays will be performed at 
Genentech, while all other assays will be performed at UCSF.
8.3.4.1
Tumor PD-L1 assessment
PD-L1 protein expression on tumor tissue from pre-treatment biopsies, cystectomy specimens, 
and any other tumor biospecimens obtained will be evaluated immunohistochemically and 
scored on a scale of 0, 1, 2, or 3. This scoring will be used for the determination of relationships 
between tumor PD-L1 expression and clinical responses described above.
8.3.4.2
Tissue immune subset quantification and localization
For all subjects, immune cell subsets and localization will be summarized by changes from 
baseline to after treatment using descriptive statistics.
8.3.4.3
Immune cell mRNA signatures of response
To identify individual genes whose expression levels at pre-treatment are associated with pCR, 
we will apply two-sample t tests to compare responders and non-responders. Adjusted P values 
controlling for false discovery rate (Benjamini and Hochberg method) will be derived. In addition, 
to assess association of pre-specified immune gene signature with response, the median 
expression level of the component genes will be used to represent the signature and two- 
sample t tests will be used. For genes or signatures that emerge as significantly associated with 
response, logistic regression models will be used to assess their independent association with 
response after adjusting for known clinical prognostic factors. To identify pharmacodynamic 
markers, paired t-test will be carried out to examine immune gene expression differences 
between pre-treatment and at-cystectomy samples. Additionally, association of gene expression 
levels at time of cystectomy with long term efficacy outcomes, such as PFS and DFS, will be 
explored using the Cox proportional hazards regression model. Hierarchical clustering 
superimposed with response status, relevant baseline or prognostic characteristics or 
experimental factors will be performed using Spearman correlation and complete linkage to 
visualize the discriminating power of the immune gene expression and the correlative structure 
among the genes and the samples.
8.3.4.4
T cell receptor (TCR) deep sequencing
For each individual dose level, and for each dose-expansion cohort the change in tumor- 
infiltrating TCR between pre-treatment and post-cystectomy after treatment will be assessed by 
calculating the number of unique clonotypes comprising the top 25th percentile of cumulative 
reads after sorting by clone abundance. Repertoire change between sequencing experiments 
will be measured using Morisita’s distance. 
8.3.4.5
Genomic signatures of response
It is hypothesized that tumors with highly mutated or copy-aberrant genomes will either 
overexpress native proteins or express novel mutant proteins, both of which may be recognized 
by the immune system and serve as tumor-specific antigens. Therefore the effect of genomic 
mutations on the immune landscape will be investigated in each of the expansion cohorts in this 
study as follows.

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Tumor DNA will be isolated from pre-treatment tissue and from post-cystectomy specimens, and 
will be analyzed for copy number using the Human Genome CGH 244K Microarray (Agilent, 
Santa Clara, CA) and/or by next-generation sequencing. Results will be analyzed with DNA 
Analytics software (Agilent) and with the assistance of the UCSF Genome Core and the UCSF 
Biostatistics core. For copy number paired Wilcoxon signed-rank test will be applied to test 
difference of tumor gene copy number between pre and post treatment. Two-sample Wilcoxon 
signed-rank test will be used to test the gene copy number between tumor responders and non- 
responders for pre-treatment, post-treatment and changes before and after the treatment, 
separately. Multiple testing adjustment will be done by controlling false positive rate. Next- 
generation sequencing will take place using appropriate methods and biostatistical analyses.
Annotation will be based on NCBI and UCSC databases. Chi-square test will be applied to 
obtain the significant variants associated with the clinical response.
8.3.5 Analysis of Exploratory Endpoints: Immune endpoints
8.3.5.1
Immune cell activation
For each cohort individually, and for each individual expansion cohort, flow cytometry of 
circulating immune cell subsets will also be performed on pre-treatment blood and again after 
cystectomy. Established flow cytometry panels will examine T cell activation. Immune cell 
quantification will be summarized by changes from baseline to after treatment using descriptive 
statistics. Furthermore, paired Wilcox on signed-rank test will be applied to test the pre-post 
treatment changes. When available, immune cells digested from resected tumor tissues will also 
be assessed by flow cytometry.
8.3.5.2
Circulating antibody detection and characterization
Spotted antigen arrays will be used to detect circulating antibodies will be performed on sera 
derived from the pretreatment and post-cystectomy timepoints. After standard preprocessing of 
the protein array data, Cluster and Treeview software will be used for unsupervised clustering of 
the data with Pearson correlation and complete linkage. For each array, an antigen is identified 
as being detected if its value is above the median. To determine the number of up- and 
downmodulated antibodies, the difference in log2 intensity values of pretreatment and post- 
treatment samples will be taken for each patient to identify antigens that are detected 
differentially due to treatment. Number of antibodies with at least 2- or 4-fold difference between 
pretreatment and post-treatment samples will be compared between clinical responders and 
nonresponders by performing two-sided Wilcoxon rank sum test.
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.

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The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB. Prior to obtaining IRB approval, the protocol must be approved by 
the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC). The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document.
The original signed copy of the consent document must be retained in the medical record or 
research file.
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements. The Study Chair and the UCSF 
study team will be responsible for updating any participating sites.
9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs at the 
site. The date, quantity and batch or code number of the drug, and the identification of 
participants to whom the investigational product has been dispensed by participant number and 
initials will be included.
The Principal Investigator at each participating site shall not make the investigational drug 
available to any individuals other than to qualified study participants. Furthermore, the PI at 
each study site will not allow the investigational drug to be used in any manner other than that 
specified in this protocol.

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9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee, at each study site, will prepare and maintain 
adequate and accurate participant case histories with observations and data pertinent to the 
study. Study specific Case Report Forms (CRFs) will document safety and treatment outcomes 
for safety monitoring and data analysis. All study data will be entered into OnCore® via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry with a 
secure access account. Study personnel for each study site will complete the CRFs; the PI for 
the study site will review and approve the completed CRFs.
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
study personnel at each study site. All source documentation should be kept in separate 
research folders for each patient.
In accordance with federal regulations, the PI at each study site is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.
The PI at each study site will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs  after that time can only 
be made by joint written agreement among the Study Chair, and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study. The UCSF DSMC will monitor the study in accordance with the NCI- 
approved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”. The DSMC will audit study- 
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable. See 
Appendix 2 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional 
information.
The PI at each study site will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among Study Chair and the trial statistician.
9.8
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed 
to discuss risk assessment. The following issues will be discussed as appropriate: 

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●
Enrollment information
●
Cohort updates (i.e. DLTs)
●
Adverse events (i.e. new adverse events and updates on unresolved 
adverse events and new safety information)
●
Protocol violations
●
Other issues affecting the conduct of the study
9.9
Record Keeping and Record Retention
The PI at each study site is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.
The PI at each study site is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant consent 
forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the PI at each study site shall retain records for a period of 
2 years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA is 
notified.
9.10 Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.

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At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
9.11 Regulatory Documentation
Prior to implementing this protocol at UCSF or any participating site, the protocol, informed 
consent form, HIPAA authorization and any other information pertaining to participants must be 
approved by the UCSF IRB. Prior to implementing this protocol at the participating sites, 
approval for the UCSF IRB approved protocol must be obtained from the participating site’s IRB.
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:
●
Participating Site IRB approval(s) for the protocol, appendices, informed 
consent form and HIPAA authorization
●
Participating Site IRB approved consent form
●
Participating Site IRB membership list
●
Participating Site IRB’s Federal Wide Assurance number and OHRP 
Registration number
●
Curriculum vitae and medical license for each investigator and consenting 
professional
●
Documentation of Human Subject Research Certification training for 
investigators and key staff members at the Participating Site
●
Participating site laboratory certifications and normals
●
Upon receipt of the required documents, UCSF HDFCCC will formally 
contact the site and grant permission to proceed with enrollment.
10 Protection of Human Subjects
10.1 Protection from Unnecessary Harm
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits.
10.2 Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and Its Ligands in Tolerance and 
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Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 
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Mu C-Y, Huang J-A, Chen Y, Chen C, Zhang X-G. High expression of PD-L1 in lung 
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Yokobori T, Iinuma H, Shimamura T, et al. Plastin3 Is a Novel Marker for Circulating 
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Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells 
during chronic viral infection. OriginalPaper. Nature. 2005-12-28 2005;439(7077):682-687. 
doi:doi:10.1038/nature04444
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H F, V N, RA S, et al. Programmed death 1 protects from fatal circulatory failure during 
systemic virus infection of mice. The Journal of experimental medicine. 12/17/2012 
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Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment with 
platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet. 2016/05/07/ 
2016;387(10031):1909-1920. doi:https://doi.org/10.1016/S0140-6736(16)00561-4
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Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of 
neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. OriginalPaper. 
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A N, D R, A G, et al. Updated Results of PURE-01 with Preliminary Activity of 
Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant 
Histologies. European urology. 2020 Apr 2020;77(4)doi:10.1016/j.eururo.2019.10.026
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Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell 
activation by promoting the generation of mature immunoregulatory dendritic cells. Nature 
immunology. 2009;10(1):48. 
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Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates 
antitumor and antiviral CD8+ T cell effector function. Cancer cell. 2014;26(6):923-937. 
23.
Manieri NA, Chiang EY, Grogan JL. TIGIT: a key inhibitor of the cancer immunity 
cycle. Trends in immunology. 2017;38(1):20-28. 
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Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 
inhibits human NK cell cytotoxicity. Proceedings of the National Academy of Sciences of the 
United States of America. 2009;106(42):17858-17863. doi:10.1073/pnas.0903474106
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N J, JP H, B B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. 
Journal of immunology (Baltimore, Md : 1950). 02/01/2011 
2011;186(3)doi:10.4049/jimmunol.1003081
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Bendell JC, Bedard P, Bang Y-J, et al. Abstract CT302: Phase Ia/Ib dose-escalation study 
of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab 
in patients with advanced solid tumors. 2020-08-15 2020;doi:10.1158/1538-7445.AM2020-
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Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, 
double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab 
(atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected 
NSCLC (CITYSCAPE). meeting-report. https://doiorg/101200/JCO20203815_suppl9503. 2020-
05-25 2020;doi:9503
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Maha H. A. Hussain TP, Peter Albers, Daniel Castellano, Siamak Daneshmand, Juergen 
Gschwend, Hiroyuki Nishiyama, Stephane Oudard, Darren Tayama, Nicole N. Davarpanah, 
Viraj Degaonkar, Yi Shi, Sanjeev Mariathasan, Petros Grivas, Peter H. O'Donnell, Jonathan E. 
Rosenberg, Daniel M. Geynisman, Jean H. Hoffman-Censits, Daniel Peter Petrylak, Joaquim 
Bellmunt, Robert H. Lurie Comprehensive Cancer Center NU, Chicago, IL, Barts Cancer 
Institute QMUoL, London, United Kingdom, et al. IMvigor010: Primary analysis from a phase 
III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk 
muscle-invasive urothelial carcinoma (MIUC). 2020;

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Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood 
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Adashek ML, Feldman M. Cytokine Release Syndrome Resulting From Anti-
Programmed Death-1 Antibody: Raising Awareness Among Community Oncologists. J Oncol 
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Rotz SJ, Leino D, Szabo S, Mangino JL, Turpin BK, Pressey JG. Severe cytokine release 
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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. 
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DE H, MB A, E C, et al. A contemporary update on pathology standards for bladder 
cancer: transurethral resection and radical cystectomy specimens. European urology. 2013 Feb 
2013;63(2)doi:10.1016/j.eururo.2012.10.008
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G S, R B, S B, R M, Z W, M W. Efficacy and safety of valrubicin for the treatment of 
Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study 
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Appendix 1 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on 
all pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; 
some signs or symptoms of 
disease
1
Symptoms, but ambulatory
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work)
70
Cares for self, unable to carry on 
normal activity or to do active 
work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
2
In bed < 50% of the time
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities
Up and about more than 50% of 
waking hours
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self- 
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization 
indicated Death not imminent
4
100% bedridden 
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2 Data and Safety Monitoring Plan: Multicenter Phase 2 or 3 Trial with 
Safety Lead-In
1.Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes: 
●
Review of all participant data in safety lead-in phase. 
●
Approval to enroll past safety lead-in phase by DSMC Chair or Vice Chair. 
●
Semiannual auditing after safety lead-in phase (depending on accrual). 
●
Review of serious adverse events. 
●
Minimum of a biennial regulatory auditing visit. 
 
2. Monitoring and Reporting Guidelines 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  The 
Study Chair is responsible for the overall conduct of the trial and for auditing its safety and 
progress at all participating sites.  The Study Chair will conduct continuous review of data and 
participant safety at monthly UCSF Site Committee meetings.  The discussions are documented 
in the UCSF Site Committee meeting minutes. 
All institutional Phase II or III therapeutic studies with a lead-in are designated with a high-risk 
assessment during the safety lead-in phase and a moderate risk assessment. During the safety 
lead-in phase, the DSMC will audit all visits through the first cycle of treatment for all participants 
enrolled in this phase of the trial. 
After the completion of enrollment in the safety lead-in phase, the Study Chair will submit a report 
to the DSMC Chair outlining all AEs, SAEs, and DLTs (as defined in the protocol) with a request 
to proceed onto the next phase of the trial.  Within two business days of receipt, the DSMC Chair 
or designee will review the report and issue written authorization to proceed or a request for more 
information. The report is then reviewed at the subsequent DSMC meeting. 
After DSMC authorization to enroll beyond the safety lead-in phase is granted, study data is 
audited by a DSMC Monitor/Auditor on a semiannual basis with a random selection of twenty 
percent of the participants (or at least three participants if the calculated value is less than three). 
The DSMC Monitor/Auditor will audit a maximum of 5 cycles of treatment in the participants 
selected for review or until the selected participants discontinue study participation or the trial is 
closed with the IRB. Additionally, the assigned DSMC Monitor/Auditor will review no more than 
10 total participant charts during the course of auditing this trial.  DSMC Monitor/Auditors will send 
a follow-up report to the study team within 20 business days after the auditing visit is complete for 
the PI and the study team to resolve all action items from this report within 20 business days. An 
abbreviated regulatory review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA 
logs, 1572 forms, etc.) will occur at each participant monitoring review; however, a full regulatory 
review will occur on a biennially basis by the DSMC for regulatory compliance. 
The participating site’s source documents are audited remotely via either review of redacted 
source documents downloaded by the site into the CRA console of OnCore and/or via access to 
the site’s electronic medical records.  The DSMC Monitor/Auditor will audit no more than three 
participant charts at each participating site during the course of auditing this trial. 

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Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.   
Multicenter communication 
The UCSF Coordinating Center includes the UCSF PI (Study Chair) and the UCSF study team. 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites. The 
following issues will be discussed as appropriate: 
●
Enrollment information. 
●
Adverse events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information). 
●
Protocol Violations. 
●
Other issues affecting the conduct of the study. 
 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites. The data (i.e., copies of source documents) from the 
participating sites will be downloaded into the PC console of OnCore prior to the remote 
monitoring visits in order for the DSMC to monitor the participating site’s compliance with the 
protocol and applicable FDA regulations. 
 
3. Review and Oversight Requirements 
3.1 Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or unexpected 
and whether or not considered to be associated with the investigational agent(s) 
or study procedure, will be entered into OnCore®, UCSF’s Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute.  Adverse events are further given an assignment of attribution or 
relationship to the investigational agent(s) or study procedure.  Attribution categories are: 
●
Definite – The adverse event is clearly related to the investigational agent(s) or study 
procedure. 
●
Probable – The adverse event is likely related to the investigational agent(s) or study 
procedure. 
●
Possible – The adverse event may be related to the investigational agent(s) or study 
procedure. 
●
Unrelated – the adverse event is clearly not related to the investigational agent(s) or study 
procedure. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings.  All adverse events entered into OnCore® will be reviewed on 
a monthly basis at the UCSF Coordinating Center Site Committee meetings.  All grade 3-5 
adverse events must be reported to the UCSF Coordinating Center by the participating sites 
within 10 business days of becoming aware of the event or during the next scheduled monthly 
conference call, whichever is sooner.  The UCSF Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and the attribution assignment from the UCSF Coordinating 
Center and the participating sites.  

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3.2 Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to the 
following criteria: 
●
Death. 
●
Life-threatening (i.e. results in an immediate risk of death). 
●
Requires inpatient hospitalization or prolongation of existing hospitalization. 
●
Permanent or significant disability/incapacity. 
●
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that suggests a 
significant hazard, contraindication, side effect, or precaution that may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
●
Event occurring in a gene therapy study. 
●
Event that changes the risk/benefit ratio of a study. 
●
Any other event the Principal Investigator judges to be serious or which would suggest a 
significant hazard, contraindication, side effect, or precaution. 
 
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported in 
accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported on a Med 
Watch form. 
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 
 
All serious adverse events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be reported to the UCSF 
Coordinating Center within one business days of becoming aware of the event.  The SAEs are 
reviewed and audited by the UCSF Data and Safety Monitoring Committee on an ongoing basis 
and discussed at DSMC meetings, which take place every six weeks. The date the SAE was 
sent to all required reporting agencies will be documented in OnCore®. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or definitely related 
either to the investigational drug or any research related procedure, then the Study Chair at the 
UCSF Coordinating Center or the assigned designee must be notified within 1 business day from 
the participating site(s) and the Study Chair must then notify the DSMC Chair (or Vice Chair) and 
the DSMC Director within 1 business day of this notification. 
 
3.3 Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC Chair (or Vice Chair) and the DSMC 
Director at the time the increased rate is identified via a report. The report will indicate if the 
incidence of adverse events observed in the study is above the range stated in 
the Investigator’s Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC 
Chair (or Vice Chair) and the DSMC Director must be notified within one business day and the 
IRB must be notified within their reporting guidelines. 

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
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Phase II – atezolizumab and tiragolumab
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Data and Safety Monitoring Committee Contacts: 
 
  Katie Kelley, MD (DSMC Chair) 
  
 
  
 
  
 
  UCSF HDFCCC 
  San Francisco, CA 94158 
 
John McAdams (DSMC Director)  
 
 
UCSF HDFCCC 
San Francisco, CA 94143 
 

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
 Page 118 of 121
Appendix 3 Prohibited Medications
Drug
Trade name (if applicable)
Denosumab
Xgeva, Prolia
Interleukin-2
Interferon gamma
Actimmune
Interferon alpha
Intron A, Roferon-A
Ipilimumab     
Yervoy
Cyclophosphamide
Cytoxan
Azathioprine
Imuran, Azasan
Methotrexate
Trexall, Rheumatrex
Thalidomide
Thalomid
Dexamethasone*
Prednisone*
Methylprednisolone*
Remicade
Infliximab
Etanercept
Enbrel
Adalimumab
Humira
Certolizumab
Cimzia
Golimumab
Simponi
*Inhaled corticosteroids are permitted. Systemic 
corticosteroids or anti-TNF-alpha agents are 
administered at the discretion of the treating 
physician after discussion with the Study Chair.

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
 Page 119 of 121
Appendix 4 TBNK, and Pharmacodynamic Sampling Schedule
Lab Correlative Sampling Schedule
Study Visit
Time
Sample
Screening
At visit
TBNK
Cycle 1,
Day 1
Predose
TBNK
Atezolizuab/Tiragolumab 
pharmacodynamics a
All subsequent 
cycles
Predose
TBNK
 Atezolizuab/Tiragolumab 
pharmacodynamics a
Treatment 
discontinuation visit
At visit
TBNK
 Atezolizuab/Tiragolumab 
pharmacodynamics a
At time of
cystectomy &
subsequent follow
At Visit
TBNK
up visits, including
 Atezolizuab and Tiragolumab 
pharmacodynamics a
any recurrence
biopsy
12 weeks (± 2 
weeks) after 
cystectomy
At visit
TBNK
 Atezolizuab/Tiragolumab 
pharmacodynamics a
PD = pharmacodynamic (plasma, serum, whole blood for PD biomarkers); TBNK = T, B, 
and NK cells.
a Plasma, serum, whole blood.
Refer to Laboratory Manual for additional sampling and shipping details.

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
 Page 120 of 121
Appendix 5 Anaphylaxis precautions
EQUIPMENT NEEDED
●
Tourniquet
●
Oxygen
●
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice
●
Antihistamines
●
Corticosteroids
●
Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study drug infusion, the 
following procedures should be performed:
1.
Stop the study drug infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study drug. Do not 
obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer antihistamines, epinephrine, or other medications as required by patient status and 
directed by the physician in charge.
5.
Continue to observe the patient and document observations.

 UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 03-29-2021
Protocol CC#: 14524
Phase II – atezolizumab and tiragolumab
 Page 121 of 121
Appendix 6 Safety Reporting Fax Coversheet