Clinical trial NCT03029832
Conditions: Urothelial Carcinoma
Sponsor: Genentech, Inc.
Start date: 2017-04-27; Completion date: 2018-04-25
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of MOXR0916 in combination with atezolizumab versus placebo and atezolizumab in participants with locally advanced or metastatic urothelial carcinoma (UC) who have not received prior systemic therapy in the locally advanced/metastatic setting and who are ineligible to receive cisplatin-based therapy.

Detailed description:
The study design has been amended after the decision to prematurely stop patient accrual due to enrollment challenges. As only 5 participants were enrolled, the study blinding will not be maintained, and placebo infusions will not be administered. Patients assigned to the MOXR0916 arm may continue study treatment with the combination of atezolizumab and MOXR0916 or with atezolizumab alone based on a discussion of benefit and risk with the treating investigator.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: MOXR0916 intervention 2: Atezolizumab
Intervention descriptions: intervention 1: MOXR0916, 300 milligram (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle. intervention 2: Atezolizumab, 1200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase II, Multicenter, Randomized, Placebo-Controlled, 
Double-Blind Study of MOXR0916 in Combination With 
Atezolizumab Versus Atezolizumab Alone in Patients With 
Untreated Locally Advanced or Metastatic Urothelial Carcinoma 
Who Are Ineligible for Cisplatin-Based Therapy 
NCT Number: 
NCT03029832 
Document Date: 
Protocol Version 3: 29 Sep 2017 
 
 
 




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PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol GO39590 has been amended to reflect the Sponsor’s decision to halt accrual 
due to enrollment challenges in the context of overall clinical development 
considerations for MOXR0916.  As only 5 patients were enrolled, this trial will not meet 
its scientific objectives.  Hence, study procedures that are not required for safety 
management or assessment of clinical benefit will be streamlined or modified as follows 
to minimize burden to currently enrolled patients:

The study blinding will not be maintained, and placebo infusions will not be 
administered.  Patients assigned to placebo may continue study treatment with 
atezolizumab alone.  Patients assigned to the MOXR0916 arm may continue study 
treatment with the combination of atezolizumab and MOXR0916 or with 
atezolizumab alone based on a discussion of benefit and risk with the treating 
investigator (Sections 3.1.1, 4.2, 4.3, and Appendix 1). 

Given that enrollment has been prematurely halted and the study will no longer be 
blinded, the Internal Monitoring Committee may recommend modification or 
suspension of its activities and modify its charter accordingly (Section 3.1.2). 

The imaging modality (e.g., CT vs. MRI scan, contrast-enhanced vs. non-contrast) 
and the frequency of tumor assessments will be determined by the investigator 
based on the patient’s disease characteristics and local institutional standards 
(Section 4.5.5 and Appendix 1).  As such, the requirement that patients with contrast 
allergy undergo non-contrast CT scans or MRI scans rather than receive 
corticosteroid premedication for contrast-enhanced CT imaging has been removed 
(Section 4.4.3).

Follow-up tumor assessments for patients who discontinue study treatment for 
reasons other than disease progression are no longer required (Section 4.5.5 and 
Appendix 1).

Data to support response assessment per immune-modified RECIST will not be 
captured in eCRFs (Section 4.5.5).

Blood samples for whole genome sequencing will not be collected (Appendix 1).

Autoantibody testing will not be performed (Appendix 1).

Blood samples for biomarker (plasma, serum, PBMC), pharmacokinetic (serum), or 
immunogenicity/anti-therapeutic antibody (serum) evaluation will not be collected
(Section 4.5.6.2).

Patient-reported outcomes (MDASI and EQ-5D-5L) will not be collected (Section 4.5 
and Appendix 1).

Optional biopsies should not be performed (Section 3.1.1 and Appendix 1).

Survival and anti-cancer therapy follow-up will not be performed (Section 4.6.2 and 
Appendix 1).
In addition, the protocol has been amended to incorporate safety updates and revised 


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toxicity management guidelines, in alignment with recent Dear Investigator Letters 
(April 2017, June 2017) and the annual update to the Atezolizumab Investigator’s 
Brochure (Version 10):

Guidance on the management of hypophysitis has been included (Section 5.1.5, 
Table 9).

Guidance on the management of immune-related myocarditis has been added 
(Section 5.1.5, Table 10).
In addition, the following changes have been made:

The Sponsor’s discretion in granting exceptions to post-trial access conditions has
been clarified (Section 4.3.4).

The reporting of the term “sudden death” has been updated to also require the 
presumed cause of death (Section 5.3.5.8).

Event reporting for hospitalization has been clarified (Section 5.3.5.11).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 33
PROTOCOL SYNOPSIS .................................................................................... 34
1.
BACKGROUND .......................................................................................... 47
1.1
Background on Urothelial Carcinoma .................................... 47
1.1.1
First-Line Treatment of Metastatic Urothelial 
Carcinoma............................................................................. 47
1.1.2
Immunotherapy for Urothelial Carcinoma .............................. 49
1.2
Background on Atezolizumab................................................ 49
1.2.1
Atezolizumab in Urothelial Cancer......................................... 50
1.3
Background on MOXR0916................................................... 51
1.3.1
Summary of Clinical Studies with MOXR0916....................... 51
1.3.2
Clinical Pharmacokinetics and Immunogenicity..................... 52
1.3.3
Clinical Safety........................................................................ 52
1.3.4
Clinical Efficacy ..................................................................... 53
1.4
Study Rationale and Benefit-Risk Assessment...................... 53
2.
OBJECTIVES AND ENDPOINTS ............................................................... 55
3.
STUDY DESIGN......................................................................................... 58
3.1
Description of the Study......................................................... 58
3.1.1
Overview of Study Design ..................................................... 58
3.1.2
Internal Monitoring Committee............................................... 60
3.2
End of Study and Length of Study......................................... 61
3.3
Rationale for Study Design.................................................... 61
3.3.1
Rationale for Atezolizumab Dose and Schedule.................... 61
3.3.2
Rationale for MOXR0916 Dose and Schedule ...................... 61
3.3.3
Rationale for Patient Population, Analysis 
Groups, and Enrollment Stages ............................................ 62
3.3.4
Rationale for Control Group................................................... 63
3.3.4.1
Atezolizumab as a Comparator............................................ 63
3.3.4.2
Placebo Control.................................................................... 63
3.3.5
Rationale for Stratification Factors......................................... 63
3.3.5.1
PD-L1 Expression (IC0/1 vs. IC2/3) ..................................... 64


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3.3.5.2 Bajorin Risk Factor Score/Liver Metastasis (0 vs. 
1 vs. 2 or Liver Metastasis)................................................... 64
3.3.6
Rationale for Collection of Mandatory Baseline 
Tumor Specimens (Archival or Pre-Treatment 
Biopsy) .................................................................................. 64
3.3.7
Rationale for Treatment Beyond Radiographic 
Progression........................................................................... 65
4.
MATERIALS AND METHODS .................................................................... 65
4.1
Patients.................................................................................. 65
4.1.1
Inclusion Criteria.................................................................... 65
4.1.2
Exclusion Criteria................................................................... 68
4.2
Method of Treatment Assignment and Blinding..................... 73
4.2.1
Treatment Assignment........................................................... 73
4.2.2
Blinding.................................................................................. 73
4.2.3
Unblinding.............................................................................. 73
4.3
Study Treatment.................................................................... 73
4.3.1
Formulation, Packaging, and Handling.................................. 74
4.3.1.1
MOXR0916 and Placebo...................................................... 74
4.3.1.2
Atezolizumab........................................................................ 74
4.3.2
Dosage, Administration, and Compliance.............................. 74
4.3.2.1
MOXR0916 and Placebo...................................................... 74
4.3.2.2
Atezolizumab........................................................................ 75
4.3.3
Investigational Medicinal Product Accountability ................... 76
4.3.4
Post-Trial Access to MOXR0916 and 
Atezolizumab......................................................................... 77
4.4
Concomitant Therapy ............................................................ 77
4.4.1
Permitted Therapy................................................................. 78
4.4.2
Cautionary Therapy ............................................................... 78
4.4.3
Prohibited Therapy ................................................................ 79
4.5
Study Assessments ............................................................... 79
4.5.1
Informed Consent Forms and Screening Log........................ 80
4.5.2
Medical History and Demographic Data ................................ 80
4.5.3
Physical Examinations........................................................... 81
4.5.4
Vital Signs.............................................................................. 81


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4.5.5
Tumor and Response Evaluations......................................... 81
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................ 83
4.5.6.1
Local Laboratory Tests......................................................... 83
4.5.6.2
Central Laboratory Assessments ......................................... 84
4.5.7
Electrocardiograms................................................................ 85
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 85
4.6.1
Study Treatment Discontinuation........................................... 85
4.6.2
Patient Discontinuation from Study........................................ 86
4.6.3
Study Discontinuation............................................................ 86
4.6.4
Site Discontinuation............................................................... 86
5.
ASSESSMENT OF SAFETY....................................................................... 87
5.1
Safety Plan ............................................................................ 87
5.1.1
Risks Associated with Atezolizumab and 
Potential Risks of MOXR0916 ............................................... 87
5.1.1.1
Immune-Related Hepatitis.................................................... 88
5.1.1.2
Immune-Related Pneumonitis.............................................. 88
5.1.1.3
Immune-Related Colitis........................................................ 89
5.1.1.4
Dermatologic Events ............................................................ 89
5.1.1.5
Immune-Related Pancreatitis ............................................... 89
5.1.1.6
Immune-Related Endocrinopathies ...................................... 90
5.1.1.7
Immune-Related Myocarditis ............................................... 90
5.1.1.8
Immune-Related Meningoencephalitis ................................. 90
5.1.1.9
Immune-Related Neurologic Disorders ................................ 91
5.1.1.10
Infusion-Related Reactions ................................................ 91
5.1.2
Potential Risks Specific to MOXR0916.................................. 91
5.1.2.1
Cytokine Release Syndrome and Macrophage 
Activation Syndrome............................................................ 92
5.1.2.2
Enhanced Immune Response during Acute 
Infection............................................................................... 92
5.1.2.3
Lymphopenia........................................................................ 93
5.1.3
Potential for Overlapping Toxicities with 
MOXR0916 and Atezolizumab .............................................. 93


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5.1.3.1
Systemic Immune Activation ................................................ 94
5.1.4
Dose Modification:  General Guidance .................................. 94
5.1.5
Management of Patients Who Experience 
Specific Adverse Events ....................................................... 95
5.1.5.1
Hepatic Events ..................................................................... 96
5.1.5.2
Pulmonary Events ................................................................ 97
5.1.5.3
Gastrointestinal Events ........................................................ 98
5.1.5.4
Dermatologic Events ............................................................ 99
5.1.5.5
Pancreatic Events .............................................................. 100
5.1.5.6
Endocrine Events ............................................................... 102
5.1.5.7
Immune-Related Myocarditis ............................................. 105
5.1.5.8
Immune-Related Meningoencephalitis ............................... 106
5.1.5.9
Neurologic Disorders.......................................................... 107
5.1.5.10
Infusion-Related Reactions .............................................. 108
5.1.5.11
Cytokine Release Syndrome, Macrophage 
Activation Syndrome, and SIA ......................................... 110
5.2
Safety Parameters and Definitions ...................................... 113
5.2.1
Adverse Events ................................................................... 113
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 113
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ................................................. 114
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 115
5.3.1
Adverse Event Reporting Period ......................................... 115
5.3.2
Eliciting Adverse Event Information..................................... 116
5.3.3
Assessment of Severity of Adverse Events ......................... 116
5.3.4
Assessment of Causality of Adverse Events ....................... 117
5.3.5
Procedures for Recording Adverse Events.......................... 118
5.3.5.1
Infusion-Related Reactions ................................................ 118
5.3.5.2
Diagnosis versus Signs and Symptoms ............................. 118
5.3.5.3
Adverse Events That Are Secondary to Other 
Events................................................................................ 119
5.3.5.4
Persistent or Recurrent Adverse Events ............................ 119
5.3.5.5
Abnormal Laboratory Values.............................................. 119


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5.3.5.6
Abnormal Vital Sign Values................................................ 120
5.3.5.7
Abnormal Liver Function Tests........................................... 121
5.3.5.8
Deaths................................................................................ 121
5.3.5.9
Preexisting Medical Conditions .......................................... 122
5.3.5.10
Lack of Efficacy or Worsening of Urothelial 
Carcinoma........................................................................ 122
5.3.5.11
Hospitalization or Prolonged Hospitalization .................... 122
5.3.5.12
Adverse Events Associated with an Overdose 
or Error in Drug Administration......................................... 123
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 123
5.4.1
Emergency Medical Contacts.............................................. 124
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 124
5.4.2.1
Events That Occur prior to Study Drug Initiation ................ 124
5.4.2.2
Events That Occur after Study Drug Initiation .................... 124
5.4.3
Reporting Requirements for Pregnancies............................ 124
5.4.3.1
Pregnancies in Female Patients......................................... 124
5.4.3.2
Pregnancies in Female Partners of Male 
Patients.............................................................................. 125
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions............................................................................ 125
5.5
Follow-Up of Patients after Adverse Events ........................ 125
5.5.1
Investigator Follow-Up......................................................... 125
5.5.2
Sponsor Follow-Up .............................................................. 126
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 126
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 126
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 127
6.1
Determination of Sample Size ............................................. 127
6.2
Summaries of Conduct of Study.......................................... 128
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 128
6.4
Efficacy Analyses ................................................................ 128


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6.4.1
Co-Primary Efficacy Endpoints............................................ 129
6.4.1.1
Analysis Plan for Progression-Free Survival ...................... 129
6.4.1.2
Analysis Plan for Overall Survival....................................... 129
6.4.2
Secondary Efficacy Endpoints............................................. 130
6.4.2.1
Analysis Plan for PFS and OS in PD-L1 IC2/3 
Patients .............................................................................. 130
6.4.2.2
Analysis Plan for Objective Response................................ 130
6.4.2.3
Analysis Plan for Duration of Response............................. 131
6.4.2.4
Analysis Plan for Patient-Reported Symptoms 
and Impact on Functioning................................................. 131
6.4.3
Exploratory Efficacy Endpoints............................................ 132
6.5
Safety Analyses................................................................... 132
6.6
Pharmacokinetic Analyses................................................... 133
6.7
Immunogenicity Analyses.................................................... 133
6.8
Biomarker Analyses............................................................. 133
6.9
Interim Analyses .................................................................. 134
6.9.1
Planned Interim Analyses.................................................... 134
6.9.2
Optional Interim Analyses.................................................... 134
7.
DATA COLLECTION AND MANAGEMENT ............................................. 135
7.1
Data Quality Assurance....................................................... 135
7.2
Electronic Case Report Forms............................................. 135
7.3
Source Data Documentation................................................ 135
7.4
Use of Computerized Systems ............................................ 136
7.5
Retention of Records........................................................... 136
8.
ETHICAL CONSIDERATIONS.................................................................. 136
8.1
Compliance with Laws and Regulations .............................. 136
8.2
Informed Consent................................................................ 137
8.3
Institutional Review Board or Ethics Committee.................. 138
8.4
Confidentiality...................................................................... 138
8.5
Financial Disclosure ............................................................ 139
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 139
9.1
Study Documentation .......................................................... 139


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9.2
Protocol Deviations.............................................................. 139
9.3
Site Inspections ................................................................... 139
9.4
Administrative Structure....................................................... 140
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 140
9.6
Protocol Amendments ......................................................... 141
10. REFERENCES ......................................................................................... 142
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 56
Table 2
Administration of First and Subsequent MOXR0916 Infusions ... 75
Table 3
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 76
Table 4
Management Guidelines for Hepatic Events............................... 96
Table 5
Management Guidelines for Pulmonary Events, including 
Pneumonitis ................................................................................ 97
Table 6
Management Guidelines for Gastrointestinal Events 
(Diarrhea or Colitis)..................................................................... 98
Table 7
Management Guidelines for Dermatologic Events.................... 100
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis ............................................................................... 101
Table 9
Management Guidelines for Endocrine Events......................... 103
Table 10
Management Guidelines for Immune-Related Myocarditis ...... 106
Table 11
Management Guidelines for Immune-Related 
Meningoencephalitis ................................................................. 107
Table 12
Management Guidelines for Neurologic Disorders.................... 108
Table 13
Management Guidelines for Infusion-Related Reactions .......... 110
Table 14
Diagnostic Criteria and Recommended Management for 
Systemic Immune Activation..................................................... 112
Table 15
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 117
Table 16
Causal Attribution Guidance ..................................................... 118
Table 17
Operating Characteristics for Proposed Study Design for 
Several Possible True Underlying Hazard Ratio Values........... 128
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 59


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LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 148 
Appendix 2 
Modified Bajorin Risk Score ...................................................... 153 
Appendix 3 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 154 
Appendix 4 
New York Heart Association Functional Classification .............. 163 
Appendix 5 
Anaphylaxis Precautions ........................................................... 164 
Appendix 6 
Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 165 


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY 
OF MOXR0916 IN COMBINATION WITH 
ATEZOLIZUMAB VERSUS ATEZOLIZUMAB ALONE 
IN PATIENTS WITH UNTREATED LOCALLY 
ADVANCED OR METASTATIC UROTHELIAL 
CARCINOMA WHO ARE INELIGIBLE FOR 
CISPLATIN-BASED THERAPY
PROTOCOL NUMBER:
GO39590
VERSION NUMBER:
3
EUDRACT NUMBER:
2016-004165-58
IND NUMBER:
132240
TEST PRODUCT:
MOXR0916 (RO7021608)
MPDL3280A (RO5541267)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files. Please return a copy to your local 
study monitor.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND STUDY OF MOXR0916 IN 
COMBINATION WITH ATEZOLIZUMAB VERSUS ATEZOLIZUMAB 
ALONE IN PATIENTS WITH UNTREATED LOCALLY ADVANCED 
OR METASTATIC UROTHELIAL CARCINOMA WHO ARE 
INELIGIBLE FOR CISPLATIN-BASED THERAPY
PROTOCOL NUMBER:
GO39590
VERSION NUMBER:
3
EUDRACT NUMBER:
2016-004165-58
IND NUMBER:
132240
TEST PRODUCTS:
MOXR0916 (RO7021608)
MPDL3280A (RO5541267)
PHASE:
Phase II
INDICATION:
Urothelial carcinoma 
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
The Sponsor has determined that the original scientific aims of this study are no longer 
evaluable as a result of the Sponsor’s decision to prematurely halt enrollment due to slow 
patient accrual.  The original scientific aims of this study are described below solely for 
reference.
This study will evaluate the efficacy and safety of MOXR0916 plus atezolizumab compared with 
placebo plus atezolizumab in patients with locally advanced or metastatic urothelial carcinoma
(UC) who have not received prior systemic therapy in the locally advanced or metastatic setting 
and who are ineligible to receive cisplatin-based therapy.  The total randomized population 
includes the following overlapping analysis groups for assessing efficacy:

Primary population:  All patients randomized during Stage 1 of enrollment 

Programmed death-ligand 1 (PD-L1) tumor-infiltrating immune cell (IC) 2/3 population:  All 
randomized patients with tumor PD-L1 immunohistochemistry (IHC) score of IC2/3 
Specific objectives and corresponding endpoints for the study are outlined below.  Unless 
otherwise specified, efficacy objectives will be evaluated in both analysis populations.
Primary Efficacy Objective
Corresponding Endpoints
To evaluate the efficacy of 
MOXR0916 plus atezolizumab 
compared with placebo plus 
atezolizumab in the primary 
population
PFS (defined as the time from randomization to the 
first occurrence of disease progression or death from 
any cause, whichever occurs first) as determined by 
the investigator according to RECIST v1.1
OS, defined as the time from randomization to death 
from any cause


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Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab in the 
PD-L1 IC2/3 population
PFS as determined by the investigator according to 
RECIST v1.1
OS, defined as the time from randomization to death 
from any cause
To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab
Objective response (defined as a CR or PR) on two 
consecutive occasions 4 weeks apart as 
determined by the investigator according to 
RECIST v1.1
DOR, (defined as the time from the first occurrence 
of a documented objective response to disease 
progression or death from any cause, whichever 
occurs first) as determined by the investigator 
according to RECIST v1.1
Time to pain progression as measured by patient-
reported pain severity according to the MDASI 
Time to pain palliation as measured by patient-
reported pain severity according to the MDASI 
Time to fatigue progression as measured by patient-
reported fatigue severity according to the MDASI  
Proportion of patients reporting symptom 
interference with daily living at the time of 
progression according to the MDASI
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab
Objective response, DOR, and PFS according to 
immune-modified RECIST
Objective response, DOR and PFS as determined by 
an IRF according to RECIST v1.1
Time to progression of patient-reported symptoms 
(other than pain and fatigue) as measured by the 
MDASI.
Change from baseline in patient-reported symptoms 
and symptom interference with daily living as 
measured by the MDASI
Safety Objective
Corresponding Endpoints
To evaluate the safety of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab
Incidence of adverse events, with severity 
determined through use of NCI CTCAE v4.0
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
Pharmacokinetic Objective
Corresponding Endpoints
To characterize pharmacokinetics of 
MOXR0916 and atezolizumab when 
administered in combination
Serum concentration of MOXR0916 at specified 
timepoints
Serum concentration of atezolizumab at specified 
timepoints


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Exploratory Pharmacokinetic 
Objective
Corresponding Endpoints
To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of MOXR0916
Serum concentration or PK parameters for 
MOXR0916 and efficacy endpoints
Serum concentration or PK parameters for 
MOXR0916 and safety endpoints
Immunogenicity Objective
Corresponding Endpoints
To evaluate the immune response to 
MOXR0916 and atezolizumab
Presence of ATAs to MOXR0916 during the study 
relative to the presence of ATAs at baseline
Presence of ATAs to atezolizumab during the study 
relative to the presence of ATAs at baseline
Exploratory Immunogenicity 
Objective
Corresponding Endpoint
To evaluate potential effects of ATAs
ATA status and efficacy, safety, or PK endpoints
Exploratory Biomarker Objective
Corresponding Endpoints
To evaluate candidate biomarkers that 
may be associated with response to 
MOXR0916 and atezolizumab 
(i.e., predictive biomarkers), 
progression to a more severe disease 
state (i.e., prognostic biomarkers), 
acquired resistance to MOXR0916 
and atezolizumab, susceptibility to 
developing adverse events (i.e., safety 
biomarkers), or that may provide 
evidence of MOXR0916 and 
atezolizumab activity (i.e. 
pharmacodynamic biomarkers)
Expression of PD-L1 in tumor tissue and measures 
of efficacy
Tumor mutational load and measures of efficacy
Biomarkers in blood and tumor tissue and efficacy, 
safety, PK, immunogenicity, or other biomarker 
endpoints
Exploratory Health Status Utility 
Objective
Corresponding Endpoint
To evaluate health status utility scores 
of patients treated with MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab
Health status as measured using the EQ-5D-5L
questionnaire for health economic modeling
ATAanti-therapeutic antibodies; CRcomplete response; CTCAECommon Terminology 
Criteria for Adverse Events; DORduration of objective response; EQ-5D-5LEuro QoL 5 
Dimensions 5-Level; ICtumor-infiltrating immune cell; IRFindependent review facility; 
MDASIM. D. Anderson Symptom Inventory; NCINational Cancer Institute; OS overall 
survival; PD-L1programmed death-ligand 1; PFSprogression-free survival; 
PKpharmacokinetics; PRpartial response; RECIST Response Evaluation Criteria in Solid 
Tumors.
Study Design
Description of Study
This is a Phase II, multicenter, randomized, placebo-controlled, double-blind study to evaluate 
the safety and efficacy of MOXR0916 in combination with atezolizumab versus placebo and 
atezolizumab in patients with locally advanced or metastatic UC who have not received prior 
systemic therapy in the locally advanced/metastatic setting and who are ineligible to receive 
cisplatin-based therapy.




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local institutional standards.  
All adverse events will be monitored and recorded for at least 90 days after the last dose of 
study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first.  
After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event if the event is believed to be related to prior study treatment.  Adverse 
events will be graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.0.
Target Population
Patients with locally advanced or metastatic UC who have not received prior systemic therapy in 
the locally advanced or metastatic setting and who are ineligible to receive cisplatin-based 
therapy will be enrolled in this study.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator’s judgment

ECOG Performance Status of 2 

Life expectancy 12 weeks

Histologically or cytologically confirmed locally advanced (T4b, any N; or any T, N 23) or 
metastatic UC (M1, Stage IV) (also termed transitional cell carcinoma [TCC] or urothelial 
cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, 
and urethra)
Patients with mixed histologies are required to have a dominant transitional cell pattern.
Locally advanced bladder cancer must be inoperable on the basis of involvement of 
pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis 
(N2N3).

Availability of a representative tumor specimen to enable central testing for determination of 
PD-L1 status and exploratory research on biomarkers 
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 15 slides containing unstained, freshly cut, serial sections, must 
be submitted along with an associated pathology report prior to study enrollment.  If 
only 1014 slides are available, the patient may still be eligible for the study, after 
discussion with and approval by the Medical Monitor. 
Submitted archival tumor tissue must be evaluated for PD-L1 expression prior to 
enrollment.  Patients whose tumor tissue is not evaluable for PD-L1 expression are not 
eligible. 
If patients have multiple adequate tissue samples from procedures performed at 
different times during the course of their UC; priority should be given to the tissue most 
recently collected.  Multiple samples may be submitted for a given patient, on the basis 
of availability; however, the requirement for a block or 15 unstained slides should be 
satisfied by a single biopsy or resection specimen.  If multiple tumor specimens are 
submitted, patients may be eligible if at least one specimen is evaluable for PD-L1. In 
the event that enrollment is limited to PD-L1 selected patients, the highest PD-L1 score 
among the submitted samples will be used to determine eligibility.
Transurethral resection of bladder tumor (TURBT) specimens must contain a muscle 
invasive component (i.e., T2 or greater) of the bladder tumor as documented in the
pathology report.  If the TURBT specimens do not contain a muscle invasive 
component, then specimens obtained at the time of cystectomy/nephroureterectomy or 
metastatic spread (i.e., sample from a metastatic lesion) will be required prior to 
randomization.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is 
therefore not acceptable.


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Fine-needle aspiration (defined as samples that do not preserve tissue architecture 
and yield cell suspension and/or smears), brushing, and cell pellets, pleural effusions 
and lavage samples are not acceptable.
Patients who do not have tissue specimens that meet eligibility requirements may 
undergo a biopsy prior to enrollment.  Acceptable samples include core needle 
biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, 
or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.
Prior to signing the main study informed consent form, patients may sign a pre-
screening consent form to specifically allow the collection and testing of archival or 
fresh tumor specimens. 

No prior systemic therapy for inoperable locally advanced or metastatic UC
For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemo-radiation for UC, a treatment-free interval 12 months between the last 
treatment administration and Cycle 1, Day 1 is required in order to be considered 
treatment naive in the metastatic setting.

Ineligible for cisplatin-based chemotherapy as defined by any one of the following criteria:
–
Impaired renal function (glomerular filtration rate [GFR] 30 but 60 mL/min); GFR may
be assessed by calculation from serum/plasma creatinine (Cockcroft-Gault formula) or 
direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate)
–
NCI CTCAE v4.0 Grade 2 audiometric hearing loss (25 dB at two contiguous 
frequencies or more severe)
–
NCI CTCAE v4.0 Grade 2 peripheral neuropathy (i.e., sensory alteration or 
paresthesias, including tingling)
–
ECOG Performance Status of 2

Measurable disease according to RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since radiation.

Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 14 days prior to initiation of study treatment:
–
White blood cell (WBC) counts 2,500/L
–
ANC 1500/L (without granulocyte colony-stimulating factor support 14 days prior to 
Cycle 1, Day 1)
–
Lymphocyte count 500/L
–
Platelet count 100,000/L (without transfusion 14 days prior to Cycle 1, Day 1)
–
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Patients with a solitary kidney or chronic kidney disease with low erythropoietin 
production may use erythropoietin-stimulating agents.
–
AST, ALT, and alkaline phosphatase (ALP) 3 upper limit of normal (ULN), with the 
following exception:
Patients with documented liver or bone metastases:  ALP 5 ULN
–
Serum bilirubin 1.5 ULN 
Patients with known Gilbert disease who have serum bilirubin level 3ULN may 
be enrolled.
–
Measured or calculated creatinine clearance 30 mL/min (calculated using the 
Cockcroft-Gault formula)
–
Serum albumin 2.5 g/dL
–
Prothrombin time (PT)/INR and activated partial thromboplastin time (aPTT) 
1.5 ULN


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This applies only to patients who are not receiving therapeutic anticoagulation; 
patients receiving therapeutic anti-coagulation should be on a stable dose

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% per year 
during the treatment period and for at least 6 months after the last dose of study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 
6 months after the last dose of study treatment to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or lactating, or intending to become pregnant or breast feed during the study or
6 months afterward
Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment.

Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months 
prior to initiation of study treatment, unstable arrhythmia, or unstable angina 
Patients with a known left ventricular ejection fraction (LVEF) 40% will be excluded
Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF 40%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.  

Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, 
cirrhosis, and inherited liver disease

Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation 
of need for a major surgical procedure during the course of the study.
TURBT is considered a minor surgical procedure

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications


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
Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 
3 weeks prior to initiation of study treatment; the following exceptions are allowed:
–
Palliative radiotherapy for bone metastases or soft tissue lesions that is completed 
7 days prior to baseline imaging
–
Radiotherapy for brain metastases as stipulated below
–
Prior local intravesical chemotherapy or immunotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment
–
Hormone-replacement therapy or oral contraceptives
–
Patients should be recovered from any toxicities associated with permitted anti-cancer 
therapies

Prior treatment with CD137 or OX40 agonists, antiCTLA-4, antiPD-1, antiPD-L1, anti-
CD-27, anti-GITR therapeutic antibody or pathway-targeting agents

Treatment with any other investigational agent or participation in another clinical study with 
therapeutic intent within 28 days prior to initiation of study treatment

Untreated CNS metastases or active (progressing or requiring corticosteroids for 
symptomatic control) CNS metastases
Patients with a history of treated asymptomatic CNS metastases are eligible, 
provided they meet all of the following criteria:
–
Measurable disease outside the CNS
–
No ongoing requirement for corticosteroids as therapy for CNS disease, with 
corticosteroids discontinued for 2 weeks prior to enrollment
–
Anticonvulsants at a stable dose are allowed
–
No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior 
to Cycle 1, Day 1
–
No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected during screening must 
receive radiation therapy and/or surgery for CNS metastases.  Following treatment, 
these patients may then be eligible without the need for an additional brain scan prior 
to enrollment, if all other criteria are met.

Any history of leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment.  
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment.

Malignancies other than UC within 5 years prior to Cycle 1, Day 1
Patients with localized low-risk prostate cancer (defined as Stage pT2b, Gleason 
score 7, and prostate-specific antigen (PSA) at prostate cancer diagnosis 20 ng/mL) 
treated with curative intent and without PSA recurrence are eligible. 
Patients with pre-existing low-risk prostate cancer (defined as Stage cT1/T2a, Gleason 
score 7 and PSA 10 ng/mL) who are treatment-naive and undergoing active 
surveillance are eligible. 
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of 
metastasis or death 5% at 5 years) are eligible provided they meet all of the following 


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criteria:
Malignancy treated with expected curative intent (e.g., adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal 
carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any disease-
specific tumor markers

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or calcium 
12 mg/dL or corrected serum calcium ULN)

History of autoimmune disease with the following caveats:
Patients with a history of autoimmune-related endocrinopathy (e.g. hypothyroidism) on 
a stable dose of replacement hormone (e.g. thyroid hormone) may be eligible for this 
study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for 
the study provided all of following conditions are met:
–
Rash must cover 10% of body surface area
–
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids
–
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 
12 months

Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antiTNF-
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for 
systemic immunosuppressive medication during the course of the study with the following 
exceptions:
Patients who have received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication are eligible for 
the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study.

Treatment with systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to 
initiation of study treatment

History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or 
evidence of active pneumonitis on screening chest computed tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
History of drug-induced pneumonitis that was asymptomatic (defined by radiographic 
findings only) and reversible (without any anti-inflammatory therapies) is permitted

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative HBsAg 
test and a positive total hepatitis B core antibody (HBcAb) test at screening, are 
eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at 
screening


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Patients who have a positive HCV antibody test are eligible for the study if a 
polymerase chain reaction assay is negative for HCV RNA

Positive HIV test at screening

Active tuberculosis

Severe infection within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

Patients with recent infections that are not judged to be severe (as described above) are 
excluded if they have either:
–
Signs or symptoms of infection within 2 weeks prior to initiation of study treatment
Patients with uncomplicated viral upper respiratory tract infections are eligible 
provided symptoms have resolved to baseline.
–
Received oral or IV antibiotics (including anti-fungal or anti-viral therapy) within 2 weeks 
prior to initiation of study treatment for suspected or confirmed infection
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease or for dental extraction) are 
eligible.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks before initiation of study treatment, 
or anticipation of need for such a vaccine during the course of the study.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary 
cells 

Known allergy or hypersensitivity to any component of the atezolizumab formulation

Known allergy or hypersensitivity to any component of the MOXR0916 formulation
End of Study
The end of the study is defined as the date when the number of OS events specified for the final 
analysis has been observed. Additionally, the Sponsor may decide to terminate the study at 
any time.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 45 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
MOXR0916 will be administered at the 300-mg dose level by IV infusion every 3 weeks.
Atezolizumab will be administered at the 1200-mg dose level by IV infusion every 3 weeks.
Comparator
MOXR0916 placebo will be administered by IV infusion every 3 weeks.
Statistical Methods
The Sponsor has determined that the original scientific aims of this study are no longer 
evaluable as a result of the Sponsor’s decision to prematurely halt enrollment due to slow 
patient accrual.  However, the original statistical considerations and analysis plan are 
retained below for reference.
Efficacy Analyses
The co-primary and secondary efficacy analyses will be conducted among all randomized 
patients in appropriate study populations (primary population or PD-L1 IC2/3 population) with 
patients grouped according to their assigned treatment (i.e., intent-to-treat [ITT]) analysis.  
Specifically, formal hypothesis testing of the co-primary efficacy endpoints of progression-free 


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survival (PFS) and overall survival (OS) will be conducted in the ITT primary patient population 
at significance levels of 0.005 and 0.045, respectively. 
Other secondary endpoints, including PFS and OS in the PD-L1 IC2/3 subpopulation, as well as 
objective response rate (ORR), duration of response (DOR), and patient-reported outcome
(PROs; including pain, fatigue, other symptoms, and interference scores from the M. D. 
Anderson Symptom Inventory [MDASI]) in both the primary patient population and in the PD-L1 
IC2/3 population will also be analyzed but are not included in the formal hypothesis testing 
framework.  Results will be presented with 95% confidence intervals unless otherwise specified.
Determination of Sample Size  
The primary objective of this study is to test the hypothesis of greater treatment effect of 
MOXR0916 plus atezolizumab on duration of PFS and OS relative to the placebo plus 
atezolizumab.  For the co-primary endpoints of PFS and OS in the primary patient population, at 
70% event maturity (112 PFS or OS events), the trial will have 81% power to detect a PFS 
hazard ratio of 0.50 at a two-sided significance level of 0.005 (corresponding to an improvement 
from 3 to 6 months in median PFS), and 80% power to detect an OS hazard ratio of 0.58 at a 
two-sided significance level of 0.045 (corresponding to an improvement from 13.3 to 22.9 
months in median OS).  Total type I error will be controlled at a 0.05 significance level. 
Notably, the trial is able to detect only very large benefits in OS.  The trial will not, however, 
have adequate power to detect all potentially clinically meaningful differences in OS.  For 
example, with 112 OS events, there is only 45% power to detect a hazard ratio of 0.70 
(corresponding to an improvement from 13.3 to 19 months in median OS) at a two-sided 
significance level of 0.045.  Thus, a statistically negative outcome in the co-primary OS analysis 
does not necessarily rule out a clinically meaningful outcome. 
Additionally, with 60 PFS events in the PD-L1 IC2/3 population (corresponding to 75% event 
maturity), there is 77% power to detect a HR of 0.50 at a two-sided significance level of 0.05.  
The upper bound of the two-sided 95% CI for the HR will be 0.83.
Interim Analyses
There will be no interim efficacy analyses prior to the primary PFS analysis in the primary 
population.  Interim efficacy analyses for OS will be conducted.
An Internal Monitoring Committee (IMC) will convene approximately every 6 months during 
enrollment to review available safety data and to make recommendations regarding study 
conduct to ensure the safety of patients enrolled on the study.  In the absence of significant 
safety concerns or other extenuating circumstances, accrual will continue in the study while the 
reviews are being conducted.  Pending review of accumulating safety data, the IMC may 
choose to meet more frequently, if necessary.  On the basis of these interim safety results, 
however, the IMC may recommend to continue, modify, or terminate the study.  However, as 
the IMC will review only safety data, it cannot undertake decisions to halt the trial based on 
early efficacy or futility.
The members, roles, responsibilities and communication processes of the IMC will be outlined 
in a separate charter.
There will be no interim efficacy analyses prior to the primary PFS analysis in the primary 
population.  Following the primary PFS analysis, however, the Sponsor may choose to conduct 
up to two additional interim efficacy analyses for OS.  The decision to conduct an optional 
interim analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed and 
interpreted by members of the Sponsor study team and appropriate senior management 
personnel who will be unblinded at the treatment group level.  Access to treatment assignment 
information will follow the Sponsor’s standard procedures.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADCC
antibody-dependent cell-mediated cytotoxicity
ALP
alkaline phosphatase
aPTT
activated partial thromboplastin
ATA
anti-therapeutic antibody
CNS
central nervous system
CRO
contract research organization
CRS
Cytokine release syndrome
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DMC
Data Monitoring Committee
DOR
duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
European Quality-of-Life 5-Dimension Questionnaire
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
GC
gemcitabine and cisplatin
GFR
glomerular filtration rate
HBcAb
antibody against hepatitis B core antigen
HBsAb
antibody against hepatitis B surface antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
IC
tumor-infiltrating immune cell
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IRF
independent review facilty
ITT
intent-to-treat


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Abbreviation
Definition
IV
intravenous
LOQ
lower limit of quantification
LPLV
last patient, last visit
MAS
macrophage activation syndrome
MDASI
M. D. Anderson Symptom Inventory
MTD
maximum tolerated dose
MVAC
methotrexate, vinblastine, doxorubicin, and cisplatin
NCI
National Cancer Institute
NGS
next generation sequencing
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PBMC
peripheral blood mononuclear cells
PET
positron emission tomography
PFS
progression-free survival
PD-1
programmed death-1
PD-L1
programmed death-ligand 1
PK
pharmacokinetic
PRO
patient-reported outcome
PSA
prostate-specific antigen
PT
Prothrombin time
QTcF
QT interval corrected using Fridericia’s formula
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SIA
systemic immune activation
TCC
transitional cell carcinoma
TURBT
transurethral resection of bladder tumor
UBC
urothelial bladder cancer
UC
urothelial carcinoma
UCC
urothelial cell carcinoma
ULN
upper limit of normal
WBC
white blood cell
WES
whole exome sequencing
WGS
whole genome sequencing
WHO
World Health Organization


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1.
BACKGROUND
1.1
BACKGROUND ON UROTHELIAL CARCINOMA
Bladder cancer is the ninth most common cause of cancer with an estimated global 
incidence of 429,000 cases in 2012 (Ferlay et al. 2015). 
In the United States, the
expected incidence and mortality from bladder cancer in 2016 is 76,960 and 
16,390 cases, respectively (American Cancer Society 2016). The disease is 3 to 4 times 
more common in males than females and typically affects older patients, who have an 
average age of 73 years at time of diagnosis (American Cancer Society 2016).
Urothelial carcinoma (UC; also termed transitional cell carcinoma [TCC], urothelial 
bladder cancer [UBC], or urothelial cell carcinoma [UCC] of the urinary tract) is the 
predominant histologic type of cancer arising in the urinary tract. While bladder is the 
most frequent location, UC may also originate in the renal pelvis, ureter, or urethra.  
The urothelium is exposed to potential carcinogens that are excreted in the urine or 
activated from precursors in the urine, and environmental exposures appear to account 
for most cases of UC. Smoking is the most well established risk factor for UC, 
accounting for about 50% of all cases. Other carcinogens have also been implicated, as 
the risk for developing bladder cancer is increased among workers in the dye, rubber, 
leather, and aluminum industries; painters; and people who live in communities with high 
levels of arsenic in the drinking water (American Cancer Society 2016).  Consistent with 
the important role of chemical carcinogens in this disease, UC is associated with a high 
rate of somatic mutations compared with other common cancers (Alexandrov et al. 2013; 
Weinstein et al. 2014).
Approximately 5% of UC patients present with metastatic disease at diagnosis.  In 
addition, approximately half of the patients with locally advanced UC progress to 
metastatic disease within 2 years of cystectomy. With an overall 5-year survival rate of 
5.2%, patients with metastatic UC represent a persistent high unmet need
(Surveillance, Epidemiology and End Results [SEER] 2016). 
1.1.1
First-Line Treatment of Metastatic Urothelial Carcinoma 
Cisplatin-based combination chemotherapy results in superior survival when compared 
with single-agent cisplatin and is the preferred initial therapy for patients with metastatic 
UC. Common cisplatin-based regimens include methotrexate, vinblastine, doxorubicin, 
and cisplatin (MVAC) and gemcitabine and cisplatin (GC).  A Phase III study of 
405 patients showed that both regimens have comparable efficacy including similar 
objective response rate (ORR; 49% for GC vs. 46% for MVAC), time to progression 
(7 months in each arm) and overall survival (OS; 14.0 months for GC vs. 15.2 months for 
MVAC; von der Maase et al. 2005).  Although GC resulted in fewer Grade 3 and 4 
adverse events than MVAC, both regimens are associated with substantial toxicities 
(such as febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and 
neuropathy).


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Given this toxicity profile, a substantial proportion of metastatic UC patients are
considered medically “unfit” or ineligible to receive cisplatin-based regimens because of
baseline comorbidities (Sonpavde et al. 2014, Thompson et al. 2014). Indeed, two 
independent retrospective studies of medical claims in the SEER-Medicare database 
showed that only about 50% of patients receive treatment with any chemotherapy for 
first-line metastatic UC, and among these, only 36% received cisplatin-based therapy
(Sonpavde et al. 2014; Galsky et al. 2015).  
A consensus-working group has defined patients who meet at least one of the following 
criteria as “unfit” for cisplatin-based chemotherapy based on an increased risk of 
cisplatin toxicity (Galsky et al. 2011):

World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG)
Performance Status of 2 or a Karnofsky Performance Status of 60% to 70%

Creatinine clearance 60 mL/min

A hearing loss of 25 dB at two contiguous frequencies or more severe

Grade 2 peripheral neuropathy 

New York Heart Association Class III heart failure
Cisplatin-ineligible patients who are otherwise candidates for chemotherapy are typically 
offered carboplatin-based regimens (Cathomas et al. 2015). A randomized Phase III 
study of 238 cis-ineligible patients with previously untreated advanced UC compared 
carboplatin and gemcitabine to methotrexate, carboplatin, and vincristine (De Santis et al. 
2012). In this study, the confirmed ORR of the carboplatin and gemcitabine arm was 
36.1% versus 21.0% for the methotrexate, carboplatin, and vincristine arm and the study 
demonstrated no difference in OS between the two treatment arms (median OS 
9.3 vs. 8.1 months; HR0.94; 95% CI: 0.72, 1.22; p0.64). Notably, patients with both 
impaired renal function and poor performance status had especially poor outcomes and 
increased acute toxicity with either combination chemotherapy in the study.  In a post 
hoc analysis, OS decreased significantly as the number of Bajorin risk factors (ECOG 
Performance Status of 2 or presence of visceral metastases) increased
(Bajorin et al. 1999).  
For patients with ECOG 2, treatment options include single-agent chemotherapy or 
best supportive care. Responses to single-agent chemotherapy are generally of short 
duration, with unclear impact on survival.  Outcomes for patients not receiving any 
chemotherapy are extremely poor, with a median OS of only 3 months 
(Sonpavde et al. 2014; Galsky et al. 2015). 
Given the poor treatment outcomes for the cisplatin-ineligible UC patient population, a 
substantial need for chemotherapy-free treatment options exists. However, although 
there is an increasing understanding of the molecular biology and signaling pathways 
that underlie bladder cancer development and progression (particularly the fibroblast 
growth factor receptor, vascular endothelial growth factor, and epidermal growth factor 


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receptor/human epidermal growth factor 2pathways), no targeted agents related to 
these pathways currently have a role in the treatment of UC.
1.1.2
Immunotherapy for Urothelial Carcinoma
The strategy of blocking inhibitory T-cell pathways known as immune checkpoints in 
order to reinvigorate anti-tumor immune responses has been validated across diverse 
malignancies by the therapeutic successes of targeting cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4), programmed death-1 (PD-1), and programmed 
death-ligand 1 (PD-L1) (Hodi et al. 2010; Robert et al. 2014; Borghaei et al. 2015; 
Brahmer et al. 2015; Larkin et al. 2015; Motzer et al. 2015; Robert et al. 2015; 
Rosenberg et al. 2016, Fehrenbacher et al. 2016).
High tumor mutational load has been associated with clinical benefit in ipilimumab-
treated melanoma patients and pembrolizumab-treated nonsmall cell lung cancer 
(NSCLC) patients, demonstrating a genetic basis for response to checkpoint inhibition
(Snyder et al. 2014; Rizvi et al. 2015).  These results underscore the role of novel 
epitopes derived from mutated genes in eliciting tumor-specific T-cell responses.  The 
observation that UC is associated with the third highest mutation rate of all studied 
cancers provides a strong rationale for evaluating checkpoint inhibition in this disease
(Weinstein et al. 2014).
As described further below, investigation of the antiPD-L1 checkpoint inhibitor 
atezolizumab has culminated in the approval in the United States for the treatment of
patients with locally advanced or metastatic UC who have previously been treated with 
platinum-containing chemotherapy.  
1.2
BACKGROUND ON ATEZOLIZUMAB
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1. Binding of PD-L1 to PD-1 and B7-1 inhibits T-cell 
proliferation and activation, cytokine production, and cytolytic activity, leading to the 
functional inactivation or exhaustion of T cells (Butte et al. 2007; Yang et al. 2011).  
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1 pathway represents an attractive strategy for restoring tumor-
specific T-cell immunity.
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude 
and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 


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to Fc・receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.1
Atezolizumab in Urothelial Cancer
Study GO29293 (IMvigor 210) is an ongoing single-arm, open-label, Phase II study 
evaluating atezolizumab as a single agent in two cohorts of patients with locally 
advanced or metastatic UC (Rosenberg et al. 2016; Balar et al. 2016; Dreicer et al. 
2016). Cohort 1 enrolled first-line patients who were ineligible to receive cisplatin-based 
chemotherapy, and Cohort 2 enrolled patients who had progressed during or following 
platinum-based chemotherapy. The co-primary endpoints of the study were
independent review facility (IRF)assessed ORR according to Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 (both cohorts) and investigator-assessed ORR 
according to modified RECIST criteria (Cohort 2 only). 
Cohort 2 demonstrated that compared with a historical control ORR of 10%, treatment 
with atezolizumab resulted in a significantly improved ORR of 16% in all patients. ORR 
was enriched in patients with tumor-infiltrating immune cell (IC) PD-L1
immunohistochemistry (IHC) scores of 2/3, with an observed ORR of 28% and CR rate
of 15%. Durable responses were observed, with seventy one percent of responses 
ongoing at the time of data cutoff and median duration of response not yet reached after 
a median follow-up of 17.5 months (Dreicer et al. 2016).  Median OS was 7.9 months (CI:
6.7, 9.3) in all patients and 11.9 months (CI: 9.0, 17.9) in the IC 2/3 population.
Atezolizumab was well tolerated with a low rate of treatment-related Grade 34 toxicities 
and no treatment-related Grade 5 adverse events (Dreicer et al. 2016).  Results from 
this cohort have led to the approval of atezolizumab in the United States for the 
treatment of patients with locally advanced or metastatic UC who have disease 
progression during or following platinum-containing chemotherapy or have disease 
progression within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy.
In Cohort 1, ORR in all patients was 24% (CI: 16, 32) in all patients with 7% CRs.  
Responses were durable, with 75% of responses ongoing at the time of data cutoff, and 
median duration of response not reached after a median follow-up of 14.4 months. 
Median OS in all patients was 14.8 months (CI: 10.1, not estimable; Balar et al. 2016). 
Atezolizumab was well tolerated with a low rate of treatment-related Grade 34 toxicities


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and one treatment-related Grade 5 adverse event of sepsis (Balar et al. 2016).  The OS
and tolerability profile observed in this Phase II study compare favorably with historical 
benchmarks for carboplatin-based chemotherapy and strongly support further evaluation 
of atezolizumab in cisplatin-ineligible patients with metastatic UC.
1.3
BACKGROUND ON MOXR0916
OX40 is a member of the TNF receptor superfamily that is transiently expressed by 
T cells upon engagement of the TCR.  Ligation of OX40 in the context of TCR 
engagement provides co-stimulatory signals to CD4and CD8effector T cells, resulting 
in enhanced proliferation, survival, and effector function.  Conversely, OX40 signaling 
leads to functional inhibition and loss of regulatory T cells.  In murine tumor models, 
OX40 engagement by an agonist anti-OX40 antibody can promote anti-tumor T-cell 
responses and tumor shrinkage (Moran et al. 2013).
MOXR0916 is an agonist monoclonal antibody that targets human OX40.  It is a 
humanized effector-competent molecule based on a human IgG1 framework and is 
produced in Chinese hamster ovary cells.
MOXR0916 is being investigated as a single agent and in combination with 
atezolizumab in patients with locally advanced or metastatic solid tumors.
Nonclinical studies that supported the entry of MOXR0916 into clinical studies are 
described in the MOXR0916 Investigator’s Brochure.  Clinical experience with 
MOXR0916 is summarized briefly below and discussed in more detail in the MOXR0916 
Investigator’s Brochure.  
1.3.1
Summary of Clinical Studies with MOXR0916
Preliminary clinical data are available from two ongoing Phase I studies in patients with 
locally advanced or metastatic solid tumors:

Study GO29313, evaluating single-agent MOXR0916

Study GO29674, evaluating the combination of MOXR0916 and atezolizumab
Both GO29313 and GO29674 share the same overall structure that includes the 
following:

A dose-escalation stage to evaluate safety, tolerability, and pharmacokinetics and
determine the maximum tolerated dose (MTD) or maximum administered dose 

An expansion stage, that includes the following:
–
Part I: a serial biopsy cohort to explore tumor biomarkers of pharmacodynamic 
(PK) activity and obtain additional safety, tolerability, and PK data at multiple 
dose levels that mirror the dose-escalation scheme
–
Part II: multiple indication-specific cohorts enrolled at a selected dose to better 
characterize the preliminary efficacy of the study regimen in different cancer 
types


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1.3.2
Clinical Pharmacokinetics and Immunogenicity
In Study GO29313, preliminary PK data (0.2 to 1200 mg of MOXR0916, every 21 days)
for MOXR0916 appeared to show linear pharmacokinetics at doses of 160 mg. The
observed data are generally consistent with the expected pharmacokinetics of an IgG1 
antibody in humans.
In Study GO29674, the preliminary data for serum pharmacokinetics of MOXR0916
(0.8 to 1200 mg, every 21 days) administered in combination with 1200 mg atezolizumab 
appeared to be similar to available single-agent PK data of MOXR0916.  Similarly, 
preliminary PK data suggest similar atezolizumab pharmacokinetics in combination with 
MOXR0916 compared with historical single-agent PK data for atezolizumab at the 
1200 mg dose.
The development of anti-therapeutic antibodies (ATAs) has been observed in some 
patients in most dose groups.  Serum MOXR0916 concentrations over time appear to be 
reduced in some patients who were ATA positive compared with patients who were ATA 
negative. At higher dose levels (300 mg), the effect of ATA on pharmacokinetics 
appeared to be limited, and serum concentrations were maintained throughout all dosing 
cycles. No clear relationship between detection of ATAs and adverse events or infusion
reactions has been observed. However, data are limited, and no definitive conclusions 
can be made. Immunogenicity assessment is ongoing in both studies.
1.3.3
Clinical Safety
Overall, MOXR0916 has been well tolerated as a single agent and in combination with 
atezolizumab.   
As of 1 July 2016, preliminary safety data are available for 164 patients with refractory 
solid tumors who received MOXR0916 at doses between 0.2 to 1200 mg intravenous (IV)
every 21 days, including 101 patients treated at the 300 mg dose level selected for 
expansion.  No dose limiting toxicities were observed and no maximum tolerated dose 
was reached.  Adverse events attributed to MOXR0916 across dose levels were 
generally Grade 1 or 2 in maximum severity and transient or manageable (Hansen et al. 
2016).
As of 12 July 2016, preliminary safety data are available for 211 patients with locally 
advanced or solid tumors who received MOXR0916 at doses between 0.8 and 1200 mg 
in combination with atezolizumab 1200 mg IV every 21 days.  These include 170 
patients treated at the 300-mg dose level of MOXR0916 selected for expansion, of 
whom 26 patients were enrolled in a dedicated UC cohort.  No dose limiting toxicities 
were observed and no maximum tolerated dose was reached (Infante et al. 2016).  The 
most frequently observed adverse events regardless of attribution (occurring in 10% of 
all patients) include fatigue, nausea, diarrhea, constipation, pyrexia, decreased appetite, 
vomiting, abdominal pain, and anemia.  Adverse events attributed to the combination of 


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MOXR0916 and atezolizumab across dose levels were generally Grade 1 or 2 in 
maximum severity and transient or manageable.  No disease-specific safety trends were 
observed in the UC expansion cohort.  Overall, the preliminary data on the frequency 
and severity of adverse events attributed to the combination of MOXR0916 and 
atezolizumab in the ongoing Study GO29674 has not been distinguishable from the
more thoroughly characterized toxicity profile of atezolizumab as a single agent
(Atezolizumab Investigator’s Brochure).  
1.3.4
Clinical Efficacy
Based on ongoing indication-specific expansion cohorts in Study GO29313, MOXR0916 
appears to have limited efficacy as a single agent.  In Study GO29674, the combination 
of MOXR0916 and atezolizumab is being evaluated in ongoing expansion cohorts for 
patients with UC, nonsmall cell lung cancer, triple-negative breast cancer, renal cell 
carcinoma, and melanoma, with preliminary anti-tumor activity observed in each cohort.  
Mature response rate, duration of response (DOR), survival data, and the relationship 
between biomarkers and efficacy are not yet available for these ongoing cohorts.  
Comparative efficacy with respect to atezolizumab monotherapy cannot be determined 
from Study GO29674 based on the single-arm Phase I design.
1.4
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The approval of atezolizumab for the second-line therapy of patients with UC marked a 
notable advance in a stagnant therapeutic landscape otherwise comprised of cytotoxic 
chemotherapy regimens.  Available data from the pivotal Phase II trial IMvigor210 
demonstrate that the tolerability and durability of response observed with atezolizumab 
are qualitatively distinct from those observed with chemotherapy.  In particular, median 
OS in this study was 7.9 months for patients previously treated with platinum-based 
regimens and 14.8 months for first-line cisplatin-ineligible patients (Balar et al. 2016; 
Dreicer et al. 2016; Rosenberg et al. 2016).  In contrast, the median OS for first-line 
cisplatin-ineligible UC patients treated with carboplatin/gemcitabine in a large Phase III 
study was 9.3 months (De Santis et al. 2012).
Nevertheless, despite the robust activity observed with PD-L1/PD-1 inhibitors across 
diverse malignancies, durable clinical benefit appears limited to a minority of patients. 
Although several published studies suggest that the expression of PD-L1 in tumors 
correlates with response to PD-L1/PD-1 inhibition (Topalian et al. 2012; Herbst et al. 
2014; Borghaei et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; Rosenberg et 
al. 2016), more refined patient selection strategies to reliably identify those most likely to 
respond are required.  In addition to improving patient selection, broadening the 
population eligible to benefit from checkpoint blockade through combination therapies 
that address intrinsic or acquired mechanisms of resistance to PD-L1/PD-1 inhibitors is
an urgent priority.  Resistance may occur at the level of the effector T cell, which may be 
downregulated by multiple co-inhibitory inputs. Resistance may also originate with other 
immunosuppressive cell types in the tumor microenvironment, such as regulatory 


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T cells, myeloid-derived suppressor cells, and tumor-associated macrophages.  
OX40 is a co-stimulatory receptor expressed on antigen experienced T cells but not
detected on naïve T cells. OX40 signaling, upon engagement with its ligand OX40L in
the context of antigen recognition by the T-cell receptor, enhances the proliferation and
survival of effector T cells and inhibits the suppressive function of regulatory T cells
(Moran et al. 2013). In multiple murine syngeneic tumor models, targeting of OX40 with
an agonist antibody results in co-stimulation of effector T cells, as measured by
proliferation and inflammatory cytokine production, as well as reduction of regulatory T 
cells. This dual mechanism of action is predicted to complement the activity of PD-L1
blockade by enhancing priming of anti-tumor T-cell responses as well as reversing
regulatory T cell-mediated suppression of intratumoral effector T cells. Indeed, the
combination of antibodies targeting OX40 and PD-L1, has demonstrated greater
anti-tumor activity in selected murine tumor models than either antibody as a single
agent (see the MOXR0916 and Atezolizumab Investigator’s Brochures).
OX40 expression has been detected on T cells in human tumor specimens from multiple 
cancer indications, including UC (Vetto et al. 1997; Ramstad et al. 2000; Petty et al. 
2002, Ziai et al. 2015).  Furthermore, expression levels of OX40 and PD-L1 are 
moderately correlated across tumor types (Genentech data on file).  Hence, combination
therapy targeting OX40 and PD-L1 may prove applicable to a broad population with
diverse cancers including UC.
To date, the combination of the OX40 agonist MOXR0916 with the PD-L1 inhibitor 
atezolizumab has been evaluated in a large Phase Ib study (GO29674) that includes 
indication-specific expansion cohorts.  The single-arm design, the uncontrolled biases in 
Phase I patient selection, and the size constraints of individual expansion cohorts in 
Study GO29674 preclude straightforward conclusions about the efficacy of the 
combination relative to atezolizumab monotherapy.  Hence, this Phase II trial is 
proposed as a randomized comparison of MOXR0916/atezolizumab to 
placebo/atezolizumab in a defined population of patients for whom atezolizumab 
represents an acceptable standard of care in order to establish proof-of-concept for the 
combination of anti-OX40 and anti-PD-L1.
While no direct benefits have been established at this time, the available nonclinical and 
clinical data provide a strong rationale for investigating the potential synergistic benefit of 
these combinations in patients with UC.  Data from the ongoing Studies GO29313 and 
GO29674 suggest MOXR0916 has been generally well tolerated as a single agent and 
in combination with atezolizumab (Hansen et al. 2016; Infante et al. 2016).  To date, 
there are no identified risks with MOXR0916. Nevertheless, the postulated mechanisms 
of action of anti-OX40 are predicted to complement and enhance the immune-
potentiating activity of anti−PD-L1; hence, the combination may be associated with a 
higher frequency and/or greater severity of immune-related adverse events than 
observed with anti-PD-L1 as a single agent.


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Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-related causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness, endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, 
and myasthenia gravis, have been observed (see Atezolizumab Investigator’s Brochure 
for detailed safety results).  To date, these events have been manageable with treatment.  
Engagement of the OX40 co-stimulatory pathway may further increase the risk of 
autoimmune inflammation as well as cytokine release syndrome.  Therefore, MOXR0916 
may cause adverse events similar to but independently of atezolizumab, may 
exacerbate atezolizumab-related adverse events, or may have non-overlapping toxicities 
with atezolizumab. 
The largest clinical experience to date with the combination of complementary 
modulators of adaptive immunity is derived from trials of anti-CTLA4 in combination with 
anti-PD-1 (Wolchok et al. 2013, Antonia et al. 2014; Hammers et al. 2014; Larkin et al. 
2015; Antonia et al. 2016).  Based on these data, it is anticipated that combination 
immune-related adverse events will be monitorable and manageable in the clinical 
setting, though the frequency of immune-related adverse events may be increased as 
compared with either single agent alone. The extensive nonclinical and clinical 
experience with immune checkpoint inhibitors to date has been incorporated into the 
design and safety management plan (see Section 5.1) of this study in order to reduce 
the potential risks to participating patients.  Moreover, an Internal Monitoring Committee 
(IMC) will be established (see Section 3.1.2) to monitor cumulative safety data at regular 
intervals and provide recommendations on study conduct to ensure the safety of trial 
participants.     
2. 
OBJECTIVES AND ENDPOINTS 
The Sponsor has determined that the original scientific aims of this study are no longer 
evaluable as a result of the Sponsor’s decision to prematurely halt enrollment due to 
slow patient accrual.  The original scientific aims of this study are described below 
solely for reference. 
This study will evaluate the efficacy and safety of MOXR0916 plus atezolizumab 
compared with placebo plus atezolizumab in patients with locally advanced or metastatic 
UC who have not received prior systemic therapy in the locally advanced or metastatic 
setting and who are ineligible to receive cisplatin-based therapy.   
• 
The total randomized population includes the following overlapping analysis groups 
for assessing efficacy (see Section 3.1 and Figure 1): 
• 
Primary population:  All patients randomized during Stage 1 of enrollment (see 
Section 3.1.1)  
• 
PD-L1 IC2/3 population:  All randomized patients with tumor PD-L1 IHC score of 
IC2/3  
 
Specific objectives and corresponding endpoints for the study are outlined below.  


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Unless otherwise specified, efficacy objectives will be evaluated in both analysis 
populations.  
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoints 
• To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab in the 
primary population 
• PFS (defined as the time from randomization to the 
first occurrence of disease progression or death from 
any cause, whichever occurs first) as determined by 
the investigator according to RECIST v1.1 
• OS, defined as the time from randomization to death 
from any cause 
Secondary Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab in the PD-L1 
IC2/3 population 
• PFS as determined by the investigator according to 
RECIST v1.1 
• OS, defined as the time from randomization to death 
from any cause 
• To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab  
 
• Objective response (defined as a CR or PR) on two 
consecutive occasions ≥ 4 weeks apart as determined 
by the investigator according to RECIST v1.1 
• DOR, (defined as the time from the first occurrence of 
a documented objective response to disease 
progression or death from any cause, whichever 
occurs first) as determined by the investigator 
according to RECIST v1.1 
• Time to pain progression as measured by patient-
reported pain severity according to the MDASI  
• Time to pain palliation as measured by patient-
reported pain severity according to the MDASI  
• Time to fatigue progression as measured by patient-
reported fatigue severity according to the MDASI   
• Proportion of patients reporting symptom interference 
with daily living at the time of progression according to 
the MDASI 
Exploratory Efficacy Objectives 
Corresponding Endpoints 
• To evaluate the efficacy of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab 
• Objective response, DOR, and PFS according to 
immune-modified RECIST  
• Objective response, DOR and PFS as determined by 
an IRF according to RECIST v1.1 
• Time to progression of patient-reported symptoms 
(other than pain and fatigue) as measured by the 
MDASI. 
• Change from baseline in patient-reported symptoms 
and symptom interference with daily living as 
measured by the MDASI 


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Table 1 
Objectives and Corresponding Endpoints (cont.) 
Safety Objective 
Corresponding Endpoints 
• To evaluate the safety of MOXR0916 
plus atezolizumab compared with 
placebo plus atezolizumab 
• Incidence of adverse events, with severity determined 
through use of NCI CTCAE v4.0 
• Change from baseline in targeted vital signs 
• Change from baseline in targeted clinical laboratory 
test results 
Pharmacokinetic Objective 
Corresponding Endpoints 
• To characterize pharmacokinetics of 
MOXR0916 and atezolizumab when 
administered in combination 
• Serum concentration of MOXR0916 at specified 
timepoints 
• Serum concentration of atezolizumab at specified 
timepoints 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
• To evaluate potential relationships 
between drug exposure and the efficacy 
and safety of MOXR0916 
• Serum concentration or PK parameters for 
MOXR0916 and efficacy endpoints 
• Serum concentration or PK parameters for 
MOXR0916 and safety endpoints 
Immunogenicity Objective 
Corresponding Endpoints 
• To evaluate the immune response to 
MOXR0916 and atezolizumab 
• Presence of ATAs to MOXR0916 during the study 
relative to the presence of ATAs at baseline 
• Presence of ATAs to atezolizumab during the study 
relative to the presence of ATAs at baseline 
Exploratory Immunogenicity Objective 
Corresponding Endpoint 
• To evaluate potential effects of ATAs 
• ATA status and efficacy, safety, or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoints 
• To evaluate candidate biomarkers that 
may be associated with response to 
MOXR0916 and atezolizumab 
(i.e., predictive biomarkers), progression 
to a more severe disease state 
(i.e., prognostic biomarkers), acquired 
resistance to MOXR0916 and 
atezolizumab, susceptibility to 
developing adverse events (i.e., safety 
biomarkers), or that may provide 
evidence of MOXR0916 and 
atezolizumab activity (i.e. 
pharmacodynamic biomarkers) 
• Expression of PD-L1 in tumor tissue and measures of 
efficacy 
• Tumor mutational load and measures of efficacy 
• Biomarkers in blood and tumor tissue (listed in Section 
4.5.6) and efficacy, safety, PK, immunogenicity, or 
other biomarker endpoints  
Exploratory Health Status Utility 
Objective 
Corresponding Endpoint 
• To evaluate health status utility scores 
of patients treated with MOXR0916 plus 
atezolizumab compared with placebo 
plus atezolizumab  
• Health status as measured using the EQ-5D-5L 
questionnaire for health economic modeling 
 


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Table 1 
Objectives and Corresponding Endpoints (cont.) 
ATA = anti-therapeutic antibodies; CR = complete response; CTCAE = Common Terminology Criteria 
for Adverse Events; DOR = duration of objective response; EQ-5D-5L = Euro QoL 5 Dimensions 5-
Level; IC = tumor-infiltrating immune cell; IRF = independent review facility; MDASI = M. D. Anderson 
Symptom Inventory; NCI = National Cancer Institute; OS = overall survival; PD-L1 = programmed 
death-ligand 1; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase II, multicenter, randomized, placebo-controlled, double-blind study to 
evaluate the safety and efficacy of MOXR0916 in combination with atezolizumab versus 
placebo and atezolizumab in patients with locally advanced or metastatic UC who have 
not received prior systemic therapy in the locally advanced/metastatic setting and who 
are ineligible to receive cisplatin-based therapy. 
This study consists of a screening period, a treatment period, and a post-treatment 
follow-up period.  Tumor specimens from patients will be prospectively tested for PD-L1 
expression per IHC by a designated central laboratory prior to randomization (see 
Sections 4.1.1 and 4.5.6.2).  The IHC scores will have two categories based on 
expression on tumor-infiltrating immune cells (IC0/1 and IC2/3). 
 
 
 
 
 
  
 
 
   
Patients will be randomized in a 1:1 ratio (experimental to control arm) to receive one of 
the following:  
• 
Experimental arm:  MOXR0916 plus atezolizumab 
• 
Control arm:  placebo plus atezolizumab 
 
Randomization will be stratified by the following factors: 
• 
PD-L1 status as centrally determined by IHC (IC0/1 or IC2/3) 
• 
Modified Bajorin risk score (0, 1, or 2), which is derived from the ECOG 
Performance Status and the presence or absence of visceral metastases (Bajorin et 
al. 1999; see Appendix 2) 




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
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease

Absence of decline in ECOG Performance Status that can be attributed to disease 
progression

Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions

Written consent to acknowledge deferring other treatment options in favor of 
continuing study treatment at the time of initial radiographic disease progression per 
RECIST v1.1

No further radiographic progression of disease at the next imaging assessment and 
continued demonstration of clinical benefit per the investigator. 
No crossover will be allowed.
Patients will undergo tumor assessments at screening and at intervals during the study
to be determined by the investigator based on the patient’s disease characteristics and 
local institutional standards (see Section 4.5.5 and Appendix 1).  
All adverse events will be monitored and recorded for at least 90 days after the last dose 
of study treatment or until initiation of another systemic anti-cancer therapy, whichever 
occurs first (see Section 5.3.1).  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event if the event is believed to be 
related to prior study treatment.  Adverse events will be graded according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE),
Version 4.0.
An updated schedule of activities is provided in Appendix 1. 
3.1.2
Internal Monitoring Committee
This study established an IMC to review available safety data and to make 
recommendations regarding study conduct to ensure the safety of patients enrolled on 
the study.  The IMC Chair is a medical oncologist who is not the Medical Monitor and is 
not associated with the study.  Other IMC members include key study team members 
including the drug safety scientist, biostatistician, statistical programmer, and clinical 
pharmacologist. The responsibility, membership, and communication flow of the IMC is 
further described in the IMC charter.
For the study as originally designed, the IMC planned to review cumulative safety data 
approximately every 6 months, or more frequently if recommended by the IMC or 
Sponsor, until the study was unblinded for primary analysis. However, given that 
enrollment has been prematurely halted (for reasons unrelated to safety) and the study 
will no longer be blinded, the IMC may recommend modification or suspension of its 
activities and modify its charter accordingly.


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined as the date when the number of OS events specified for
the final analysis in Section 6.4 has been observed. Additionally, the Sponsor may 
decide to terminate the study at any time.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 45 months.
3.3
RATIONALE FOR STUDY DESIGN
The study design has been streamlined subsequent to the Sponsor’s decision to halt 
enrollment due to study accrual.  For procedures and assessments that have been 
removed, the corresponding rationale has been deleted or modified accordingly.
3.3.1
Rationale for Atezolizumab Dose and Schedule
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is the approved dosage for atezolizumab (Tecentriq™U.S. 
Package Insert).
Anti-tumor activity has been observed across doses from 1 mg/kg to 20 mg/kg Q3W.  
The MTD of atezolizumab was not reached and no DLTs have been observed at any 
dose in Study PCD4989g. The fixed dose of 1200 mg Q3W (equivalent to an average 
body weight−based dose of 15 mg/kg Q3W) has been selected on the basis of both 
nonclinical studies (Deng et al. 2016) and available clinical pharmacokinetic, efficacy, 
and safety data as described below.
The pharmacokinetics of atezolizumab monotherapy have been characterized in patients 
in Study PCD4989g at doses 0.01 mg/kg to 20 mg/kg Q3W, including the fixed dose 
1200 mg (equivalent to 15 mg/kg).  Exposure to atezolizumab increased dose-
proportionally over the dose range of 1 mg/kg to 20 mg/kg.  While a subset of 
ATA-positive patients in Study PCD4989g receiving 0.3 to 3 mg/kg atezolizumab Q3W
experienced a reduction of atezolizumab minimum serum concentration (Cmin) to below 
the PK assay lower limit of quantification (LOQ), patients receiving 10 to 20 mg/ kg 
atezolizumab, including the fixed 1200-mg dose, maintained geometric mean Cmin that 
was in excess of both the LOQ and the target serum concentration of 6 mg/mL.
 
 
3.3.2
Rationale for MOXR0916 Dose and Schedule
The proposed regimen of MOXR0916 300 mg administered every 21 days has been 
selected on the basis of available clinical data from Studies GO29313 and GO29674 as 


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below:

MOXR0916 has been evaluated across a wide dose range as a single agent
(0.21200 mg) and in combination with atezolizumab (0.81200 mg) without DLTs
or clear dose related trends in the incidence or severity or adverse events.

The MOXR0916 dose of 300 mg administered every 21 days is expected to achieve
sustained saturation of OX40 receptor in tumors throughout the dosing interval (data
on file).

Available data indicate minimal impact of ATA on exposure at doses 300 mg.

The pharmacokinetics of MOXR0916 appear to be generally consistent with that of
a typical IgG1, monoclonal antibody, supporting the proposed every 21-day dosing
interval (see MOXR0916 Investigator’s Brochure).
MOXR0916 is being evaluated at 300 mg Q3W in ongoing dose expansion cohorts in 
both Studies GO29313 (single agent) and GO29674 (combination with atezolizumab).  
Preliminary safety and PK data from these ongoing cohorts continue to support the 
proposed Phase II dose and schedule.
3.3.3
Rationale for Patient Population, Analysis Groups, and 
Enrollment Stages
Inoperable locally advanced/metastatic UC is a uniformly lethal disease with high unmet 
medical need.  Patients who are ineligible for cisplatin-based regimens due to 
comorbidities have particularly poor outcomes, characterized by transient responses at 
the cost of significant toxicity, with available standard therapies.  Even the most fit 
among these patients, who are eligible for carboplatin-based combinations, experience a 
median OS of 89 months (see Section 1.1.1). In contrast, Phase II data (IMvigor210, 
Cohort 1) for atezolizumab in previously untreated cisplatin-ineligible patients with 
advanced UC demonstrated favorable tolerability, DORs and a median OS of 
14.8 months (Balar et al. 2016; see Section 1.2.1).  These data robustly support further 
evaluation of atezolizumab in first-line cisplatin-ineligible UC patients. 
 
 
 
 
 
 
 
 
 
 


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Tumor PD-L1 status does not indicate simply the expression of the target of 
atezolizumab.  Rather, it reflects adaptive induction of PD-L1 in response to T-cell-
derived interferon-and hence the presence of a pre-existing anti-tumor immune 
response (Taube et al. 2012; Herbst et al. 2014).  PD-L1 expression on tumor-infiltrating 
immune cells has been shown to be associated with other hallmarks of pre-existing 
immunity, such as high expression of effector T cell-associated and interferon--
associated genes (Fehrenbacher et al. 2016).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
3.3.4
Rationale for Control Group
3.3.4.1
Atezolizumab as a Comparator
The primary hypothesis tested by this study is whether the addition of MOXR0916 to 
atezolizumab enhances the clinical activity of atezolizumab in patients with cisplatin-
ineligible UC.  Therefore, it is appropriate to compare against atezolizumab as the active 
control.  Moreover, as described above in Section 3.3.3), outcomes with atezolizumab 
compare favorably to those achieved with standard available therapies for this 
population.
3.3.4.2
Placebo Control
Placebo for MOXR0916 will no longer be utilized subsequent to the unblinding of the 
study.   
3.3.5
Rationale for Stratification Factors
Patients will be stratified on the basis of PD-L1 expression and Bajorin risk model/liver 
metastasis.


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3.3.5.1
PD-L1 expression (IC0/1 vs. IC2/3)
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, renal, ovarian, 
melanoma, malignant lymphoma, multiple myeloma, and colon carcinoma), and elevated 
PD-L1 expression was reported to be associated with a worse prognosis in patients with 
several cancers, including lung cancer, renal cell carcinoma, melanoma, colorectal 
cancer, ovarian cancer, and others (Mu et al. 2011; Herbst et al. 2014; 
Powles et al. 2014).
Responses to atezolizumab have been observed in patients with mUC whose tumors 
demonstrate a PD-L1 IHC score of IC2/3 as well as in patients with an IHC score of 
IC0/1 (Dreicer et al. 2016).  In Phase I and II studies of atezolizumab, higher levels of 
PD-L1 expression have been associated with higher response rates in patients with 
urothelial carcinoma.  Because PD-L1 expression may impact efficacy outcomes, the 
randomization will be stratified by PD-L1 expression by IHC in order to minimize 
potential imbalances between treatment arms within levels of PD-L1 expression.
3.3.5.2
Bajorin Risk Factor Score/Liver Metastasis (0 vs. 1 vs. 2 or 
Liver Metastasis)
The Bajorin risk model is a prognostic model that was developed to predict OS for 
patients with metastatic UC who were treated with cisplatin-based chemotherapy 
(Bajorin et al. 1999).  The model includes two pre-treatment variables:  Karnofsky 
performance status (less than 80% vs. at least 80%) and presence/absence of visceral 
(lung, liver, or bone) metastases.  A post hoc analysis of the EORTC Trial 30986 in 
cisplatin-ineligible patients, based on Bajorin risk groups (0, 1, or 2 risk factors), 
demonstrated that as the number of risk factors increased, OS decreased significantly 
(De Santis et al. 2012).  Because OS is a co-primary efficacy endpoint and the Bajorin 
risk model identifies risk factors for OS, the randomization will be stratified by Bajorin risk 
score to minimize imbalances between treatment arms within levels of the Bajorin risk 
score.
 
 
 
 
 
3.3.6
Rationale for Collection of Mandatory Baseline Tumor 
Specimens (Archival or Pre-Treatment Biopsy)
In this study, tumor specimens from patients will be prospectively tested for PD-L1 
expression by a central laboratory during the screening or pre-screening period, and 


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patients who are enrolled will be stratified according to tumor tissue PD-L1 expression.  
3.3.7
Rationale for Treatment Beyond Radiographic Progression
Cancer immunotherapies may result in early radiographic progression (including the 
appearance of new lesions) that is followed by delayed tumor shrinkage consistent with 
the time required to mobilize an effective anti-tumor immune response (Wolchok et al. 
2009).  Additionally, responding tumors may appear to initially increase in size because 
of the influx of immune cells (Hoos et al. 2010; Pennock et al. 2012).  Such 
unconventional “pseudoprogression” response patterns have been described in patients 
treated with anti-CTLA-4 (Wolchok et al. 2009) and anti-PD-L1/anti−PD-1 agents (Hodi 
et al. 2014). Evidence of tumor growth followed by a response was also observed in 
several tumor types in the atezolizumab Phase I study PCD4989g.  In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed ICs and no viable cancer cells.
Cisplatin-ineligible patients with metastatic UC have limited options that offer 
unsatisfactory survival outcomes at the cost of the toxicities associated with 
chemotherapy (see Section 1.1.1).  Given the potential for pseudoprogression
associated with atezolizumab-based therapy, and the limited efficacy and high toxicity 
associated with available standard therapies, selected patients may be considered for
treatment beyond apparent radiographic progression per RECIST v1.1, provided the 
benefit-risk ratio is judged to be favorable by the investigator (see criteria in Section 3.1).  
Patients should be discontinued for unacceptable toxicity or symptomatic deterioration 
attributed to disease progression as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, biopsy results (if available), and 
clinical status.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients with locally advanced or metastatic UC who have not received prior systemic 
therapy in the locally advanced or metastatic setting and who are ineligible to receive 
cisplatin-based therapy will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 years

Ability to comply with the study protocol, in the investigator’s judgment

ECOG Performance Status of 2 

Life expectancy 12 weeks

Histologically or cytologically confirmed locally advanced (T4b, any N; or any T, 


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N 23) or metastatic UC (M1, Stage IV) (also termed TCC or UCC of the urinary 
tract; including renal pelvis, ureters, urinary bladder, and urethra)
Patients with mixed histologies are required to have a dominant transitional cell 
pattern.
Locally advanced bladder cancer must be inoperable on the basis of 
involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky 
nodal metastasis (N2N3).

Availability of a representative tumor specimen to enable central testing for 
determination of PD-L1 status and exploratory research on biomarkers (see 
Section 4.5.6.2) 
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 15 slides containing unstained, freshly cut, serial sections, 
must be submitted along with an associated pathology report prior to study 
enrollment.  If only 1014 slides are available, the patient may still be eligible 
for the study, after discussion with and approval by the Medical Monitor. 
Submitted archival tumor tissue must be evaluated for PD-L1 expression prior 
to enrollment.  Patients whose tumor tissue is not evaluable for PD-L1 
expression are not eligible. 
If patients have multiple adequate tissue samples from procedures performed 
at different times during the course of their UC; priority should be given to the 
tissue most recently collected.  Multiple samples may be submitted for a given 
patient, on the basis of availability; however, the requirement for a block or 15 
unstained slides should be satisfied by a single biopsy or resection specimen.  
If multiple tumor specimens are submitted, patients may be eligible if at least 
one specimen is evaluable for PD-L1. In the event that enrollment is limited to 
PD-L1 selected patients, the highest PD-L1 score among the submitted 
samples will be used to determine eligibility.
Transurethral resection of bladder tumor (TURBT) specimens must contain a 
muscle invasive component (i.e., T2 or greater) of the bladder tumor as 
documented in the pathology report.  If the TURBT specimens do not contain a 
muscle invasive component, then specimens obtained at the time of 
cystectomy/nephroureterectomy or metastatic spread (i.e., sample from a 
metastatic lesion) will be required prior to randomization.
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 
is therefore not acceptable.
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, and cell 
pellets, pleural effusions and lavage samples are not acceptable.
Patients who do not have tissue specimens that meet eligibility requirements 
may undergo a biopsy prior to enrollment.  Acceptable samples include core 
needle biopsies for deep tumor tissue (minimum three cores) or excisional, 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal 
lesions.


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Prior to signing the main study informed consent form, patients may sign a pre-
screening consent form to specifically allow the collection and testing of archival 
or fresh tumor specimens. 
Refer to Section 4.5.6 for additional information on tumor specimens collected.

No prior systemic therapy for inoperable locally advanced or metastatic UC
For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemo-radiation for UC, a treatment-free interval 12 months between the last 
treatment administration and Cycle 1, Day 1 is required in order to be 
considered treatment naive in the metastatic setting.

Ineligible for cisplatin-based chemotherapy as defined by any one of the following 
criteria:
–
Impaired renal function (glomerular filtration rate [GFR] 30 but 60 mL/min); 
GFR may be assessed by calculation from serum/plasma creatinine (Cockcroft-
Gault formula) or direct measurement (i.e., creatinine clearance or 
ethyldediaminetetra-acetate)
–
NCI CTCAE v4.0 Grade 2 audiometric hearing loss (25 dB at two contiguous 
frequencies or more severe)
–
NCI CTCAE v4.0 Grade 2 peripheral neuropathy (i.e., sensory alteration or 
paresthesias, including tingling)
–
ECOG Performance Status of 2

Measurable disease according to RECIST v1.1
Previously irradiated lesions can be considered as measurable disease only if 
progressive disease has been unequivocally documented at that site since 
radiation.

Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment:
–
White blood cell (WBC) counts 2,500/L
–
ANC 1500/L (without granulocyte colony-stimulating factor support 14 days
prior to Cycle 1, Day 1)
–
Lymphocyte count 500/L
–
Platelet count 100,000/L (without transfusion 14 days prior to Cycle 1, Day 1)
–
Hemoglobin 9.0 g/dL
Patients may be transfused to meet this criterion.
Patients with a solitary kidney or chronic kidney disease with low 
erythropoietin production may use erythropoietin-stimulating agents.
–
AST, ALT, and alkaline phosphatase (ALP) 3 upper limit of normal (ULN), 
with the following exception:
Patients with documented liver or bone metastases:  ALP 5 ULN
–
Serum bilirubin 1.5 ULN 


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Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x 
ULN may be enrolled.
–
Measured or calculated creatinine clearance 30 mL/min (calculated using the 
Cockcroft-Gault formula)
–
Serum albumin 2.5 g/dL
–
Prothrombin time (PT)/INR and activated partial thromboplastin time (aPTT) 
1.5 ULN
This applies only to patients who are not receiving therapeutic 
anticoagulation; patients receiving therapeutic anti-coagulation should be 
on a stable dose

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a contraceptive method with a failure rate of 1% 
per year during the treatment period and for at least 6 months after the last dose of 
study treatment
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices and copper intrauterine 
devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 6 months after the last dose of study treatment to avoid exposing the 
embryo.  Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or lactating, or intending to become pregnant or breast feed during the 


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study or 6 months afterward
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.

Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater, see Appendix 4), myocardial infarction, or 
cerebrovascular accident within 3 months prior to initiation of study treatment, 
unstable arrhythmia, or unstable angina 
Patients with a known left ventricular ejection fraction (LVEF) 40% will be 
excluded
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF 40%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.  

Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis, cirrhosis, and inherited liver disease

Major surgical procedure within 4 weeks prior to initiation of study treatment or 
anticipation of need for a major surgical procedure during the course of the study.
TURBT is considered a minor surgical procedure

Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications

Any approved anti-cancer therapy, including chemotherapy or hormonal therapy,
within 3 weeks prior to initiation of study treatment; the following exceptions are 
allowed:
–
Palliative radiotherapy for bone metastases or soft tissue lesions that is
completed 7 days prior to baseline imaging
–
Radiotherapy for brain metastases as stipulated below
–
Prior local intravesical chemotherapy or immunotherapy is allowed if completed 
at least 4 weeks prior to the initiation of study treatment
–
Hormone-replacement therapy or oral contraceptives
–
Patients should be recovered from any toxicities associated with permitted anti-
cancer therapies

Prior treatment with CD137 or OX40 agonists, antiCTLA-4, antiPD-1, antiPD-L1, 
anti-CD-27, anti-GITR therapeutic antibody or pathway-targeting agents

Treatment with any other investigational agent or participation in another clinical 
study with therapeutic intent within 28 days prior to initiation of study treatment

Untreated CNS metastases or active (progressing or requiring corticosteroids for 
symptomatic control) CNS metastases
Patients with a history of treated asymptomatic CNS metastases are eligible, 


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provided they meet all of the following criteria:
–
Measurable disease outside the CNS
–
No ongoing requirement for corticosteroids as therapy for CNS disease, 
with corticosteroids discontinued for 2 weeks prior to enrollment
–
Anticonvulsants at a stable dose are allowed
–
No stereotactic radiation within 7 days or whole-brain radiation within 
14 days prior to Cycle 1, Day 1
–
No evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study
Patients with new asymptomatic CNS metastases detected during screening 
must receive radiation therapy and/or surgery for CNS metastases.  Following 
treatment, these patients may then be eligible without the need for an additional 
brain scan prior to enrollment, if all other criteria are met.

Any history of leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently)
Patients with indwelling catheters (e.g., PleurX) are allowed.

Uncontrolled tumor-related pain
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to enrollment.  
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for loco-regional therapy if appropriate prior to enrollment.

Malignancies other than UC within 5 years prior to Cycle 1, Day 1
Patients with localized low-risk prostate cancer (defined as Stage ≤ pT2b, 
Gleason score 7, and prostate-specific antigen (PSA) at prostate cancer 
diagnosis 20 ng/mL) treated with curative intent and without PSA recurrence 
are eligible. 
Patients with pre-existing low-risk prostate cancer (defined as Stage cT1/T2a, 
Gleason score 7 and PSA 10 ng/mL) who are treatment-naive and 
undergoing active surveillance are eligible. 
Patients with malignancies of a negligible risk of metastasis or death (e.g., risk 
of metastasis or death 5% at 5 years) are eligible provided they meet all of the 
following criteria:
Malignancy treated with expected curative intent (e.g., adequately treated 
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or 
ductal carcinoma in situ treated surgically with curative intent)
No evidence of recurrence or metastasis by follow-up imaging and any 


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disease-specific tumor markers

Uncontrolled or symptomatic hypercalcemia (1.5 mmol/L ionized calcium or 
calcium 12 mg/dL or corrected serum calcium ULN)

History of autoimmune disease with the following caveats:
Patients with a history of autoimmune-related endocrinopathy (e.g.,
hypothyroidism) on a stable dose of replacement hormone (e.g., thyroid 
hormone) may be eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable insulin 
regimen may be eligible for this study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are 
met:
–
Rash must cover 10% of body surface area
–
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids
–
No occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months

Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
antiTNF-agents) within 2 weeks prior to initiation of study treatment, or 
anticipation of need for systemic immunosuppressive medication during the course 
of the study with the following exceptions:
Patients who have received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication are eligible for the study.
Patients who received mineralocorticoids (e.g., fludrocortisone), 
corticosteroids for chronic obstructive pulmonary disease or asthma, or 
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency 
are eligible for the study.

Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or five half-lives of the drug, whichever is 
longer, prior to initiation of study treatment

History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed 
tomography (CT) scan 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
History of drug-induced pneumonitis that was asymptomatic (defined by 


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radiographic findings only) and reversible (without any anti-inflammatory 
therapies) is permitted

Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a 
positive hepatitis B surface antigen (HBsAg) test at screening
Patients with a past or resolved HBV infection, defined as having a negative 
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at 
screening, are eligible for the study.

Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test at screening
Patients who have a positive HCV antibody test are eligible for the study if a 
polymerase chain reaction assay is negative for HCV RNA

Positive HIV test at screening

Active tuberculosis

Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia

Patients with recent infections that are not judged to be severe (as described above) 
are excluded if they have either:
Signs or symptoms of infection within 2 weeks prior to initiation of study 
treatment
Patients with uncomplicated viral upper respiratory tract infections are 
eligible provided symptoms have resolved to baseline.
Received oral or IV antibiotics (including anti-fungal or anti-viral therapy) 
within 2 weeks prior to initiation of study treatment for suspected or 
confirmed infection
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary 
tract infection or chronic obstructive pulmonary disease or for dental 
extraction) are eligible.

Prior allogeneic stem cell or solid organ transplantation

Treatment with a live, attenuated vaccine within 4 weeks before initiation of study 
treatment, or anticipation of need for such a vaccine during the course of the study.

History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster 
ovary cells 

Known allergy or hypersensitivity to any component of the atezolizumab formulation

Known allergy or hypersensitivity to any component of the MOXR0916 formulation


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Treatment Assignment
This is a randomized, double-blind study.  After written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient (including determination of tumor PD-L1 
status by central testing), the study site will obtain the patient’s identification number and 
treatment assignment from the interactive voice or web-based response system (IxRS).
Patients will be randomized to one of two treatment arms:  MOXR0916 plus 
atezolizumab or placebo plus atezolizumab. Randomization will occur in a 1:1 ratio 
using a permuted-block randomization method to ensure a balanced assignment to each 
treatment arm.  Randomization will be stratified according to the following criteria:

PD-L1 expression in ICs by IHC (IC0/1 or IC2/3)

Modified Bajorin risk factors (see Appendix 2)
Following unblinding by the investigator (Section 4.2.3), patients assigned to the 
placebo arm will discontinue placebo infusions and continue atezolizumab alone.  
Patients assigned to the MOXR0916 arm may continue study treatment with the 
combination of atezolizumab and MOXR0916 or with atezolizumab alone based on a 
discussion of benefit and risk with the treating investigator. 
4.2.2
Blinding
Under the original study design, the Sponsor and its agents (with the exception of the 
IxRS service provider, laboratory personnel performing PK or biomarker analyses, and 
the IMC members) were to be blinded to treatment assignment until the primary analysis.  
Study site personnel and patients were to be blinded to treatment assignment throughout 
the study.  Subsequent to the decision to halt enrollment, subjects will be unblinded as 
outlined below.
4.2.3
Unblinding
Because this trial will not meet its study objectives following the Sponsor’s decision to 
halt accrual, blinding as a method to minimize bias in study conduct or interpretation 
is no longer necessary.  The investigator will break the treatment code by contacting 
the IxRS.  Investigators are encouraged to consult with the Medical Monitor prior to 
performing emergency unblinding.  The investigator should document and provide an 
explanation for any premature unblinding (e.g., accidental unblinding, unblinding due to 
a serious adverse event).  Unblinding should not result in the withdrawal of patients from 
the study.
4.3
STUDY TREATMENT 
The investigational medicinal products (IMP) for this study are MOXR0916, placebo, and 
atezolizumab.


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4.3.1
Formulation, Packaging, and Handling
4.3.1.1
MOXR0916 and Placebo
Placebo will no longer be supplied by the Sponsor.
MOXR0916 will be supplied by the Sponsor as a sterile liquid in either of the following 
two configurations:

A single-use, 15-mL glass vial containing approximately 10 mL (200 mg) of 
MOXR0916 solution.

A single-use, 6-mL glass vial containing approximately 5 mL (300 mg) of 
MOXR0916 solution.
For information on the formulation, packaging, and handling of MOXR0916, see the 
pharmacy manual and MOXR0916 Investigator’s Brochure.
4.3.1.2
Atezolizumab 
The atezolizumab Drug Product will be supplied by the Sponsor as a sterile liquid in a 
single-use, 20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of 
atezolizumab solution.
For information on the formulation, packaging and handling of atezolizumab, see the 
pharmacy manual and the Atezolizumab Investigator's Brochure
4.3.2
Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
Administration of MOXR0916 and atezolizumab will be performed in a monitored setting 
where there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions.  For anaphylaxis precautions, see 
Appendix 5.  
Any overdose or incorrect administration of MOXR0916 or atezolizumab should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
4.3.2.1
MOXR0916 and Placebo
The dose of MOXR0916 to be administered in this study is 300 mg IV Q3W.  This dose 
is fixed and not dependent on body weight.  Patients randomized to the control arm will 
discontinue placebo infusions following unblinding by the investigator (Section 4.2.3).


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Table 2
Administration of First and Subsequent MOXR0916 Infusions
First Infusion
Subsequent Infusions

No premedication is permitted.

Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature) should be 
recorded within 60 minutes prior to the 
infusion.

MOXR0916 should be infused over 
60 (10) minutes.

If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, 
and 60 minutes (5 minutes for all 
timepoints) and at 30 (10) minutes after 
the infusion.

Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.

If the patient experienced an 
infusion-related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.

Vital signs should be recorded within 
60 minutes prior to the infusion.

MOXR0916 should be infused over 
30 (10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (10) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion.

If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded every 15 (±5) minutes during 
the infusion, at the end of the infusion 
(±5 minutes), and at 30 (5) minutes after 
the infusion.
There will be no dose modification for MOXR0916 in this study.  General guidance on
treatment interruption or discontinuation is provided in Section 5.1.4.  Guidelines on 
study drug administration in the context of management of specific adverse events, 
including infusion-related reactions (see Table 13) is provided in Section 5.1.5.
4.3.2.2
Atezolizumab
The dose of atezolizumab to be administered in this study is 1200 mg IV Q3W.  This 
dose is fixed and not dependent on body weight.
Atezolizumab will be administered after the MOXR0916 infusion, as described in 
Section 4.3.2.1.  There is no minimum observation time between infusions in the 
absence of symptoms or signs related to the first infusion.  In the event of a Grade 1 or 2
infusion-related reaction associated with the MOXR0916 infusion, atezolizumab will not 
be administered until resolution of symptoms or signs to baseline.
Atezolizumab infusions will be administered per the instructions outlined in Table 3.


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Table 3 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted. 
• 
Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature) should be 
recorded between the MOXR0916 and 
atezolizumab infusions, within 60 minutes 
prior to the atezolizumab infusion. 
• 
Atezolizumab should be infused over 
60 (± 15) minutes. 
• 
If clinically indicated, vital signs should be 
recorded during the infusion at 15, 30, 45, 
and 60 minutes (± 5 minutes for all 
timepoints) and at 30 (± 10) minutes after 
the infusion. 
• 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
• 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
• 
Vital signs should be recorded between 
the MOXR0916 and atezolizumab 
infusions, within 60 minutes prior to the 
atezolizumab infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (± 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
• 
If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be recorded every 15 (±5) minutes during 
the infusion, at the end of the infusion 
(±5 minutes), and at 30 (± 5) minutes after 
the infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
There will be no dose modification for atezolizumab in this study.  General guidance on 
treatment interruption or discontinuation is provided in Section 5.1.4.  Guidelines on 
study drug administration in the context of management of specific adverse events, 
including infusion-related reactions (see Table 13) is provided in Section 5.1.5 and in the 
Atezolizumab Investigator’s Brochure.  
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (MOXR0916/placebo and atezolizumab) 
will be provided by the Sponsor where required by local health authority regulations.  
The study site will acknowledge receipt of IMPs using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.  
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 


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Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to MOXR0916 and Atezolizumab
The Sponsor (Genentech, a member of the Roche Group) will offer post-trial access to 
the study drugs (MOXR0916, for patients assigned to the experimental arm only, and 
atezolizumab, for patients assigned to either arm) free of charge to eligible patients in 
accordance with the Roche Global Policy on Continued Access to Investigational 
Medicinal Product, as outlined below.
A patient will be eligible to receive study treatment after completing the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met:

The combination of MOXR0916 and atezolizumab is commercially marketed in the 
patient's country and is reasonably accessible to the patient (e.g., is covered by the 
patient's insurance or wouldn't otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study treatment or data suggest 
that the study treatment is not effective for UC
Exceptions may be granted at the Sponsor’s discretion.

The Sponsor has reasonable safety concerns regarding the study treatment as 
treatment for UC

Provision of study treatment is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug to the study completion/ 
discontinuation visit.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.


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4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Oral contraceptives

Hormone-replacement therapy

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin)

Inactivated vaccinations

Megestrol administered as an appetite stimulant 

Mineralocorticoids (e.g., fludrocortisone)

Corticosteroids administered for chronic obstructive pulmonary or asthma

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency

Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below:
After Cycle 2, palliative radiotherapy is permitted, provided that the lesion to be 
irradiated is not the only site of measurable disease.  Study treatment may be 
continued during palliative radiotherapy. 

Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below:
Patients experiencing a mixed response requiring local therapy for control of 
three or fewer lesions may still be eligible to continue study treatment.  Patients 
who receive local therapy directed at a target lesion will no longer be evaluable 
for radiographic response but will remain evaluable for progression.  Such 
cases must be discussed with and approved by the Medical Monitor
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator.
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience infusion-
associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, 
diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or 
equivalent medications per local 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 2-adrenergic agonists; see 
Appendix 5).
4.4.2
Cautionary Therapy 
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 


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immunologic effects of treatment with MOXR0916 and atezolizumab.  Therefore, in 
situations in which systemic corticosteroids or TNF-inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids and TNF-inhibitors may be 
administered at the discretion of the investigator.
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with MOXR0916 and 
atezolizumab therapy (refer to the MOXR0916 and Atezolizumab Investigator's 
Brochures for details).
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section 4.4.3) may be used during the study at the discretion of the investigator
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent (see 
Section 4.1.2), and during study treatment until disease progression is documented 
and the patient has discontinued study treatment, with the exception of palliative 
radiotherapy and local therapy under certain circumstances (see Section 4.4.1 for 
details).

Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment.

Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with MOXR0916 and atezolizumab, 
and for 6 months after the last dose of MOXR0916 and atezolizumab.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is longer)
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with MOXR0916 and atezolizumab.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of MOXR0916 and atezolizumab.
4.5
STUDY ASSESSMENTS 
Following the Sponsor’s decision to curtail enrollment, certain study assessments have 


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been modified or discontinued, and a streamlined schedule of activities is provided in 
Appendix 1.  All activities must be performed and documented for each patient.  Patients 
will be closely monitored for safety and tolerability throughout the study.  Patients should 
be assessed for toxicity prior to each dose; dosing will occur only if the clinical 
assessment and local laboratory test values are acceptable.
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or 
other administrative disruption that precludes the visit, the visit should be scheduled on 
the nearest following feasible date.
Collection of any non-safety-related data or patient samples may be terminated by the 
Sponsor at any time if further collection of such data or samples is also not related to the 
study’s primary objective. The decision to discontinue any data collection will be
communicated to sites (Institutional Review Boards and Ethics Committees) by means of
a memorandum and will not require a protocol amendment.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
Prior to signing the main Informed Consent Form for the study, patients may give 
consent specifically for the collection and testing of archival or fresh tumor tissue for 
PD-L1 expression by signing a Prescreening Informed Consent Form.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including stage, date of diagnosis, and prior cancer therapies and procedures), 
reproductive status, smoking history, use of alcohol, and drugs of abuse will be recorded 
at baseline. A history of pleural or pericardial effusion or of ascites requiring intervention 
should be entered in the medical history. In addition, all medications (e.g., prescription 
drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study treatment will 
be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity. Race/ethnicity 
will be recorded because of the potential contribution of this variable to differences in 
observed pharmacokinetics, pharmacodynamics, toxicity, and/or response to treatment.


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4.5.3
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurological systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.
ECOG Performance Status (see Appendix 6) should be assessed per the schedule of 
assessments in Appendix 1).
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
Vital signs should be measured within 60 minutes prior to the first infusion, between the 
MOXR0916 and atezolizumab infusions (within 60 minutes prior to the atezolizumab 
infusion) and, if clinically indicated, during or after the infusions (see Section 4.3.2).  In 
addition, vital signs should be measured at other specified timepoints as outlined in the 
schedule of activities (see Appendix 1).
Vital signs collected at the screening visit and the treatment discontinuation visit should 
be recorded in the eCRF.  For all other visits, only those vital signs that are obtained 
prior to the first study drug infusion of the day or that constitute an adverse event (e.g., 
temperature for event of fever) or a primary manifestation of an adverse event (e.g., 
blood pressure associated with an infusion related reaction or heart rate associated with 
an arrhythmia) should be recorded in the eCRF.  All vital signs collected per protocol 
should be documented in the patient's medical record.
Blood oxygen saturation will be measured by pulse oximetry.
4.5.5
Tumor and Response Evaluations
Patients will undergo tumor assessments at baseline and during the study, with the 
imaging modality (e.g., CT vs. MRI scan, contrast-enhanced vs. non-contrast) and the
frequency to be determined primarily by the investigator based on the patient’s disease 
characteristics and local institutional standards (i.e., approximately every 612 weeks).  
At the investigator’s discretion, tumor assessments may be performed at any time if 
progressive disease is suspected.  Tumor assessments will continue until radiographic
disease progression (or loss of clinical benefit as determined by the investigator for 
patients who continue treatment after disease progression according to RECIST v1.1), 


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withdrawal of consent, loss to follow-up, death, or study termination by the Sponsor, 
whichever occurs first.
Patients who continue treatment beyond radiographic disease progression per 
RECIST v1.1 will be monitored with a follow-up scan in 6 (1) weeks. Tumor 
assessments should be continued every 6 (1) weeks thereafter until two consecutive 
scans demonstrate stability or improvement with respect to the first scan that showed 
radiographic disease progression, at which point the scan frequency may be liberalized 
at the investigator’s discretion.
All measurable and evaluable lesions should be assessed and documented at screening.  
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to randomization do not have to be repeated at screening.  
Screening assessments should include CT scans (with IV contrast recommended unless 
contraindicated or MRI scans of the chest, abdomen, and pelvis.  A spiral CT scan of the 
chest may be obtained but is not a requirement.  If a CT scan with contrast is 
contraindicated (i.e., in patients with contrast allergy or impaired renal clearance), a non-
contrast CT scan of the chest and MRI scans of the abdomen, pelvis, and head are 
recommended. 
Brain imaging (either MRI or contrast-enhanced CT) is required at screening for any
patient with treated brain metastases (see Section 4.1.2) and as clinically indicated
based on symptoms or signs suggestive of new or worsening CNS metastases. An MRI 
scan of the head is required to confirm or refute the diagnosis of CNS metastases at 
baseline in the event of an equivocal CT scan. Patients with treated asymptomatic CNS 
metastases may be eligible, provided they meet all of the criteria detailed in 
Section 4.1.2.
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition should be consistent with the standards for a 
full-contrast diagnostic CT scan.
Bone scans (technetium-99m [TC-99m]) or sodium fluoride (NaF) PET should be 
performed at screening if clinically indicated.  If bone metastases are present at 
screening and cannot be seen on CT or MRI scans, or if clinically indicated, TC-99m and 
NaF-PET bone scans should be repeated when complete response is identified in target 
disease or when progression in bone is suspected. 
CT scans of the neck or extremities should also be performed if clinically indicated and 
repeated throughout the study if there is evidence of disease at screening.  At the
investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 may be used.


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All measurable and evaluable lesions should be re-assessed at each subsequent tumor 
evaluation.  The same radiographic procedures used to assess disease sites at 
screening should be used for subsequent tumor assessments (e.g., the same contrast 
protocol for CT scans).
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 3).
Assessments should be performed by the same evaluator, if possible, to ensure internal 
consistency across visits.  Results must be reviewed by the investigator before dosing at 
the next cycle.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
4.5.6.1
Local Laboratory Tests
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology:  CBC, including WBC count, RBC count, hemoglobin, hematocrit, 
platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells).  A manual differential can be done if clinically indicated.

Chemistry panel (serum or plasma):  sodium, potassium, magnesium, chloride, 
bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin, alkaline phosphatase, ALT, AST, LDH
Bicarbonate is not a required analyte for patients in countries where it is not
considered a standard chemistry measurement.

Serum amylase and lipase

Serum ferritin and C-reactive protein (CRP)

Coagulation (PT or INR, and aPTT)

Thyroid function testing:  thyroid-stimulating hormone, free thyroxine (T4)

HIV serology

HBV serology (HBsAg, antibody against HBsAg [HBsAb], and antibody against 
hepatitis B core antigen [HBcAb])
If a patient has a positive serology for HBcAb at screening, an HBV DNA test 
must also be performed.  The test sample should be collected prior to initiation 
of study treatment, but the result is not required to determine eligibility.

HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA
HCV RNA test is required prior to Cycle 1, Day 1 for consideration of eligibility if 
patient has positive serology for anti-HCV.

Pregnancy test
All women of childbearing potential (see Section 4.1.1) will have a serum 
pregnancy test at screening. Urine or serum pregnancy tests will be performed 
at specified subsequent visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test.


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
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted 
4.5.6.2
Central Laboratory Assessments
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis. Instruction manuals and supply kits will be 
provided for these central assessments. For sampling procedures, storage conditions, 
and shipment instructions, see the laboratory manual.

A tumor tissue sample, either an archival specimen or a pre-treatment biopsy, must 
be submitted at baseline for determination of PD-L1 expression and for exploratory 
research on biomarkers
A representative FFPE tumor specimen in a paraffin block (preferred) or at least 
15 slides containing unstained, freshly cut, serial sections must be submitted 
along with an associated pathology report prior to study enrollment.  If only 
1014 slides are available, the patient may still be eligible for the study, after 
discussion with and approval by the Medical Monitor.  After signing of the 
Informed Consent Form, retrieval and submission of an archival tumor sample 
can occur 28 days prior to initiation of study treatment.
Acceptable samples include those from resections, core-needle biopsies (at 
least three cores, embedded in a single paraffin block), or excisional, incisional, 
punch, or forceps biopsies.  Fine-needle aspiration (defined as samples that do 
not preserve tissue architecture and yield cell suspension and/or smears), 
brushing, cell pellets from pleural effusion, and lavage samples are not 
acceptable.  Tumor tissue from bone metastases that have been decalcified is 
not acceptable.
Patients whose tumor tissue is not evaluable by the central laboratory for 
expression of PD-L1 are not eligible. Samples must contain a minimum of 
50 viable tumor cells that preserve cellular context and tissue architecture 
regardless of needle gauge or retrieval method in order to be evaluable.  Tumor 
tissue should be of good quality based on total and viable tumor content.  If 
multiple tumor specimens are submitted (e.g., an archival specimen and tissue 
from relapsed disease), patients may be eligible if at least one specimen is 
evaluable for PD-L1. The highest PD-L1 score among the submitted samples 
will be used for the purpose of stratification and, in the event that enrollment is 
limited to PD-L1 selected patients, to determine eligibility.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.
Data arising from sample analysis will be subject to the confidentiality standards 


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described in Section 8.4.
4.5.7
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.
All ECG recordings should be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recordings 
should be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs should be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.
Copies of ECG tracings will be kept as part of the patient's permanent study file at the 
site. 
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must discontinue study treatment (MOXR0916 and atezolizumab) if they 
experience any of the following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event

Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment

Use of non-protocol anti-cancer therapy

Pregnancy

Symptomatic deterioration attributed to disease progression

Radiographic disease progression per RECIST v1.1, with the exception of patients 
who meet all of the criteria for treatment beyond radiographic progression outlined in 
Section 3.1
Patients have the right to voluntarily withdraw from study treatment at any time for any
reason. In addition, the investigator has the right to withdraw a patient from study
treatment at any time. Reasons for withdrawal from study treatment may include, but
are not limited to, the following:

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Patients will return to the clinic for a treatment discontinuation visit 30 days after the 
last dose of study treatment.  The visit at which response assessment shows 
progressive disease may be used as the treatment discontinuation visit.  Patients who 
discontinue study treatment for any reason other than progressive disease or loss of 
clinical benefit will continue to undergo tumor response assessments and PRO 
assessments as outlined in the schedule of activities (see Appendix 1).  
4.6.2
Patient Discontinuation from Study
After study treatment discontinuation, all adverse events will be monitored and recorded 
for at least 90 days after the last dose of study treatment or until initiation of another 
systemic anti-cancer therapy, whichever occurs first (see Section 5.3.1).  Patients will 
discontinue from study upon completion of safety follow-up, or upon any of the 
following (whichever occurs first):

Death

Loss to follow-up

Study termination by the Sponsor

Patient withdraws consent for follow-up
If a patient withdraws consent for follow-up, this request must be documented in the 
source documents and signed by the investigator. The primary reason for withdrawal of 
consent from the study should be documented on the appropriate eCRF.  Patients will 
not be actively followed for any reason after consent has been withdrawn. In such cases, 
the study staff may use a public information source (e.g., county records) to obtain 
information about survival status only.  Patients who withdraw from the study will not be 
replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment


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
Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
MOXR0916 is not approved for any non-experimental use, and clinical development is 
ongoing.  Atezolizumab received accelerated approval in the United States for the 
treatment of patients with locally advanced or metastatic urothelial carcinoma whose 
disease has worsened during or following platinum-containing chemotherapy, or within 
12 months of receiving platinum-containing chemotherapy.  The safety plan for patients 
in this study is based on clinical experience with MOXR0916 and atezolizumab in 
completed and/or ongoing studies. The anticipated important safety risks for 
MOXR0916 and atezolizumab are outlined below. 
 
 
 
 Please refer to the 
respective Investigator's Brochures for a complete summary of safety information for 
MOXR0916 and atezolizumab.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for treatment interruption or discontinuation, are 
provided below (see Section 5.1.5).
5.1.1
Risks Associated with Atezolizumab and Potential Risks of 
MOXR0916
The safety plan for patients in this study is based largely on the clinical experience with 
atezolizumab in completed and ongoing studies.  Based on the available
characterization of mechanism of action, and preliminary clinical data from ongoing 
studies, MOXR0916 may cause adverse events similar to but independently of 
atezolizumab, may exacerbate the frequency or severity of atezolizumab-related 
adverse events, or may have non-overlapping toxicities with atezolizumab.  Hence all 
risks associated with atezolizumab are regarded as potential risks for MOXR0916.  The 
anticipated important safety risks for atezolizumab are outlined below. Refer to the 
Atezolizumab Investigator's Brochure and MOXR0916 Investigator’s Brochure for 


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complete summaries of safety information.
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of MOXR0916 and atezolizumab will be 
performed in a monitored setting in which there is immediate access to trained personnel 
and adequate equipment and medicine to manage potentially serious reactions.  After 
initiation of study treatment, all adverse events and serious adverse events will be 
recorded during the trial and for up to 90 days after the last dose of study treatment or 
until the initiation of another systemic anti-cancer therapy, whichever occurs first. See 
Section 5.3 for details regarding safety reporting for this study.  
Specific anticipated or potential toxicities associated with administration of MOXR0916
and atezolizumab as well as the measures taken intended to avoid or minimize such 
toxicities in this trial are described in the following sections. General guidance on 
treatment interruption or discontinuation in response to adverse events is provided in 
Section 5.1.4.  Management guidelines for specific adverse events are described in
Section 5.1.5.
5.1.1.1
Immune-Related Hepatitis
Cases of hepatitis, some leading to fatal outcomes, have been observed in clinical trials 
with atezolizumab. Most of these hepatic events however were non-serious elevations 
of liver enzymes. 
 
  
The risk of immune-related hepatitis with MOXR0916 in combination with atezolizumab 
is unknown.  
 
Patients with clinically significant liver disease or hepatic enzyme elevations will be 
excluded from this study (see Section 4.1.2), and hepatic enzymes will be regularly 
monitored during the study (see Appendix 1).
Guidelines for management of patients who develop hepatic toxicity are provided in 
Section 5.1.5.1. 
5.1.1.2
Immune-Related Pneumonitis
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab. The majority of patients with 
pulmonary events experienced only mild to moderate events. Across atezolizumab 
clinical trials, pneumonitis events occurred more frequently in the NSCLC patient 
population versus other tumor populations, most likely due to higher baseline incidence, 
higher prevalence of other risk factors, and atezolizumab-induced immunologic response 
to the tumor.  
 The risk of immune-related pneumonitis with MOXR0916 in 


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combination with atezolizumab is unknown.  
 
 
 
Patients with a history of idiopathic pulmonary fibrosis, pneumonitis (including drug 
induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan will be 
excluded from this trial.
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.  
Guidelines for management of patients who develop immune-related pneumonitis are 
provided in Section 5.1.5.2. 
5.1.1.3
Immune-Related Colitis
Cases of diarrhea or colitis have been observed in clinical trials with atezolizumab. 
 
 
 
The risk of 
immune-related colitis with MOXR0916 in combination with atezolizumab is unknown.  
 
 
Guidelines for management of patients who develop diarrhea or colitis are provided in 
Section 5.1.5.3. 
5.1.1.4
Dermatologic Events
Treatment-emergent rash has been associated with atezolizumab and observed 
following MOXR0916 monotherapy and in combination with atezolizumab.  The risk of 
dermatologic toxicity with MOXR0916 in combination with atezolizumab is unknown.  
The majority of cases of rash were mild in severity and self-limited, with or without 
pruritus.  A dermatologist should evaluate persistent and/or severe rash or pruritus.  
A biopsy should be considered unless contraindicated.
Guidelines for management of patients who develop diarrhea or colitis are provided in 
Section 5.1.5.4. 
5.1.1.5
Immune-Related Pancreatitis
Symptoms of abdominal pain associated with elevations of amylase and lipase
suggestive of pancreatitis have been associated with the administration of atezolizumab.  
Most events identified were non-serious elevations in lipase or amylase. The risk of 
immune-related pancreatitis with MOXR0916 or MOXR0916 in combination with 


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atezolizumab is unknown.  
 
 
 
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.  
Guidelines for management of patients who develop pancreatic events, including 
pancreatitis are provided in Section 5.1.5.5. 
5.1.1.6
Immune-Related Endocrinopathies
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have 
been associated with the administration of atezolizumab.  
 
 
The risk of immune-related
endocrinopathies with MOXR0916 in combination with atezolizumab is unknown.  
 
 
 
  
Guidelines for management of patients who develop endocrine events are provided in 
Section 5.1.5.6. 
5.1.1.7
Immune-Related Myocarditis
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  The risk of immune-related myocarditis with MOXR0916 or 
MOXR0916 in combination with atezolizumab is unknown.  
 
 
 
5.1.1.8
Immune-Related Meningoencephalitis
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab, and has been reported in a patient receiving 
atezolizumab.  The risk of immune-related meningoencephalitis with MOXR0916 or 
MOXR0916 in combination with atezolizumab is unknown.  
 
 
.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 


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identified alternate etiology, should be treated according to the guidelines provided in
Section 5.1.5.8.
5.1.1.9
Immune-Related Neurologic Disorders
Guillain-Barré syndrome, including one fatal event, has been observed in patients
receiving atezolizumab.  Myasthenic syndrome/myasthenia gravis has also been
observed in patients receiving atezolizumab.  The risk of immune-related neurologic 
disorders with MOXR0916 or MOXR0916 in combination with atezolizumab is unknown.  
 
 
  Patients should be monitored for
symptoms of motor and sensory neuropathy.  Diagnostic work-up is essential for an
accurate characterization to differentiate between alternative etiologies of neuropathies. 
Guidelines for management of patients who develop neurologic events are provided in 
Section 5.1.5.9. 
5.1.1.10
Infusion-Related Reactions
Infusion-related reactions are known to occur with the administration of monoclonal 
antibodies and have been observed in patients receiving atezolizumab. The identified 
reactions occurred within 24 hours and were generally mild to moderate in severity, and 
few patients developed serious adverse events. The signs and symptoms of infusion-
related reactions following atezolizumab share considerable overlap with several very 
common atezolizumab risks including influenza-like illness, pyrexia, and rash.  
Infusion-related reactions have also been observed following MOXR0916.  Similar to 
atezolizumab, most events have been mild to moderate in nature.  
 
 
 
. 
Guidelines for management of patients who develop infusion-related reactions are 
provided in Sections 5.1.5.10 and 4.3.2.
5.1.2
Potential Risks Specific to MOXR0916
In addition to the risks associated with atezolizumab in Section 5.1.2, which are all 
considered potential risks for MOXR0916, the following potential risks are described for 
MOXR0916 based on its particular mechanism of action.  As an agonist of OX40, 
MOXR0916 is anticipated to enhance effector T-cell proliferation, survival and function, 
and to reverse regulatory T cell-mediated immunosuppression.  Therefore MOXR0916 


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may increase the risk of cytokine release syndromes as well as autoimmune 
inflammation (referred to immune-related adverse events in Section 5.1.1).  In addition, 
due to the intact Fc effector function of MOXR0916, lymphopenia via 
antibody-dependent cell-mediated cytotoxicity (ADCC) is a theoretical risk. 
5.1.2.1
Cytokine Release Syndrome and Macrophage Activation 
Syndrome
Cytokine release syndrome (CRS), macrophage activation syndrome (MAS), as well as
systemic immune activation (SIA, Section 5.1.3.1), may be considered as part of a 
continuum of disorders associated with an exaggerated immune response, with 
overlapping signs, symptoms and presentation.  The supportive and interventional 
management for these disorders is largely the same, with additional diagnostic features 
described for MAS (Tothova and Berliner 2015; Jordan et al. 2011) and SIA.
Mild flu-like symptoms such as fever, headache, and myalgias may occur following 
infusion (hours to days).  In contrast, severe, exaggerated cytokine release observed
with CD28 superagonists (Suntharalingam et al. 2006) is not anticipated in response to 
MOXR0916 given that OX40 expression is transient and restricted to antigen-
experienced T cells.  
 
 
MAS has been reported with blinatumomab as well as chimeric antigen receptor 
adoptive T-cell therapy (Teachey et al. 2013; Lee et al. 2014).  While MAS has not been 
described with immune checkpoint inhibitors or stimulatory T-cell agonists (including 
atezolizumab and MOXR0916), a theoretical risk remains.  MAS should be included in 
the differential diagnosis for patients who develop a sepsis-like syndrome or severe 
CRS, and workup should include serum ferritin, typically dramatically elevated in MAS, 
as well as complete blood count, liver function tests, serum triglycerides, and 
coagulation profile.  A bone marrow evaluation should also be considered (Henter et al. 
1991; Henter et al. 2007; Tothova and Berliner 2015).  Cytokine-specific treatment with 
agents such as tocilizumab should be considered in the event of severe or life-
threatening cytokine release syndrome and/or suspected MAS (see Section 5.1.5.11).
5.1.2.2
Enhanced Immune Response during Acute Infection
OX40L has been shown to regulate inflammation in the innate immune response to 
infection in an animal model of polymicrobial sepsis (Karulf et al. 2010); improved 
survival, decreased cytokine production, and a decrease in remote organ damage were 
observed in OX40L(-/-) mice.  These observations suggest that concurrent 
administration of an OX40 agonist has the potential to exacerbate inflammation in 
response to an emergent infection. 
 


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or in Study GO29674 of MOXR0916 in combination with atezolizumab.
Patients with evidence of active or recent infections will be excluded from the study.  
In addition, individuals who have received a live-attenuated viral vaccine within 4 weeks 
of Day 1 or anticipate the need for such a vaccine for the duration of the study will be 
excluded.  Patients will also be closely monitored for any infection that occurs during the 
course of the study.  In the case of a newly onset clinically significant infection during the 
study, study treatment will be temporarily suspended until resolution (see Section 5.1.4).  
5.1.2.3
Lymphopenia
Given the IgG1 backbone of MOXR0916 with intact Fc effector function, 
ADCC-mediated reduction in lymphocyte count is a potential risk.  In nonclinical studies 
with cynomolgus monkeys, repeat dose toxicity studies did not demonstrate a decrease 
in overall lymphocyte counts.  Transient lymphopenia was observed following the use of 
another monoclonal antibody directed against OX40 (Curti et al. 2013); however, this 
was not a DLT in the Phase I trial.
 
 
 
Patients with a lymphocyte count less than 500 cells/L will be excluded from this trial 
(see Section 4.1.2); complete blood counts will be monitored regularly (see Appendix 1).  
5.1.3
Potential for Overlapping Toxicities with MOXR0916 and 
Atezolizumab
No nonclinical toxicology studies have been conducted with the combination of 
MOXR0916 and atezolizumab. Based on nonclinical and/or clinical studies with each 
molecule as a single agent, as well as molecules with similar mechanisms of action, 
there is a potential for overlapping toxicity in patients treated with the combination of 
MOXR0916 and atezolizumab.  Since the expected pharmacological activity of these two 
molecules is to increase adaptive T-cell immune responses via complementary 
mechanisms, the combination may be associated with heightened immune-mediated 
toxicity relative to either agent alone.  Such toxicity could manifest as a higher incidence 
or greater severity of autoimmune inflammation events (including each of the events 
detailed in Section 5.1.1), cytokine release syndromes (including macrophage activation 
syndrome and SIA (see Sections 5.1.2.2 and 5.1.3.1), and sequelae of enhanced 
response to acute infection (see Section 5.1.2.2).
The largest clinical experience to date with the combination of complementary 
modulators of adaptive immunity is derived from trials of ipilimumab combined with 
nivolumab (Wolchok et al. 2013; Antonia et al. 2014; Hammers et al. 2014, Antonia et al. 
2016).  In a Phase I trial of this combination in patients with advanced melanoma, an 


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increased frequency of immune-related toxicities, including Grade 3/4 events, was 
observed for the recommended Phase II concurrent regimen of nivolumab 1 mg/kg and 
ipilimumab 3 mg/kg Q3W, as compared with either single agent alone (Wolchok et al. 
2013; Sznol et al. 2014).  Nevertheless, most immune-related events in this trial were 
qualitatively similar to those observed with ipilimumab or nivolumab monotherapy and 
were largely manageable and reversible.  
Based on these data, and the combination safety profile demonstrated to date in 
Study GO29674, it is anticipated that immune-related adverse events following treatment 
with MOXR0916 and atezolizumab will likewise be monitorable and manageable in the 
setting of this combination study, which has incorporated the extensive experience with 
immune checkpoint inhibitors to date into the design and safety management plan (see 
Section 5.1.5) in order to reduce the potential risks to participating patients.  
5.1.3.1
Systemic Immune Activation
SIA is a rare condition characterized by an excessive immune response.  Given the 
mechanism of action of atezolizumab, SIA is considered a potential risk when 
atezolizumab is given in combination with other immunomodulating agents, including 
MOXR0916.
SIA should be included in the differential diagnosis for patients who, in the absence of an 
alternative etiology, develop a sepsis-like syndrome after administration of study 
treatment.  
Recommendations regarding early identification and treatment of SIA are provided in 
Section 5.1.5.11.
5.1.4
Dose Modification: General Guidance
There will be no dose modifications for MOXR0916 or atezolizumab in this study.  
Patients may temporarily suspend study treatment as appropriate for management of
toxicity, as described in Section 5.1.5.  Based on the available characterization of 
mechanism of action, MOXR0916 may cause adverse events similar to but
independently of atezolizumab, may exacerbate the frequency or severity of
atezolizumab-related adverse events, or may have non-overlapping toxicities with
atezolizumab. Since these scenarios cannot be distinguished one from another in the
clinical setting, immune-related toxicities should generally be attributed to both agents,
and dose interruptions or treatment discontinuation in response to immune-related 
adverse events should be applied to both MOXR0916 and atezolizumab.
Characterization of the safety profiles of MOXR0916 and atezolizumab is ongoing, and it
is plausible that specific immune-mediated toxicities will emerge that can be attributed
with confidence to one agent rather than the combination. In such cases, selective
interruption or discontinuation of either MOXR0916 or atezolizumab and the associated
benefit/risk for individual patients should be discussed with the Medical Monitor. 


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Similarly, individual patients may be rechallenged with study drugs in a selective or 
staggered fashion following recovery from treatment-related toxicity after discussion of 
benefit and risk with the Medical Monitor.
In general, if a planned administration of MOXR0916 and atezolizumab is delayed for 
12 weeks for management of toxicity, then the patient should discontinue study 
treatment and be followed for safety and efficacy as specified in study assessments.
However, if, in the judgment of the investigator, the patient is likely to derive clinical 
benefit from resuming MOXR0916 and atezolizumab after a hold 12 weeks after onset 
of the adverse event, study treatment may be restarted with the approval of the Medical 
Monitor. For example, if patients must be tapered off steroids used to treat adverse 
events, study treatment may be held for 12 weeks after event onset. The acceptable 
length of interruption will depend on agreement between the investigator and the 
Medical Monitor.  
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be
allowed with Medical Monitor approval. The acceptable length of interruption will depend
on agreement between the investigator and the Medical Monitor.
5.1.5
Management of Patients Who Experience Specific Adverse 
Events
Toxicities associated or possibly associated with MOXR0916 and/or atezolizumab
treatment should be managed according to standard medical practice.  Additional tests, 
such as autoimmune serology or biopsies, should be used to evaluate for a possible 
immunogenic etiology.
Although most immune-related adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications.  Discontinuation of MOXR0916 and 
atezolizumab may not have an immediate therapeutic effect, and in severe cases, 
immune-related toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids, or other immunosuppressive agents. 
Guidelines for management of specific adverse events are outlined in the subsections 
below.  These guidelines are intended to inform rather than supplant clinical discretion in 
managing individual cases. The investigator should consider the benefit-risk balance a 
given patient might be experiencing prior to further administration of MOXR0916 and 
atezolizumab.  In patients who have met the criteria for permanent discontinuation, 
resumption of MOXR0916 and atezolizumab may be considered if the patient is deriving 
benefit and has fully recovered from the immune-related event. Such patients can be 
rechallenged with MOXR0916 and/or atezolizumab only after approval by both the 
investigator (or an appropriate delegate) and the Medical Monitor has been documented. 


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5.1.5.1
Hepatic Events
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 treatment.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.  
Management guidelines for hepatic events are provided in Table 4.
Table 4
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue MOXR0916 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 MOXR0916 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 MOXR0916 and 
atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
study treatment, permanently discontinue MOXR0916 and 
atezolizumab and contact Medical Monitor. c
Hepatic event, 
Grade 3 or 4

Permanently discontinue MOXR0916 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.
LFTliver function tests.
a MOXR0916 and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks
after event onset) to allow for corticosteroids to be reduced to 10 mg/day oral prednisone 
or equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before MOXR0916 and atezolizumab can be resumed.
c Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be rechallenged with 
MOXR0916 and atezolizumab only after approval by both the investigator (or an appropriate 
delegate) and the Medical Monitor has been documented.


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5.1.5.2
Pulmonary Events
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 5.
Table 5
Management Guidelines for Pulmonary Events, including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1

Continue MOXR0916 and atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold MOXR0916 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 MOXR0916 and 
atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
study treatment, permanently discontinue MOXR0916 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 MOXR0916 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.
BALbronchoscopic alveolar lavage
a MOXR0916 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.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b  If corticosteroids have been initiated, they must be tapered over ≥ 1 month to 
≤10 mg/day oral prednisone or equivalent before MOXR0916 and atezolizumab can be 
resumed.
c Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be rechallenged with 
MOXR0916 and atezolizumab only after approval by both the investigator (or an 
appropriate delegate) and the Medical Monitor has been documented.


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5.1.5.3
Gastrointestinal Events 
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 three to five specimens for standard paraffin block to check for inflammation and 
lymphocytic infiltrates to confirm colitis diagnosis.  Management guidelines for 
gastrointestinal events are provided in Table 6.
Table 6
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue MOXR0916 and atezolizumab.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold MOXR0916 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 MOXR0916 
and atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding MOXR0916 and atezolizumab, permanently
discontinue study treatment and contact Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold MOXR0916 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 intravenous 
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 MOXR0916 
and atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical Monitor if 
event does not resolve to Grade 1 or better within 12 weeks. c


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Table 6
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue MOXR0916 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 intravenous 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a MOXR0916 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.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b    If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 
mg/day oral prednisone or equivalent before MOXR0916 and atezolizumab can be 
resumed.
c Resumption of MOXR0916 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 MOXR0916 and atezolizumab only after approval by both 
the investigator (or an appropriate delegate) and the Medical Monitor has been 
documented.
5.1.5.4
Dermatologic Events
A dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy 
should be performed unless contraindicated, and if possible, photos of the rash should 
also be obtained and submitted to the Sponsor.  Management guidelines for 
gastrointestinal events are provided in Table 7.


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Table 7
Management Guidelines for Dermatologic Events 
Event
Management
Dermatologic 
event, Grade 1 

Continue MOXR0916 and atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue MOXR0916 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 MOXR0916 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, resume MOXR0916
and atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical 
Monitor c
Dermatologic 
event, Grade 4

Permanently discontinue MOXR0916 and atezolizumab 
and contact Medical Monitor. c
a MOXR0916 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.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical 
Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before MOXR0916 and atezolizumab 
can be resumed.
c Resumption of study treatment may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
rechallenged with MOXR0916 and atezolizumab only after approval by both the 
investigator (or an appropriate delegate) and the Medical Monitor has been 
documented.
5.1.5.5
Pancreatic Events
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.


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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Continue MOXR0916 and atezolizumab.
Monitor amylase and lipase weekly.
For prolonged elevation (e.g., 3 weeks), consider 
treatment with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4
Withhold MOXR0916 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 MOXR0916 
and atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical 
Monitor. c
For recurrent events, permanently discontinue MOXR0916
and atezolizumab and contact Medical Monitor. c
Immune-related pancreatitis, 
Grade 3
Withhold MOXR0916 and atezolizumab for up to 12 weeks 
after event onset. a
Refer patient to gastrointestinal specialist.
Initiate treatment with 12 mg/kg/day intravenous 
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 MOXR0916 
and atezolizumab. b
If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical 
Monitor. c
For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 


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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-related pancreatitis, 
Grade 4
Permanently discontinue MOXR0916 and atezolizumab and 
contact Medical Monitor. c
Refer patient to gastrointestinal specialist.
Initiate treatment with 12 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a MOXR0916 and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks)
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before MOXR0916 and atezolizumab can be resumed.
c Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be rechallenged with 
MOXR0916 and atezolizumab, only after approval by both the investigator (or an appropriate 
delegate) and the Medical Monitor has been documented.
5.1.5.6
Endocrine Events
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental 
status changes, or constipation 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.
Management guidelines for endocrine events are provided in Table 9.


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Table 9
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue MOXR0916 and atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold MOXR0916 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 MOXR0916 and atezolizumab.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold MOXR0916 and atezolizumab.

Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume MOXR0916 and atezolizumab when symptoms 
are controlled and thyroid function is improving.

Permanently discontinue MOXR0916 and atezolizumab
and contact Medical Monitor for life-threatening immune-
related hyperthyroidism. c
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold MOXR0916 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 intravenous 
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 (if required), resume 
MOXR0916 and atezolizumab. b 

If event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy while withholding 
study treatment, permanently discontinue MOXR0916
and atezolizumab and contact Medical Monitor.c
Hyperglycemia,  
Grade 1 or 2 

Continue MOXR0916 and atezolizumab.

Initiate treatment with insulin if needed.

Monitor for glucose control.


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Table 9
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hyperglycemia, 
Grade 3 or 4

Withhold MOXR0916 and atezolizumab.

Initiate treatment with insulin.

Monitor for glucose control.

Resume MOXR0916 and atezolizumab when symptoms 
resolve and glucose levels are stable.
Hypophysitis        
pan-hypopituitarism),    
Grade 2-3

Withhold MOXR0916 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 
MOXR0916 and atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical 
Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis         
(pan-hypopituitarism),   
Grade 4

Permanently discontinue MOXR0916 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; 
a MOXR0916 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.  The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical 
Monitor.
b  If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before MOXR0916 and atezolizumab can be 
resumed.
c
Resumption of study treatment may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be rechallenged 
with MOXR0916 and atezolizumab only after approval by both the investigator (or an 
appropriate delegate) and the Medical Monitor has been documented.


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5.1.5.7
Immune-Related Myocarditis
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 Table 10.


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Table 10 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 MOXR0916 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 MOXR0916 and 
atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
study treatment, permanently discontinue MOXR0916 and 
atezolizumab and contact Medical Monitor. c
Immune-related 
myocarditis, Grade 3-4

Permanently discontinue MOXR0916 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.
a MOXR0916 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.  The acceptable length of the extended period of time must be agreed 
upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before MOXR0916 and atezolizumab can be resumed.
c
Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be rechallenged with 
MOXR0916 and atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor.
5.1.5.8
Immune-Related Meningoencephalitis
Immune-related meningoencephalitis should be suspected in any patient presenting with 


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signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to,
headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte 
imbalances needs to be distinguished from potential meningoencephalitis resulting from 
infection (bacterial, viral, or fungal) or progression of malignancy, or secondary to a 
paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Related 
Meningoencephalitis
Event
Management
Immune-related 
meningoencephalitis, 
all grades

Permanently discontinue MOXR0916 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.
a Resumption of study treatment may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be rechallenged with 
MOXR0916 and atezolizumab only after approval by both the investigator (or an appropriate 
delegate) and the Medical Monitor has been documented.
5.1.5.9
Neurologic Disorders
Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic work-up is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in
Table 12.


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Table 12 Management Guidelines for Neurologic Disorders
Event
Management
Immune-related 
neuropathy, 
Grade 1

Continue MOXR0916 and atezolizumab.

Investigate etiology.
Immune-related 
neuropathy, 
Grade 2 

Withhold MOXR0916 and atezolizumab for up to 12 weeks 
after event onset.

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume MOXR0916 
and atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding study treatment, permanently discontinue 
MOXR0916 and atezolizumab and contact Medical 
Monitor. c
Immune-related 
neuropathy, 
Grade 3 or 4

Permanently discontinue MOXR0916 and atezolizumab and 
contact Medical Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré
syndrome (any 
grade)

Permanently discontinue MOXR0916 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 intravenous 
prednisone or equivalent.
a MOXR0916 and atezolizumab may be withheld for a longer period of time 
(i.e., >12 weeks after event onset) to allow for corticosteroids to be reduced to 
10 mg/day oral prednisone or equivalent.  The acceptable length of the extended 
period of time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before MOXR0916 and atezolizumab can 
be resumed.
c Resumption of study treatment may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
rechallenged with MOXR0916 and with atezolizumab only after approval by both the 
investigator (or an appropriate delegate) and the Medical Monitor has been 
documented.
5.1.5.10
Infusion-Related Reactions
Guidelines for medical management of infusion-related reactions during Cycle 1 are 
provided in Table 13.  For subsequent cycles, infusion-related reactions should be 
managed according to institutional guidelines.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab associated infusion-related reactions, due to its potential for 
causing agranulocytosis.
Note:  In principle, patients who cannot tolerate infusion of one agent could continue 


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study treatment with the other agent alone, if tolerated.  In practice, it might not always 
be possible to attribute an infusion-related event selectively to one agent.  An 
infusion-related event that begins during the first infusion of the day (MOXR0916) can 
reliably be attributed to MOXR0916, but an adverse event with onset after the second 
infusion has begun could represent a reaction to atezolizumab or a delayed-onset 
reaction to MOXR0916.  Therefore, subsequent cycles of study treatment in a patient 
who experiences a Grade 3 or Grade 4 infusion-related event will be handled as follows:

Patients who experience a Grade 3 event that begins during the MOXR0916
infusion, but prior to the atezolizumab infusion, and is hence attributed solely to 
MOXR0916, can receive subsequent cycles of atezolizumab as tolerated.  
Rechallenge with MOXR0916 following premedication in subsequent cycles, 
following approval of the Medical Monitor, is allowed provided that the next dose 
of MOXR0916 is infused over a minimum of 90 minutes.  

Patients who experience a Grade 3 event that begins after the atezolizumab 
infusion has begun, and hence following the MOXR0916 infusion, will 
permanently discontinue atezolizumab.  As attribution to MOXR0916 cannot be 
excluded, administration of subsequent cycles of MOXR0916 requires the 
precautions described above.

Patients who experience a Grade 4 event that is attributed solely to MOXR0916
will permanently discontinue MOXR0916.  Patients who experience a Grade 4 
event that is temporally related to atezolizumab, such that attribution to 
MOXR0916 cannot be excluded will permanently discontinue both atezolizumab 
and MOXR0916. 


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Table 13 Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time 
of event onset.

After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be 
increased to the original rate.
IRR, Grade 2

Interrupt MOXR0916 or atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion 
at half the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretics, and/or 
analgesics and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.  No further administration of either study drug 
will occur at this visit.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue MOXR0916 and/or atezolizumab 
and contact Medical Monitor. a
IRRinfusion-related reaction; IVintravenous.
a Resumption of study treatment may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  Patients can be rechallenged
with MOXR0916 and/or atezolizumab, as applicable, only after approval by both the 
investigator (or an appropriate delegate) and the Medical Monitor has been 
documented.
5.1.5.11
Cytokine Release Syndrome, Macrophage Activation 
Syndrome, and SIA
Cytokine release syndrome, macrophage activation syndrome, and SIA may be 
considered as part of a continuum, with overlapping symptoms and presentation.  The 
supportive and interventional management for these disorders is largely the same, with 
additional diagnostic features described for MAS (Jordan et al. 2011; Tothova and 
Berliner 2015) and SIA provided in Table 14.
Recommendations regarding early identification and management of SIA are provided 
below.  In the event of suspected SIA, study treatment should be withheld and the 
Medical Monitor should be contacted immediately for additional guidance.
Early disease recognition is critical, and SIA should be suspected if, in the absence of an 


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alternative etiology, the patient meets two or more of the following criteria:

Hypotension that is refractory to aggressive IV fluid challenge
Vasopressor support may be required.

Respiratory distress that requires aggressive supportive care
Supplemental oxygen and intubation may be required.

Fever 38.5C

Acute renal or hepatic failure

Bleeding from coagulopathy

Any of the following unexplained laboratory abnormalities (change from baseline):  
cytopenias (in two or more lineages), significant transaminitis, and coagulopathy
For patients with suspected SIA, an initial evaluation should include the following:

CBC with peripheral smear

PT, PTT, fibrinogen, and D-dimer

Ferritin

Triglycerides

AST, ALT, and total bilirubin

LDH

Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
Laboratory tests with normal results should be repeated frequently in patients for whom 
a high clinical suspicion of SIA exists.
If cytopenias are present (Grade 2 in two or more lineages) or ferritin is 3000 ng/mL, 
the following evaluations should also be performed:  

Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis)

Soluble interleukin 2 (IL-2) receptor (sCD25)

Natural killer cell activity

Cytomegalovirus, Epstein-Barr virus, and herpes-simplex virus evaluation (for 
reactivated or active disease)

Diagnostic criteria and recommended management for SIA are provided in 
Table 14.  The diagnostic criteria apply only when alternative etiologies have been 
excluded.




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


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functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:
General Drug Development Adverse Events

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
Adverse Events of Interest Specific to MOXR0916 in Combination with 
Atezolizumab

Conditions (regardless of grade) suggestive of an autoimmune disorder, including 
but not limited to hepatitis, pneumonitis, colitis, endocrinopathies, pancreatitis, 
thyroiditis, rheumatoid arthritis, Type I diabetes, vasculitis, neuritis, systemic lupus 
erythematosus, Sjögren’s syndrome, and multiple sclerosis.


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
Grade 3 acute infection (bacterial, viral, zoonotic, or fungal)

Grade 3 events suggestive of hypersensitivity, cytokine release, 
systemic inflammatory response, or infusion reaction syndromes, including but not 
limited to influenza-like illness, fever, chills, rash, urticaria, dyspnea, wheezing, 
angioedema, tachycardia, and hypotension occurring within 24 hours of the end of 
the infusion.

Grade 3 events suggestive of cytokine release syndrome (occurring 24 hours 
after the end of the infusion), including but not limited to influenza-like illness, 
nausea, headache, fevers, chills, tachycardia, hypotension, and shortness of breath.

Grade 3 lymphopenia that also represents 50% decrease from baseline 
(regardless of whether the event otherwise meets criteria for reporting of an 
abnormal laboratory value as an adverse event, as described in Section 5.3.5.5).  

Grade 3 rash, vitiligo, or pruritus

Grade 3 diarrhea

Grade 3 AST/ALT/total bilirubin elevationasymptomatic

Grade 2 AST/ALT/total bilirubin elevationwith constitutional symptoms

Grade 2 hypoxia or dyspnea not attributable to underlying malignancy or other 
pulmonary disease

Grade 2 pleural effusion

Grade 2 pericardial effusion

Any adverse event, regardless of grade, requiring systemic corticosteroids for 
management
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 


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(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study treatment, all adverse events will be reported until 90 days
after the last dose of study treatment or until initiation of new systemic anti-cancer 
therapy, whichever occurs first, and serious adverse events and adverse events of 
special interest will continue to be reported immediately until 90 days after the last dose 
of study treatment or until initiation of new systemic anti-cancer therapy, whichever 
occurs first.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 15 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 15 Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2 .
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 16):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 16 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" on the Adverse Event eCRF.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Infusion-Related Reaction eCRF. 
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3baseline value) in combination with either 
an elevated total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 baseline value in combination with total 
bilirubin 2 ULN (of which 35% is direct bilirubin)

Treatment-emergent ALT or AST 3 baseline value in combination with clinical 
jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2 ) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol-
specified adverse event reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of malignancy should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur within 90 days of 
the last dose of study treatment, regardless of relationship to study drug, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 5.4.2). The IMC (Section 3.1.2 ) will monitor the frequency of deaths from all 
causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Urothelial Carcinoma
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events, with the exception of
medically significant events that lead to hospitalization (and therefore represent serious
adverse events) or study conduct change such as treatment interruption.  These data 
will be captured as efficacy assessment data only.  In most cases, the expected pattern 
of progression will be based on RECIST v1.1 criteria.  In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration.  However, every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol e.g., for study drug administration 
or insertion of access device for study drug administration 

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 


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instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information:
Medical Monitors:
, M.D., Ph.D.
Telephone Nos.:
Office: 
Mobile:  
Email:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to 
 Pharmacovigilance and 
Drug Safety Services immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 90 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse
Event of Special Interest Reporting Form provided to investigators should be completed
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur 90 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 6 months after the last 


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dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
5.4.3.2
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 
6 months after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
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.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
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.
5.4.3.3
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 the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 


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follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

MOXR0916 Investigator's Brochure

Atezolizumab Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.


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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The Sponsor has determined that the original scientific aims of this study are no longer 
evaluable as a result of the Sponsor’s decision to prematurely halt enrollment due to 
slow patient accrual.  However, the original statistical considerations and analysis plan
are retained below for reference. 
This study is designed to evaluate the safety and activity of MOXR0916 plus 
atezolizumab or placebo plus atezolizumab in previously untreated patients with locally 
advanced or metastatic UC who have not received prior systemic therapy in the locally 
advanced/metastatic setting and who are ineligible to receive cisplatin-based therapy. 
As described in Section 3.1.1, this study will enroll up to approximately 225 patients with 
evaluable tissue at approximately 75 sites globally.  
  
 
 
 
 
 
 
6.1
DETERMINATION OF SAMPLE SIZE
The primary objective of this study is to test the hypothesis of greater treatment effect of 
MOXR0916 plus atezolizumab on duration of PFS and OS relative to the placebo plus 
atezolizumab. For the co-primary endpoints of PFS and OS in the primary patient 
population, at 70% event maturity (112 PFS or OS events), the trial will have 81% power 
to detect a PFS hazard ratio of 0.50 at a two-sided significance level of 0.005
(corresponding to an improvement from 3 to 6 months in median PFS), and 80% power 
to detect an OS hazard ratio of 0.58 at a two-sided significance level of 0.045 
(corresponding to an improvement from 13.3 to 22.9 months in median OS). Total type I 
error will be controlled at a 0.05 significance level. 
Notably, the trial is able to detect only very large benefits in OS. The trial will not, 
however, have adequate power to detect all potentially clinically meaningful differences 
in OS. For example, with 112 OS events, there is only 45% power to detect a hazard 
ratio of 0.70 (corresponding to an improvement from 13.3 to 19 months in median OS) at 
a two-sided significance level of 0.045. Thus, a statistically negative outcome in the 
co-primary OS analysis does not necessarily rule out a clinically meaningful outcome. 


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Operating characteristics (power and expected total number of events) for true 
underlying hazard ratio values of 0.50, 0.60, and 0.75 are provided in Table 17.
Table 17 Operating Characteristics for Proposed Study Design for Several 
Possible True Underlying Hazard Ratio Values
True Underlying Hazard Ratio
0.50
0.60
0.75
Expected number of 
events 
102
107
113
Power of log-rank test a
93%
74%
32%
95% confidence interval 
for true hazard ratio b
(0.34, 0.74)
(0.41, 0.88)
(0.52, 1.08)
Note: Operating characteristics are based on the following assumptions: event times are 
exponentially distributed, median overall survival in the control arm is 13.3 months, and patients 
are enrolled over 13 months and followed for an additional 32 months
a Two-sided 0.045.
b Confidence intervals are based on the assumption that the point estimate is equal to the true 
underlying value of the hazard ratio in each column.
Additionally, with 60 PFS events in the PD-L1 IC2/3 population (corresponding to 75% 
event maturity), there is 77% power to detect a HR of 0.50 at a two-sided significance 
level of 0.05. The upper bound of the two-sided 95% CI for the HR will be 0.83.  
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, study treatment administration, and discontinuation from the study will be 
summarized by treatment arm. The reasons for study treatment discontinuation will be 
also tabulated. Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be listed by treatment arm and evaluated for their 
potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including but not limited to age, sex, baseline 
ECOG, and presence of visceral metastases) will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate. Summaries will be presented overall and by treatment group.
6.4
EFFICACY ANALYSES
The co-primary and secondary efficacy analyses will be conducted among all 
randomized patients in appropriate study populations (primary population or PD-L1 IC2/3 
population) with patients grouped according to their assigned treatment (i.e., ITT) 
analysis. Specifically, formal hypothesis testing of the co-primary efficacy endpoints of 


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PFS and OS will be conducted in the ITT primary patient population at significance 
levels of 0.005 and 0.045, respectively. 
Other secondary endpoints, including PFS and OS in the PD-L1 IC2/3 subpopulation, as 
well as ORR, DOR, and PROs (including pain, fatigue, other symptoms, and interference 
scores from the MDASI) in both the primary patient population and in the PD-L1 IC2/3 
population will also be analyzed but are not included in the formal hypothesis testing 
framework. Results will be presented with 95% confidence intervals unless otherwise 
specified. 
6.4.1
Co-Primary Efficacy Endpoints
6.4.1.1
Analysis Plan for Progression-Free Survival 
PFS is defined as the time from randomization to the date of first documented disease 
progression or death, whichever occurs first. Disease progression for PFS analysis will 
be determined on the basis of investigator assessment with the use of RECIST v1.1.
The primary PFS analysis will occur after approximately 112 events (corresponding to 
70% event information) have been observed in the primary population. This analysis is 
expected to occur approximately 18 months after enrollment of the first patient.
Data for a patient without disease progression or death as of the clinical data cutoff date 
will be censored at the time of the last tumor assessment (or at the date of 
randomization plus 1 day if no tumor assessment was performed after the baseline visit). 
Data from a patient who is lost to follow-up will be included in the analysis and censored 
on the last date of tumor assessment that the patient was known to be progression-free.
The two-sided stratified log-rank test will be used to compare PFS between the two 
treatment arms. Kaplan-Meier methodology will be used to estimate the PFS curve and 
median PFS for each treatment arm. Stratified Cox proportional-hazards models will be 
used to estimate the HR and its 95% CI. The results from the unstratified log-rank test 
will also be provided.
Prior to this primary PFS efficacy analysis, no interim analysis will be conducted for any 
of the efficacy endpoints, and patient study treatment assignment will remain blinded to 
members of the study team who are not part of the IMC.
6.4.1.2
Analysis Plan for Overall Survival 
OS is defined as the time from randomization to death from any cause. Data for patients 
who are alive at the time of the analysis data cutoff will be censored at the last date they 
were known to be alive. Data from patients without post-baseline information will be 
censored at the date of randomization plus 1 day.
The two-sided stratified log-rank test will be used to compare OS between the two 
treatment arms. Kaplan-Meier methodology will be used to estimate the OS curve and 


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median OS for each treatment arm. Stratified Cox proportional-hazards models will be 
used to estimate the HR and its 95% CI. The results from the unstratified test will also 
be provided.
Two interim analyses and one final analysis of OS are planned in the primary patient 
population. The final OS analysis will occur after approximately 112 events 
(corresponding to 70% event information) have been observed in the primary population. 
This analysis is expected to occur approximately 45 months after enrollment of the first 
patient.
The first OS interim analysis will be conducted at the time of unblinding for the primary 
PFS analysis in the primary patient population. Approximately 48 events, 
(corresponding to 43% information relative to final analysis) are expected at the time of 
the first OS interim analysis. The second interim analysis will be conducted after 
approximately 80 events (corresponding to 71% information relative to final analysis), 
have been observed in the primary population. The second OS interim analysis is 
expected to occur approximately 27 months after enrollment of the first patient. 
The actual number of observed OS events and the amount of information at the interim 
analyses may be different from the estimates presented above. The stopping 
boundaries have been computed using the Lan-DeMets approximation to O’Brien-
Fleming boundaries. The stopping boundaries for superior (inferior) efficacy will be HR 
0.39 (HR 2.59) and HR 0.57 (HR 1.74) at the interim analyses and HR 0.68 (HR 
1.47) at the final analysis. The overall type I error rate is controlled at the level of 
4.5%, with cumulative of 0.001 and 0.014 spent at the first and second interim 
analyses. 
 
 
 
6.4.2.2
Analysis Plan for Objective Response
Objective response is defined as the percentage of patients who had experienced 
objective response (complete or partial response)as determined by using RECIST v1.1
as assessed by the investigators. Objective response will be evaluated by treatment 
arm. Patients will be grouped according to the treatment arm assigned at randomization, 
and patients without post-baseline overall response assessments will be counted as 


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non-responders.
6.4.2.3
Analysis Plan for Duration of Response
DOR is defined as the time from the first occurrence of a documented objective 
response to the time of the first documented disease progression or death from any 
cause (whichever occurs earlier). Objective response (described above) and disease 
progression for the DOR analysis will be determined on the basis of investigator 
assessment with the use of RECIST v1.1.
The analysis of DOR will include only patients who achieved an objective response to 
study treatment. DOR will be estimated using the Kaplan-Meier methodology. Because 
the determination of DOR is based on a non-randomized subset of patients, no formal 
hypothesis testing will be performed. 
6.4.2.4
Analysis Plan for Patient-Reported Symptoms and Impact on 
Functioning
The MDASI-supported endpoints will be analyzed in the primary population, regardless 
of PD-L1 status, and in the PD-L1 IC2/3 population.  Baseline is defined as the last 
available assessment prior to the first dose of study treatment.
MDASI completion compliance will be documented and calculated as the number of 
forms received divided by the number expected at every assessment. 
Each MDASI symptom score is based on a one-item scale and ranges from 0 to 10 
(indicating a severe symptom).  Symptom severity will be categorized as follows:
asymptomatic/mild (03), moderate (46), and severe (710). 
The 6-item Symptom Interference score will be derived according to the MDASI user 
manual: a prorated score ranging from 0 to 10 will be computed if more than 50% of the 
constituent items (items 14 to 19) are completed; the score will be considered missing if
less than 50% of the items are completed (Cleeland et al. 2000). Patients with a score 
of 5 or higher on the Symptoms Interference score are considered functionally impaired.  
Secondary endpoints include time to pain progression, time to fatigue progression, and 
time to pain palliation. Pain or fatigue progression events will be defined as the first
increase of ≥2 points from baseline. The pain palliation event will be defined as the first 
decrease of >2 points from baseline in the absence of opioid initiation or increase. The 
same time-to-event methods as described above for OS and PFS in Section 6.4 will be 
applied to these endpoints. Data for patients with missing baseline assessment, or 
without a post-baseline assessment will be censored at the date of randomization plus 1 
day. 
For the secondary endpoint of proportion of patients reporting symptom interference with 
daily living at the time of progression, the Symptom Interference score obtained on or 
immediately prior to the date of radiographic progression according to RECIST v1.1 will 


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be utilized.  
6.4.3
Exploratory Efficacy Endpoints
PFS, ORR, and DOR may be evaluated using definitions of response per immune-
modified RECIST criteria by treatment arm in both the primary and PD-L1 IC2/3 patient 
populations.
Progression events for symptoms other than pain or fatigue will be defined as the first 
increase of 2 points from baseline. The same time-to-event methods as described 
above for OS and PFS in Section 6.4 will be applied to these endpoints.
MDASI scores and change from baseline may be descriptively analyzed using means, 
standard deviations, medians, and ranges for continuous variables and proportions for 
categorical variables, as appropriate.  Mean changes in symptom scores and Symptom 
Interference scores from baseline will be used to evaluate the patients’ longitudinal 
experience of disease and treatment.
Additional exploratory analyses may be performed to evaluate the relationship between 
symptom severity and symptom interference with daily living and clinical progression as 
determined by the investigator.
The EQ-5D-5L will be included to derive utility to inform pharmacoeconomic models and 
therefore will not be part of the CSR.
6.5
SAFETY ANALYSES
Safety analyses will be conducted in the entire, pooled ITT population of all randomized 
patients, regardless of PD-L1 status, who received at least one dose of MOXR0916 or 
atezolizumab. 
Safety analyses will be performed by treatment arm and will be based on actual 
treatment received. Specifically, a patient will be included in the MOXR0916 plus
atezolizumab arm of the safety analyses if the patient received any amount of 
MOXR0916, regardless of the initial treatment assignment at randomization.
During enrollment, interim safety data will be reviewed approximately every six months 
by an IMC as described in Section 3.1.2). Thereafter, analysis of safety data will be 
conducted by the Sponsor at the time of the primary PFS analysis in the primary 
population and at subsequent analyses of OS.
Safety endpoints will include incidence, nature, and severity of adverse events (using 
NCI CTCAE, Version 4), including serious adverse events and adverse events of special 
interests, changes in vital signs, physical findings, and clinical laboratory results 
following the administration of MOXR0916 plus atezolizumab. Drug exposure will be 
summarized, including duration and dosage. Verbatim description of adverse events will 


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be mapped to the Medical Dictionary for Regulatory Activities thesaurus terms and 
graded according the NCI CTCAE, Version 4. All adverse events that occur during or 
after the first study treatment, until 90 days after the last dose of study treatment or 
initiation of another systemic anti-cancer therapy, whichever occurs first, will be 
summarized by treatment arm and NCI CTCAE grade. In addition, serious adverse 
events and adverse events leading to study treatment discontinuation or interruption will 
be summarized accordingly. Multiple occurrence of the same event will be counted once 
at the maximum severity. Laboratory data with values outside of the normal ranges will 
be identified. Additionally, selected laboratory data, including ATA results, will be 
summarized by treatment arm and grade. Vital signs will also be summarized by 
treatment arm and visit. Deaths and causes of deaths will be summarized. 
6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum MOXR0916 concentration versus time data will be tabulated 
and plotted. The pharmacokinetics of MOXR0916 will be summarized by estimating 
area under the curve, Cmax, Cmin, clearance, and Vss (if data allow). Descriptive statistics 
will include means, medians, ranges, and standard deviations, as appropriate.
Individual and mean serum atezolizumab concentration versus time data will be 
tabulated, plotted, and compared to historical data.
Additional PK analyses will be conducted as appropriate.
6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analyses will include patients with any ATA assessments with 
patients grouped according to treatment received.
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized by treatment group.
Patients are considered to be ATA positive if they are ATA negative or with missing data 
at baseline but develop an ATA response following study treatment administration 
(treatment-induced ATA response), or if they are ATA positive at baseline and the titer of 
one or more post-baseline samples is at least 4-fold greater (i.e., 0.60 titer units) than 
the titer of the baseline sample (treatment-enhanced ATA response). Patients are 
considered to be ATA negative if they are ATA negative or with missing data at baseline 
and all post-baseline samples are negative, or if they are ATA positive at baseline but do 
not have any post-baseline samples with a titer that is at least 4-fold greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses.
6.8
BIOMARKER ANALYSES
Exploratory biomarker analyses will be performed in tumor tissue and blood in an effort 


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to better understand the association of these markers with study-drug response, 
including efficacy and/or adverse events. Specific evaluations may include, but not be 
limited to, PD-L1 expression by IHC, OX40 expression by IHC, presence of CD8 and 
tumor infiltrating lymphocytes by IHC, expression of immune and tumor biology 
associated genes, and next-generation sequencing for identification of somatic 
mutations and characterization of tumor mutational load and other aberrations 
associated with UBC tumor biology. Biomarker analyses may be reported in a separate 
report.
Exploratory biomarker analyses may be performed in either the primary population, the 
PD-L1 IC2/3 population, or for select biomarkers deemed not to be related to PD-L1 
status, in the entire, pooled ITT population.
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analyses
There will be no interim efficacy analyses prior to the primary PFS analysis in the 
primary population. Interim efficacy analyses for OS will be conducted as described in 
Section 6.4.1.2.
An IMC will convene approximately every 6 months during enrollment to review available 
safety data and to make recommendations regarding study conduct to ensure the safety 
of patients enrolled on the study. In the absence of significant safety concerns or other 
extenuating circumstances, accrual will continue in the study while the reviews are being 
conducted. Pending review of accumulating safety data, the IMC may choose to meet 
more frequently, if necessary. On the basis of these interim safety results, however, the 
IMC may recommend to continue, modify, or terminate the study (see Section 3.1.2).
However, as the IMC will review only safety data, it cannot undertake decisions to halt 
the trial based on early efficacy or futility.
The members, roles, responsibilities and communication processes of the IMC will be 
outlined in a separate charter. 
6.9.2
Optional Interim Analyses
There will be no interim efficacy analyses prior to the primary PFS analysis in the 
primary population.  Following the primary PFS analysis, however, the Sponsor may 
choose to conduct up to two additional interim efficacy analyses for OS (i.e., beyond 
what is specified in Section 6.9.1).  The decision to conduct an optional interim analysis 
and the timing of the analysis will be documented in the Sponsor’s trial master file prior 
to the conduct of the interim analysis. The interim analysis will be performed and 
interpreted by members of the Sponsor study team and appropriate senior management 
personnel who will be unblinded at the treatment group level.  Access to treatment 
assignment information will follow the Sponsor’s standard procedures.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All pertinent eCRFs should be completed by designated, trained site staff.  eCRFs 
should be reviewed and electronically signed and dated by the investigator or a 
designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 


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departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 


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regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.


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A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.


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Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., the date when the 
number of OS events specified for the final analysis has been observed).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored by Genentech and will be managed by Genentech and a 
Contract Research Organization (CRO).  The CRO will provide clinical operations 
management, data management, and medical monitoring support. 
Treatment assignment will be conducted using an IxRS.  Data will be recorded via an 
EDC system with the use of eCRFs (see Section 7.2).  A central laboratory will be used 
for a subset of laboratory assessments as specified in Section 4.5.6.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 


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the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities
Assessment Window (Days)
Screening
Cycle 1
Cycle 2
Treatment 
Discontinuation
Follow-Up
Day 28 to 
Day 1
Day 1 Day 8
(1)
Day 15
(1)
Day 1
(3)
30 Days after 
Last Dose a
Informed consent b
x
Medical history and demographic 
information c
x
HIV, HBV, HCV serology d
x
Concomitant medications e
x
x
x
x
x
x
Adverse events f
x
x
x
x
x
x
x
Tumor assessment g
x
The imaging modality and frequency of tumor assessments will be 
determined by the investigator.
Complete physical examination h
x
x
Limited physical examination i
x j
x j
ECOG Performance Status
x
x j
x j
x
Vital signs k
x
x
x
x
Pulse oximetry, resting
x
x
x
12-lead ECG l
x
x
Weight
x
x j
x j
x
Height
x
Hematology m
x
x j
x j
x
Serum or plasma chemistry n
x
x j
x j
x


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Schedule of Activities (cont.)
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Assessment Window (Days)
Screening
Cycle 1
Cycle 2
Treatment 
Discontinuation
Follow-Up
Day 28 to 
Day 1
Day 1 Day 8
(1)
Day 15
(1)
Day 1
(3)
30 Days after 
Last Dose a
Pregnancy test o
x
x p
x
Coagulation panel (aPTT, PT/INR)
x
x
Urinalysis q
x
x
x p
x
TSH, free T4
x
x p
x
Serum amylase and lipase
x
x j
x
Serum ferritin and CRP
x
Baseline tumor tissue sample r
x
Study treatment infusion s
x
x
CRPC-reactive protein; ECOG Eastern Cooperative Oncology Group;  eCRFelectronic Case Report Form; HBcAbantibody against hepatitis 
B core antigen; HBsAb antibody against hepatitis B surface antigen; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCVhepatitis 
C virus; IVintravenous; PD-L1programmed death-ligand 1; RECIST Response Evaluation Criteria in Solid Tumors; TSHthyroid-stimulating 
hormone.
Note:  Assessments scheduled on the days of study treatment infusions should be performed before the infusion unless otherwise noted.
a Patients will be asked to return to the clinic within 30 days after the last dose of study treatment for a discontinuation visit.  Tumor assessment 
scans performed within 6 weeks prior to the treatment discontinuation visit do not need to be repeated.  The visit at which a response 
assessment shows progressive disease resulting in MOXR0916 and atezolizumab discontinuation may be used as the treatment discontinuation 
visit, in which case all assessments associated with the treatment discontinuation visit should be performed at that time.
b Written informed consent is required for performing any study-specific tests or procedures.  Signing of the Informed Consent Form can occur
prior to the 28-day screening period.  Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 
28 days prior to study entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests. 
Results for the following laboratory tests must be obtained within 14 days prior to Cycle 1, Day 1:  hematology, serum/plasma chemistry, 
coagulation panel, serum pregnancy test.


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c Medical history includes clinically significant diseases, surgeries, cancer history (including stage, date of diagnosis, and prior cancer therapies 
and procedures), reproductive status, smoking history, use of alcohol, and drugs of abuse will be recorded at baseline. A history of pleural or 
pericardial effusion or of ascites requiring intervention should be entered in the medical history.
d All patients will be tested for HIV locally prior to enrollment into the study, and HIV-positive patients will be excluded from the study.  HBsAg,
HBsAb, and HBcAb should be collected during screening and tested locally.  In patients who have positive serology for HBcAb, an HBV DNA 
test sample should be collected prior to initiation of study treatment, but the result is not required to determine eligibility. 
e Concomitant medications include any prescription medications or over-the-counter medications.  At screening, any medications the patient has 
used within the 7 days prior to the date of informed consent should be documented.  At subsequent visits, changes to current medications or 
medications used since the last documentation of medications will be recorded.
f
After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 90 days after the last dose of study 
treatment or initiation of another anti-cancer therapy, whichever occurs first.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study treatment.  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 treatment or 
study-related procedures until a final outcome can be reported. 
g The imaging modality (e.g., CT vs. MRI scan, contrast-enhanced vs. non-contrast) and the frequency of tumor assessments will be determined 
primarily by the investigator based on the patient’s disease characteristics and local institutional standards (i.e., approximately every 
612 weeks).  At the investigator’s discretion, tumor assessments may be performed at any time if progressive disease is suspected. Tumor 
assessments will continue until radiographic disease progression (or loss of clinical benefit as determined by the investigator for patients who 
continue treatment after disease progression according to RECIST v1.1), withdrawal of consent, initiation of new anti-cancer therapy, loss to 
follow-up, death, or study termination by the Sponsor, whichever occurs first.  Patients who continue treatment beyond radiographic disease 
progression per RECIST v1.1 will be monitored with a follow-up scan in 6 (±1) weeks or earlier if clinically indicated. Tumor assessments should 
be continued every 6 (±1) weeks thereafter until two consecutive scans demonstrate stability or improvement with respect to the first scan that 
showed radiographic disease progression, at which point the scan frequency may be liberalized at the investigator’s discretion.
h Complete physical exam includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline should be recorded on the General 
Medical History and Baseline Conditions eCRF.
i
Perform a limited, symptom-directed physical examination at specified timepoints or as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
j
ECOG performance status, weight, limited physical examination, local hematology and serum/plasma chemistry panels (including 


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amylase/lipase), may be obtained 96 hours before Day 1 of each cycle.
k Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF. For the first infusion of MOXR0916, vital signs should be measured 
within 60 minutes prior to the infusion and, if clinically indicated, at 15, 30, 45, and 60 minutes (5 minutes for all timepoints) during and at 
30 (10) minutes after the infusion.  For the first infusion of atezolizumab, vital signs should be measured between the MOXR0916 and 
atezolizumab infusions (within 60 minutes prior to the atezolizumab infusion), and if clinically indicated, at 15, 30, 45, and 60 minutes 
(5 minutes for all timepoints) during, and at 30 (10) minutes after the infusion. For subsequent MOXR0916 infusions, vital signs should be 
measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, every 
15 (5) minutes during the infusion, at the end of the infusion (±5 minutes), and at 30 (10) minutes after the infusion. For subsequent 
atezolizumab infusions, vital signs should be measured between the MOXR0916 and atezolizumab infusions (within 60 minutes prior to the 
atezolizumab infusion), and, if clinically indicated or if symptoms occurred during the previous infusion, every 15 (5) minutes during the infusion,
at the end of the infusion (±5 minutes), and at 30 (10) minutes after the infusion. Patients will be informed about the possibility of delayed post-
infusion symptoms and instructed to contact their study physician if they develop such symptoms.
l
Twelve-lead ECGs are required as part of the screening assessment and at the end of treatment visit.  ECGs will be reviewed by the investigator 
to determine patient eligibility at screening. 
m Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, platelet count, and WBC count with differential (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).  A manual differential can be done if clinically indicated. During screening, 
hematology results must be obtained within 14 days prior to Cycle 1, Day 1.
n Serum or plasma chemistry includes BUN or urea, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, 
glucose, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein, and albumin. Bicarbonate is not a required analyte for patients in 
countries where it is not considered a standard chemistry measurement.
o Serum pregnancy test (for women of childbearing potential, as defined in Section 4.1.1) must be performed and documented as negative within 
14 days prior to Cycle 1, Day 1.  Urine or serum pregnancy tests (for women of childbearing potential only) will be performed at the specified 
subsequent visits.  If a urine pregnancy test is positive, dosing will be delayed until the patient’s status is determined by a serum pregnancy test.
p On Day 1 of Cycle 2 and every two cycles thereafter (i.e., Cycle 4, Day 1; Cycle 6, Day 1; Cycle 8, Day 1; etc.).  Tests may be performed 
96 hours before Day 1. 
q Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood).
r
If archival tissue is unavailable or is determined to be unsuitable for required testing, a pretreatment tumor biopsy is required.  A pretreatment 
tumor biopsy may also be performed if a patient's archival tissue test results do not meet eligibility criteria.  Refer to Section 4.5.6.2 for tissue 


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Schedule of Activities (cont.)
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sample requirements.
s
MOXR0916 will be administered prior to atezolizumab. The initial dose of MOXR0916 will be delivered over 60 (15) minutes.  Subsequent 
infusions will be delivered over 30 (10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 
60 (15) minutes if the patient experienced an infusion-associated adverse event with the previous infusion. Similarly, the initial dose of 
atezolizumab will be delivered over 60 (15) minutes.  Subsequent infusions will be delivered over 30 (10) minutes if the previous infusion was 
tolerated without infusion-associated adverse events, or 60 (15) minutes if the patient experienced an infusion-associated adverse event with 
the previous infusion. Dosing will occur only if the clinical assessment, local laboratory test results, and ECG if applicable, are acceptable.  If a 
tumor assessment was performed during the previous cycle, results must be reviewed by the investigator before dosing.


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Appendix 2
Modified Bajorin Risk Score
Risk factor
No visceral 
metastases
(0 points)
Bone and/or lung 
metastases (1 point)
Liver metastases
(2 points regardless of 
ECOG)
ECOG 0 or 1 
(0 points)
000
011
2
ECOG 2    
(1 point)
101
112
2
ECOGEastern Cooperative Oncology Group.


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Appendix 3
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1
TUMOR MEASURABILITY
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval 5 mm)

10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be 
15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters").
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 mm but 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
                                           
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made.


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disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone Lesions:

Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above.

Blastic bone lesions are non-measurable.
Cystic Lesions:

Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.

Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
Lesions with Prior Local Treatment:

Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are not considered measurable unless subsequent 
progression in the lesion has been demonstrated. 
METHODS FOR ASSESSING LESIONS
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.


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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option.
CLINICAL LESIONS
Clinical lesions will only be considered measurable when they are superficial and 
10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested.
CHEST X-RAY
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.
CT AND MRI SCANS
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is 5 mm.  When CT scans 
have slice thickness of 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of 
non-target disease or new lesions on a different modality, since the same lesion may 
appear to have a different size using a new modality.


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ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation.
ASSESSMENT OF TUMOR BURDEN
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions.  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis 10 mm 
but 15 mm) should be considered non-target lesions.  Nodes that have a short axis of 


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10 mm are considered non-pathological and should not be recorded or followed.
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases").
CALCULATION OF SUM OF DIAMETERS
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden.
Measuring Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to 10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, since a normal lymph node is defined as having a 
short axis of 10 mm.
Measuring Lesions That Become Too Small to Measure
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows:

If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 


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ticked).
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is 5 mm, and in that case "too small to measure" should 
not be ticked.
Measuring Lesions That Split or Coalesce on Treatment
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion.
EVALUATION OF NON-TARGET LESIONS
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to 10 mm in short axis.  Non-
target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis 10 mm), this should be captured on the eCRF as part of the assessment of non-
target lesions.
RESPONSE CRITERIA
CRITERIA FOR TARGET LESIONS
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below:

Complete response (CR):  Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis to 10 mm.

Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR

Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters on study (including 
baseline)
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of 5 mm.

Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD


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CRITERIA FOR NON-TARGET LESIONS
Definitions of the criteria used to determine the tumor response for the group of non-
target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedule of activities.

CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level
All lymph nodes must be non-pathological in size (10 mm short axis).

Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS
Patients with Measurable and Non-Measurable Disease
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare.
NEW LESIONS
The appearance of new malignant lesions denotes disease progression; therefore, some
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a
"new" cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.


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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan.
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline.
Table 1
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial 
response; SDstable disease.
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesions would not change the assigned timepoint response.  This would be most likely to 
happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm with 
three measured lesions and during the study only two lesions were assessed, but those 
gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 


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Response Evaluation Criteria in Solid Tumors, 
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SPECIAL NOTES ON RESPONSE ASSESSMENT
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847.


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Appendix 4
New York Heart Association Functional Classification
Class
Description
I
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on physical 
activity without discomfort.  Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present event at rest.  If any physical activity is 
undertaken, discomfort is increased.
Excerpted from Oxford Textbook of Medicine. Vol 2, p. 2228. Oxford Press 1997.


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


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