Clinical trial NCT02458638
Conditions: Tumors
Sponsor: Hoffmann-La Roche
Start date: 2015-07-16; Completion date: 2020-07-28
Enrollment: 474 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary efficacy objective for this study is to evaluate non-progression rate (NPR) at 18 weeks in participants with advanced solid tumors treated with atezolizumab, defined as the percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1, or according to disease-specific criteria for prostate cancer and malignant pleural mesothelioma.

Detailed description:

Arms: arm 1: The dose of atezolizumab in this study will be 1200 milligrams (mg) administered by intravenous (IV) infusion on Day 1 of each 3-week cycle until disease progression or unacceptable toxicity.
Interventions: intervention 1: Atezolizumab (MPDL3280A), an engineered anti-programmed death-ligand 1 (PD-L1) antibody
Intervention descriptions: intervention 1: Atezolizumab will be given as IV infusion over 60 minutes on Day 1 of Cycle 1, then over 30 minutes (as tolerated) on Day 1 of each subsequent 3-week cycle.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol MO29518, Version 8 
1 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, MULTICOHORT, PHASE II 
STUDY OF ATEZOLIZUMAB IN ADVANCED SOLID 
TUMORS 
PROTOCOL NUMBER: MO29518 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2015-000269-30 
NCT NUMBER: 
NCT02458638 
IND NUMBER: 
111271 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
Dr. 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 18-Jan-2015 
DATE AMENDED:  
Version 2: 20-May-2015 
Version 3: 29-Sep-2015 
Version 4: 19-Aug-2016 
Version 5: 19-Jun-2017 
Version 6: 01-Mar-2018 
Version 7: 29-Oct-2018 
Version 8: See electronic stamp below 
 
23-Oct-2019 14:11:35
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Atezolizumab—F. Hoffmann-La Roche Ltd 
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PROTOCOL AMENDMENT, VERSION 8: RATIONALE 
Specific changes in Version 8 of Protocol MO29518 and their rationale are as follows: 
• 
Appendix 8: updated to include the changes in the Atezolizumab Investigator’s 
Brochure version 15 (IB v15), including the guidelines for management of immune-
mediated myositis and for suspected hemophagocytic lymphohistiocytosis or 
macrophage activation syndrome, removed description and management guidelines for 
systemic immune activation, updated terminology changing "immune-related" to 
"immune-mediated" (and wherever applicable throughout the protocol). 
• 
Clarified provisions for post-trial access to atezolizumab to allow for continued 
treatment of patients following last patient last visit (LPLV), and regarding data 
collection during transition to the extension study. 
• 
Change in Medical Monitor and addition of NCT number. 
• 
Terminology update to align with recent changes in the atezolizumab IB v15 changed 
"immune-related" to "immune-mediated". 
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION 8: 
SUMMARY OF CHANGES 
 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately Reportable 
to the Sponsor) 
Update of Non-Serious Adverse Events of Special Interest (AESI) to align with 
Atezolizumab IB v15 and protocols across the Atezolizumab programme, adding AESIs 
identified more recently and minor terminology updates. 
5.1.4 
Management of Specific Adverse Events  
Removal of term, description and management guidelines for systemic immune 
activation (SIA), and addition of the terms hemophagocytic lymphohistiocytosis (HLH) 
and macrophage activation syndrome (MAS) as potential risks, together with diagnostic 
criteria and management guidelines for HLH and MAS. 
SIA was defined by the Sponsor internally as an excessive activation of the immune 
system in the setting of combined immunomodulatory therapies (immune-doublets) 
characterized as systemic inflammation with fever, elevated inflammatory markers and 
multiple organ dysfunction in the absence of other etiologies. It was considered a clinical 
entity separate from other similar systemic immune entities (HLH) and (MAS) etc. As of 
today, SIA remains a Roche specific term and is not widely used in the medical 
community. It is a potential risk for Atezolizumab. The event is not described in the 
literature, hence no common definition or established guidelines for SIA exist unlike 
other established entities [HLH, MAS, or cytokine release syndrome (CRS)]. Evolving 
knowledge of safety profile of checkpoint inhibitors and a recent review of reported SlA 
cases conducted by the Sponsor did not reveal any case that is clearly differentiated 
from other established entities in the spectrum of systemic immune events (e.g. HLH, 
MAS, CRS). The current guidance in the IB and protocols for Atezolizumab has led to 
cases being reported as SIA (single agent atezolizumab or in combinations) even though 
meeting the criteria of other immune entities such as HLH, MAS or CRS. The IB version 
15 and amendments of protocols and ICFs for Atezolizumab remove the term systemic 
immune activation (SIA), and add the terms HLH and MAS as potential risks, together 
with diagnostic criteria and management guidelines for HLH and MAS. 
5.1.4.1 Systemic Immune Activation 
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 given with other immunomodulating agents.  SIA should be included 
in the differential diagnosis for patients who, in the absence of an alternative etiology, 


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4 
develop a sepsis like syndrome after administration of Atezolizumab, and the initial 
evaluation should include the following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D dimer 
• 
Ferritin 
• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
If SIA is still suspected after the initial evaluation, contact the Medical Monitor for 
additional recommendations and management. 
 
5.3.4 
Post-Trial Access to Atezolizumab 
Added language to clarify provisions for post-trial access to atezolizumab to allow for 
continued treatment of patients following LPLV, and regarding data collection during 
transition to the extension study. 
 
Patients may also take part in an extension study if the patient is still benefiting from 
treatment (defined as no registered PD) at the time of planned Last Patient Last 
Visit date. If the extension study is not set-up in time for the patient to roll over by 
the planned protocol LPLV date, nor is there a Post-Trial Access Program available, 
the patient can continue treatment in the study until the extension study is opened at 
the patient’s site. During the interim period between LPLV and a patient rolling over 
to the extension study, only safety data (AE including SAE and AESI) will continue 
to be collected in the eCRF. Other assessments (e.g. tumor assessment) can be 
performed as per standard of care. 
 
 
APPENDIX 1: Schedule of Assessments 
Added footnote 24 to clarify assessments during transition to the extension study 
following LPLV. 
 
During the interim period between LPLV and a patient rolling over to the extension 
study, only safety data (AE including SAE and AESI) will continue to be collected in 
the eCRF. Other assessments (e.g. tumor assessment) can be performed as per 
standard of care. 
 
 
APPENDIX 2: Schedule of Anti-Therapeutic Antibody, Pharmacodynamic and 
Pharmacokinetic Assessments 
Addition to footnote 2 to clarify sample collection during transition to the extension study 
following LPLV. 
 


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For patients who discontinue the study treatment, ATA and PK samples are to be 
obtained at 120 days ± 30 days after the last dose of study treatment unless the 
patient dies or withdraws consent or the study closes (during the interim period 
between LPLV and a patient rolling over to the extension study, ATA and PK 
samples do not need to be collected).  
 
 
APPENDIX 8: Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
Added guidelines for management of immune-mediated myositis and for suspected 
hemophagocytic lymphohistiocytosis or macrophage activation syndrome (see rationale 
above), and updated terminology changing "immune-related" to "immune-mediated". 
 
IMMUNE-MEDIATED MYOSITIS 
Immune-mediated myositis has been associated with the administration of 
atezolizumab.  Myositis or inflammatory myopathies are a group of disorders 
sharing the common feature of inflammatory muscle injury; dermatomyositis and 
polymyositis are among the most common disorders. Initial diagnosis is based on 
clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), biochemical 
(serum creatine kinase increase), and imaging (electromyography/MRI) features, 
and is confirmed with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 13. 


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Table 13 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor.  


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


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


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


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 17 
PROTOCOL SYNOPSIS .................................................................................... 18 
1. 
BACKGROUND .......................................................................................... 36 
1.1 
Background on Advanced Solid Tumors................................ 36 
1.2 
Background on ATEZOLIZUMAB .......................................... 43 
1.2.1 
Nonclinical Studies ................................................................ 43 
1.2.2 
Ongoing Clinical Studies ........................................................ 43 
1.2.3 
Clinical Safety ........................................................................ 44 
1.2.4 
Clinical Activity ....................................................................... 45 
1.2.4.1 
Study PCD4989g ................................................................... 45 
1.2.4.2 
Study GP28328 ..................................................................... 48 
1.2.5 
Clinical Pharmacokinetics ...................................................... 49 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 49 
1.3.1 
Rationale ............................................................................... 49 
1.3.1.1 
Cervical Cancer ..................................................................... 51 
1.3.1.2 
Nasopharyngeal Carcinoma .................................................. 51 
1.3.1.3 
MSI-H or MMR-Deficient Colorectal Cancer .......................... 52 
1.3.1.4 
BRCA 1/2 Mutated Cancers .................................................. 52 
1.3.1.5 
Soft Tissue, Visceral and Bone Sarcomas ............................. 53 
1.3.1.6 
Mesothelioma ........................................................................ 54 
1.3.1.7 
Cholangiocarcinoma/Cancer of the Biliary Tract .................... 54 
1.3.1.8 
Thyroid Cancer ...................................................................... 55 
1.3.1.9 
Gastric Adenocarcinoma/Adenocarcinoma of the 
Gastro-Esophageal Junction ................................................. 56 
1.3.1.10 
Other Solid Tumors ............................................................... 57 
1.3.1.11 
Malignant Germ Cell Tumors ................................................. 57 
1.3.1.12 
ER+/HER2- Metastatic Breast Cancer with 
Known High Mutation Load (>100 mutations) by 
Local Test .............................................................................. 57 
1.3.1.13 
Thymoma and Thymic Cancer ............................................... 58 
1.3.1.14 
Gastroenteropancreatic (GEP) and Lung 
Neuroendocrine Tumors (NETs) ............................................ 58 


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1.3.1.15 
HPV Induced Squamous Cell Carcinomas .............................. 58 
1.3.1.16 
Known MSI High or MMR Deficient Tumors 
(excluding CRC and gastric cancers)....................................... 59 
1.3.2 
Benefit-Risk ............................................................................... 60 
2. 
OBJECTIVES ................................................................................................... 61 
2.1 
Efficacy Objectives .................................................................... 61 
2.2 
Safety Objectives ...................................................................... 62 
2.3 
Pharmacokinetic Objectives ..................................................... 62 
2.4 
Exploratory Objectives .............................................................. 62 
3. 
STUDY DESIGN .............................................................................................. 62 
3.1 
Description of Study .................................................................. 62 
3.2 
End of Study .............................................................................. 67 
3.3 
Rationale for Study Design ....................................................... 67 
3.3.1 
Rationale for Atezolizumab Dose and Schedule ..................... 67 
3.3.2 
Rationale for Patient Population and Analysis 
Groups ....................................................................................... 68 
3.3.3 
Rationale for Biomarker Assessments ..................................... 69 
3.4 
Outcome Measures ................................................................... 69 
3.4.1 
Efficacy Outcome Measures..................................................... 69 
3.4.2 
Safety Outcome Measures ....................................................... 71 
3.4.3 
Pharmacokinetic Outcome Measures ...................................... 71 
3.4.4 
Exploratory Outcome Measures ............................................... 71 
4. 
MATERIALS AND METHODS ........................................................................ 72 
4.1 
Patients ...................................................................................... 72 
4.1.1 
Inclusion Criteria........................................................................ 72 
4.1.2 
Exclusion Criteria ...................................................................... 74 
4.1.3 
Cohort Specifications ................................................................ 77 
4.2 
Method of Treatment Assignment and Blinding ...................... 81 
4.3 
Study Treatment ........................................................................ 81 
4.3.1 
Atezolizumab Formulation, Packaging, and 
Handling ..................................................................................... 81 
4.3.2 
Atezolizumab Dosage, Administration, and 
Compliance ................................................................................ 82 


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4.3.3 
Investigational Medicinal Product Accountability..................... 83 
4.3.4 
Post-Trial Access to Atezolizumab........................................... 83 
4.4 
Concomitant Therapy ................................................................ 84 
4.4.1 
Permitted Therapy ..................................................................... 84 
4.4.2 
Prohibited Therapy .................................................................... 85 
4.5 
Study Assessments................................................................... 86 
4.5.1 
Informed Consent Forms and Screening Log.......................... 86 
4.5.2 
Medical History, Disease History and 
Demographic Data .................................................................... 87 
4.5.3 
Physical Examinations .............................................................. 87 
4.5.4 
Vital Signs .................................................................................. 88 
4.5.5 
Tumor and Response Evaluations ........................................... 88 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples ..................................................................................... 89 
4.5.7 
Electrocardiograms ................................................................... 91 
4.5.8 
Samples for Roche Clinical Repository.................................... 91 
4.5.8.1 
Overview of the Roche Clinical Repository.............................. 91 
4.5.8.2 
Approval by the Institutional Review Board or 
Ethics Committee ...................................................................... 91 
4.5.8.3 
Sample Collection ..................................................................... 92 
4.5.8.4 
Confidentiality ............................................................................ 92 
4.5.8.5 
Consent to Participate in the Roche Clinical 
Repository.................................................................................. 93 
4.5.8.6 
Withdrawal from the Roche Clinical Repository ...................... 94 
4.5.8.7 
Monitoring and Oversight.......................................................... 94 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation .......................................................................... 94 
4.6.1 
Patient Discontinuation ............................................................. 94 
4.6.2 
Study Treatment Discontinuation ............................................. 95 
4.6.3 
Study and Site Discontinuation................................................. 96 
5. 
ASSESSMENT OF SAFETY........................................................................... 96 
5.1 
Safety Plan ................................................................................ 96 
5.1.1 
Risks Associated With Atezolizumab ....................................... 97 
5.1.2 
General Plan to Manage Safety Concerns .............................. 97 


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5.1.2.1 
Eligibility Criteria ........................................................................ 97 
5.1.2.2 
Monitoring .................................................................................. 97 
5.1.3 
Atezolizumab Dose Modification .............................................. 98 
5.1.4 
Management of Specific Adverse Events ................................ 98 
5.2 
Safety Parameters and Definitions........................................... 98 
5.2.1 
Adverse Events ......................................................................... 99 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .......................................................................... 99 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 100 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 101 
5.3.1 
Adverse Event Reporting Period ............................................ 101 
5.3.2 
Eliciting Adverse Event Information ....................................... 101 
5.3.3 
Assessment of Severity of Adverse Events ........................... 101 
5.3.4 
Assessment of Causality of Adverse Events ......................... 102 
5.3.5 
Procedures for Recording Adverse Events............................ 103 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 103 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events ...................................................................................... 103 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 104 
5.3.5.4 
Abnormal Laboratory Values .................................................. 104 
5.3.5.5 
Abnormal Vital Sign Values .................................................... 105 
5.3.5.6 
Abnormal Liver Function Tests ............................................... 105 
5.3.5.7 
Deaths...................................................................................... 106 
5.3.5.8 
Preexisting Medical Conditions .............................................. 106 
5.3.5.9 
Lack of Efficacy or Worsening of the Advanced 
Solid Tumors Included in This Study...................................... 107 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ......................... 107 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................... 107 
5.3.5.12 
Adverse Events in Individuals Not Enrolled in the 
Study ........................................................................................ 108 
5.3.5.13 
Infusion related reactions........................................................ 108 


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5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................... 108 
5.4.1 
Emergency Medical Contacts ................................................. 109 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ........................................................................ 109 
5.4.2.1 
Events That Occur Prior to Study Drug Initiation................... 109 
5.4.2.2 
Events That Occur After Study Drug Initiation ....................... 109 
5.4.3 
Reporting Requirements for Pregnancies.............................. 109 
5.4.3.1 
Pregnancies in Female Patients............................................. 109 
5.4.3.2 
Abortions .................................................................................. 110 
5.4.3.3 
Congenital Anomalies/Birth Defects....................................... 110 
5.5 
Follow-Up of Patients after Adverse Events .......................... 110 
5.5.1 
Investigator Follow-Up ............................................................ 110 
5.5.2 
Sponsor Follow-Up.................................................................. 111 
5.6 
Post-Study Adverse Events .................................................... 111 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees .................................................................. 111 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ...................... 112 
6.1 
Determination of Sample Size ................................................ 112 
6.2 
Stopping Rules for Each Cohort ............................................. 114 
6.2.1 
Rules for Stage I...................................................................... 114 
6.2.2 
Rules for Stage II..................................................................... 115 
6.3 
Summaries of Conduct of Study............................................. 115 
6.4 
Summaries of Treatment Group Comparability ..................... 115 
6.5 
Efficacy Analyses .................................................................... 115 
6.5.1 
Primary Efficacy Endpoint....................................................... 115 
6.5.2 
Secondary Efficacy Endpoints ................................................ 116 
6.6 
Safety Analyses....................................................................... 116 
6.7 
Pharmacokinetic Analyses...................................................... 117 
6.8 
Exploratory Analyses .............................................................. 117 
6.9 
Interim Analyses ...................................................................... 117 
7. 
DATA COLLECTION AND MANAGEMENT ................................................ 117 


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7.1 
Data Quality Assurance .......................................................... 117 
7.2 
Electronic Case Report Forms ............................................... 118 
7.3 
Source Data Documentation................................................... 118 
7.4 
Use of Computerized Systems ............................................... 119 
7.5 
Retention of Records .............................................................. 119 
8. 
ETHICAL CONSIDERATIONS ..................................................................... 119 
8.1 
Compliance with Laws and Regulations ................................ 119 
8.2 
Informed Consent .................................................................... 120 
8.3 
Institutional Review Board or Ethics Committee ................... 121 
8.4 
Confidentiality .......................................................................... 121 
8.5 
Financial Disclosure ................................................................ 122 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ........................................................................................ 122 
9.1 
Study Documentation .............................................................. 122 
9.2 
Protocol Deviations ................................................................. 122 
9.3 
Site Inspections ....................................................................... 122 
9.4 
Administrative Structure .......................................................... 122 
9.5 
Publication of Data and Protection of Trade 
Secrets ..................................................................................... 123 
9.6 
Protocol Amendments............................................................. 123 
10. REFERENCES .............................................................................................. 125 
APPENDICES........................................................................................................ 134 


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LIST OF TABLES 
Table 1. 
Summary of the Advanced Solid Tumors Examined in This 
Study .................................................................................................. 36 
Table 2. 
Efficacy-Evaluable NSCLC Patients in Study PCD4989g: ORR 
by Tumor PD-L1 Expression and Objective Response Rate 
(per RECIST, Version 1.1)................................................................ 46 
Table 3. 
Efficacy-Evaluable UBC Patients in Study PCD4989g: ORR 
per RECIST v1.1 According to PD-L1 Tumor Expression .............. 47 
Table 4. 
Efficacy-Evaluable RCC Patients in Study PCD4989g: ORR 
per MSKCC Risk Stratification and PD-L1 Tumor Expression ....... 48 
Table 5. 
Efficacy-Evaluable RCC and CRC Patients in Study GP28328: 
Summary of Responses ................................................................... 49 
Table 6. 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE .................................................. 102 
 
LIST OF FIGURES 
Figure 1. 
Study Schema ................................................................................... 63 
Figure 2. 
Sample Size for Each Cohort in Stage I/II ..................................... 114 
 
 
LIST OF APPENDICES 
Appendix 1  Schedule of Assessments .............................................................. 135 
Appendix 2 Schedule of Anti-Therapeutic Antibody,  Pharmacodynamic 
and Pharmacokinetic Assessments ............................................... 142 
Appendix 3 Modified Response Evaluation Criteria in Solid Tumors .............. 143 
Appendix 4 Anaphylaxis Precautions ................................................................ 150 
Appendix 5 Preexisting Autoimmune Diseases ................................................ 151 
Appendix 6 Prostate Response Evaluation Criteria .......................................... 153 
Appendix 7 Malignant Pleural Mesothelioma Response Evaluation Criteria .. 154 
Appendix 8 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab ................................................................................... 156 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
AN OPEN-LABEL, MULTICOHORT, PHASE II 
STUDY OF ATEZOLIZUMAB IN ADVANCED SOLID 
TUMORS 
PROTOCOL NUMBER: MO29518 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2015-000269-30 
NCT NUMBER: 
NCT02458638 
IND NUMBER: 
111271 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
 
 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form to the Sponsor or their designee. Contact 
details will be provided to the investigator prior to the study start. Please retain a copy for 
your study files. 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN-LABEL, MULTICOHORT, PHASE II STUDY OF 
ATEZOLIZUMAB IN ADVANCED SOLID TUMORS 
PROTOCOL NUMBER: 
MO29518 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2015-000269-30 
NCT NUMBER: 
NCT02458638 
IND NUMBER: 
111271 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
II 
INDICATION: 
Advanced solid tumors 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective for this study is as follows: 
• 
To evaluate non-progression rate (NPR) at 18 weeks in patients with advanced solid tumors 
treated with Atezolizumab, defined as the percentage of patients with complete response 
(CR) partial response (PR) or stable disease (SD) as assessed by the Investigator 
according to Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST, v1.1) 
(except for prostate cancer and malignant pleural mesothelioma) and disease-specific 
criteria for patients with prostate cancer (see Appendix 6) and malignant pleural 
mesothelioma (see Appendix 7) 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate NPR at 24 weeks, overall response rate (ORR), best overall response (BOR), 
clinical benefit rate (CBR), duration of response (DOR), time to tumor progression (TTP) 
and progression-free survival (PFS), as assessed by the Investigator using RECIST, v1.1 
(except for prostate cancer and malignant pleural mesothelioma) and disease-specific 
criteria for patients with prostate cancer (see Appendix 6) and malignant pleural 
mesothelioma (see Appendix 7) 
• 
To evaluate NPR at 18 and 24 weeks, ORR, BOR, CBR, DOR, TTP and PFS, as assessed 
by the Investigator using modified RECIST (Appendix 3)  
• 
To evaluate overall survival (OS) 
 
Safety Objectives 
The safety objectives for this study are as follows: 
• 
To evaluate the safety and tolerability of Atezolizumab in patients with advanced solid 
tumors 
• 
To characterize the immunogenic potential of Atezolizumab by measuring anti-
Atezolizumab antibodies and to explore the potential relationship of the immunogenicity 
response with safety and efficacy 
 


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Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
• 
To characterize the pharmacokinetics of Atezolizumab 
 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the relationship between tumor tissue PD-L1 expression and measures of 
efficacy, including NPR at 18 weeks and 24 weeks, ORR, BOR, CBR, DOR, TTP, PFS and 
OS 
• 
To assess predictive and prognostic exploratory biomarkers (e.g. but not limited to protein 
and genetic markers on DNA and RNA) in archival and/or fresh tumor tissue and plasma 
and their association with disease status and/or response to study treatment 
• 
To evaluate exploratory pharmacodynamic (PD) biomarkers (e.g., genetic markers, T, B 
and NK cell enumeration, T cell subpopulations like CD8+ T, effector/memory T cells, 
regulatory T cells, changes in expression of CD25 or human leukocyte antigen-DR [HLA-
DR], interferon [IFN]-gamma production, IL-2 and other exploratory biomarkers) in tumor 
tissue, tumor microenvironment and plasma and their association with disease status, 
and/or response to study treatment, tumor immunobiology or tumor type 
 
Study Design 
Description of Study 
This will be an open-label, multicenter, multinational, multicohort, phase II study. For each 
cohort, the study will consist of a Screening Period (Day –35 to −1), a Treatment Period, a 
Treatment Discontinuation Visit occurring ≤ 30 days after the last dose of study medication and 
a 24-month Survival Follow-up Period (Figure 1).  Day 1 (baseline) will be defined as the first 
day a patient receives study medication. 
 




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The study will include 16 cohorts of patients with the following solid cancers: 
1. Cervical cancer 
2. Nasopharyngeal carcinoma 
3. Known high microsatellite instability (MSI-H) or mismatch repair (MMR) deficient colorectal 
cancer 
4. Known BRCA 1/2 mutated cancers 
a. BRCA mutated ovarian cancer 
b. BRCA mutated breast cancers  
5. Soft tissue, visceral and bone sarcomas  
a. Liposarcoma 
b. Leiomyosarcoma 
c. Gastrointestinal stromal tumor (GIST) 
d. Undifferentiated pleomorphic sarcoma  
e. Known translocation-related sarcomas 
f. 
 Radiation induced sarcoma 
g. Osteosarcoma 
h. Chondrosarcoma 
6. Mesothelioma 
a. Pleural mesothelioma 
b. Peritoneal mesothelioma 
7. Cholangiocarcinoma/cancer of the biliary tract 
8. Thyroid cancer 
a. Anaplastic thyroid cancer 
b. Follicular or papillary thyroid cancer 
c. Medullary thyroid cancer and mixed medullary and follicular or papillary thyroid 
cancer 
9. Gastric adenocarcinoma/adenocarcinoma of the gastro-esophageal junction 
10. Other solid tumors – closed to recruitment from Protocol Version 4 onwards.  
11. Malignant germ cell tumors 
12. ER+/HER2- metastatic breast cancer with known high mutation load (>100 mutations) by 
local test 
13. Thymoma and thymic cancer 
a. Thymoma 
b. Thymic cancer 
14. Gastroenteropancreatic (GEP) and lung neuroendocrine tumors (NETs) 
a. Low and intermediate grades - (typical or atypical carcinoid) 
b. Poorly differentiated grade (excluding SCLC) 
15. Known HPV induced squamous cell carcinomas 
a. Head and neck  
b. Penile cancer 
c. Vaginal cancer / vulvar cancer 
d. Anal cancer 
16. Known MSI-H or MMR deficient tumors (excluding colorectal and gastric cancers) 
 
In addition, only patients whose tissue is available for biomarker assessment testing will be 
eligible.   
Enrolled patients will receive Atezolizumab at a fixed dose of 1200 mg administered 
intravenously on the first day of each cycle.  One cycle of therapy will be defined as 21 days 


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(± 3 days).  Patients treated with Atezolizumab who have no post-baseline tumor assessment 
(per protocol mandated timelines), and enrolled patients who do not receive any dose of 
Atezolizumab will be replaced.   
Atezolizumab treatment may be continued as long as patients are experiencing clinical benefit, 
as assessed by an investigator, in the absence of unacceptable toxicity or symptomatic 
deterioration attributed to disease progression after an integrated assessment of radiographic 
data, biopsy results (if available) and clinical status. 
Patients will be permitted to continue Atezolizumab treatment after RECIST v1.1 criteria (or 
disease-specific criteria for patients with prostate cancer [Appendix 6] and malignant pleural 
mesothelioma [Appendix 7]) for progressive disease are met if they meet all of the following 
criteria:  
• 
Evidence of clinical benefit as assessed by the Investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g., new or 
worsening hypercalcemia) indicating unequivocal progression of disease  
• 
No decline in ECOG performance status that can be attributed to disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that 
cannot be managed by protocol-allowed medical interventions 
 
Patients treated with Atezolizumab in whom radiographic disease progression is confirmed at a 
subsequent tumor assessment may be considered for continued study treatment at the 
discretion of the Investigator if they continue to meet the above criteria. 
If an individual patient continues to experience clinical benefit beyond 2 years of radiologic 
progressive disease, it lies within the discretion of each investigator to continue study treatment 
based on a positive risk benefit assessment by the investigator. 
The primary objective of this study is to evaluate Investigator-determined non-progression rate 
(NPR) at 18 weeks in the individual cohorts using RECIST, v1.1 (except for prostate cancer and 
malignant pleural mesothelioma) and disease-specific criteria for patients with prostate cancer 
(see Appendix 6) and malignant pleural mesothelioma (see Appendix 7).  Secondary efficacy 
variables (including ORR, BOR, CBR, DOR, TTP and PFS) will be recorded using RECIST, 
v1.1, (except for prostate cancer and malignant pleural mesothelioma) and disease-specific 
criteria for patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma 
(see Appendix 7), and modified RECIST (see Appendix 3)  
Safety will be monitored by assessing AEs, serious AEs (SAEs), AEs of special 
interest (AESIs), laboratory findings and electrocardiogram.  The National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE, v4.0) will be used 
to quantify the intensity of AEs occurring during treatment.  Incidence, type and severity of AEs, 
SAEs, incidence of AEs and SAEs leading to Atezolizumab interruption or discontinuation and 
cause of death will be reported.  In addition, to characterize the immunogenic potential and the 
pharmacokinetic properties of Atezolizumab, blood samples will be taken at various time points 
before and after study treatment administration (see Appendix 2 for a detailed description of the 
assessments). 
This study will also have an exploratory analysis examining biomarkers. These analyses will be 
conducted on archival tissue specimens (required for patient inclusion), as well as 
prospectively-collected plasma/blood samples and freshly obtained tumor specimens.  
Collected samples will be analyzed at a central laboratory for PD-L1 expression, as well as 
other potential markers (e.g. but not limited to protein or genetic markers), to assess 
relationships between biomarker expression and patient outcomes including, but not limited to, 
response and disease progression.  
All patients will be monitored for survival for a minimum period of 24 months after the last 
patient has been enrolled in each cohort or until all patients have died, withdrawn consent or are 
lost to follow up, or the Sponsor decides to end the study, whichever occurs first.  Survival 
follow-up information will be collected via clinic visits, telephone calls and/or review of patient 
medical records approximately every 3 months from study treatment discontinuation until patient 
death, loss to follow-up, withdrawal of consent or until the study is terminated by the Sponsor.  
Patients who discontinue study treatment for reasons other than disease progression (e.g., 
toxicity) should continue to undergo scheduled tumor assessments approximately every 3 


Atezolizumab—F. Hoffmann-La Roche Ltd 
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months until death, disease progression, initiation of further systemic cancer therapy or study 
closure, whichever occurs first. 
Enrollment in this study will be based on Simon's optimal two-stage design (Simon 1989).  
Accordingly, 12 fully-evaluable patients will be enrolled in each cohort in the first stage.  If 3 or 
more of these patients exhibit non-progressive disease at the end of Stage I, then an additional 
13 fully-evaluable patients will be enrolled in Stage II.  Thus, approximately 725 patients are 
expected to participate in the study. However, if positive efficacy signals are observed in any of 
the other cohorts that include different tumor types or in a specific subgroup of patients within 
other cohorts (e.g. biomarker positive subgroup), the Sponsor in discussion with the Steering 
Committee may decide to extend the enrolment of the individual tumor type or subgroup of 
patients based on methodology explained in the Determination of Sample Size (Section 6.1).  
 
Please refer to the Schedule of Assessments (Appendix 1) for a detailed description of the 
assessments to be carried out in this study. 
 
Number of Patients 
Based on Simon’s optimal two-stage design (Simon 1989), approximately 12 to 25 fully 
evaluable patients per individual tumor type will be included.  
Allowing for expansion of cohorts into further sub-cohorts of individual tumor types and possible 
further expansion into subgroups of responders, the projected total number of patients enrolled 
in this study is approximately 725. However, cohorts may be expanded under certain conditions 
(see Section 6.1).  
 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1.  
Signed Informed Consent Form 
2.  
Ability to comply with protocol 
3.  
Male or female, 18 years of age or older 
4. Histologically documented solid tumors that are advanced (i.e. Stages III and IV disease) 
and 
− meet one of the cohort specifications in Section 4.1.3 
− have progressive disease at study entry 
− have received at least one line of prior systemic therapy or for which alternative therapy 
does not exist which is known to prolong survival  
5. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin 
blocks (preferred) or, in exceptional cases, 15 freshly cut and unstained slides, with an 
associated pathology report (in local language), for central testing. Detection of tumor in the 
provided block (or slide) needs to be confirmed by the central pathology laboratory prior to 
study enrollment. 
− Only tissue from core needle, punch or excisional biopsy sample collection will be 
accepted.  For core-needle biopsy specimens, at least three cores should be submitted 
for evaluation.  Fine-needle aspiration, brushing, bone tissue, and lavage samples are 
not acceptable 
− Patients who do not have tissue specimens meeting eligibility requirements must 
undergo a biopsy during the screening period.  Acceptable samples include core needle 
biopsies for deep tumor tissue (minimum three cores) or excisional, incisional, punch, or 
forceps biopsies for cutaneous, subcutaneous, or mucosal lesions 
6. Measurable disease as defined by RECIST, v1.1. (except for prostate cancer and malignant 
pleural mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7) 
7. ECOG Performance Status of 0 or 1 


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8. Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 3 days prior to the first study treatment (Cycle 1, Day 1): 
− Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without granulocyte colony-stimulating 
factor support within 2 weeks before Cycle 1, Day 1) 
− Lymphocyte count ≥ 500/µL 
− White blood cell counts > 2500/μL 
− Platelet count ≥ 100,000/µL (without transfusion within 2 weeks before Cycle 1, Day 1) 
− Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment 
to meet this criterion) 
− Serum bilirubin < 1.5 × upper limit of normal (ULN), with the following exception: 
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may 
be enrolled 
− Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline 
phosphatase ≤ 2.5 × ULN, with the following exceptions: 
Patients with liver involvement: AST and/or ALT ≤ 5 × ULN 
Patients with liver or bone metastases: alkaline phosphatase ≤ 5 × ULN 
− Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the 
Cockcroft-Gault glomerular filtration rate estimation: (140 − age) × (weight in kg) × (0.85 
if female)/72 × (serum creatinine in mg/dL) 
− International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
≤ 1.5 × ULN.  This applies only to patients who do not receive therapeutic 
anticoagulation; patients receiving therapeutic anticoagulation (such as low−molecular 
weight heparin or warfarin) should be on a stable dose 
− Serum albumin level > 3.2 g/dL 
9. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug 
10. For female patients of childbearing potential, agreement (by patient) to use a highly 
effective form(s) of contraception that results in a low failure rate (< 1% per year) when 
used consistently and correctly, and to continue its use for 5 months after the last dose of 
Atezolizumab.  Such methods include: combined (estrogen and progestogen containing) 
hormonal contraception, progestogen-only hormonal contraception associated with 
inhibition of ovulation together with another additional barrier method always containing a 
spermicide, intrauterine device (IUD): intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion, vasectomized partner (on the understanding that this is the only one 
partner during the whole study duration), and sexual abstinence. Oral contraception should 
always be combined with an additional contraceptive method because of a potential 
interaction with the study drug. 
11. Life expectancy > 3 months. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Malignancies other than disease under study within 5 years prior to Cycle 1 Day 1, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 5-year 
OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma 
in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated 
surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent) 
2. Uncontrolled tumor-related pain 
− Patients requiring pain medication must be on a stable regimen at study entry 
− Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to enrollment 


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− Asymptomatic metastatic lesions whose further growth would likely cause functional 
deficits or intractable pain (e.g., epidural metastasis that is not presently associated with 
spinal cord compression) should be considered for loco-regional therapy if appropriate 
prior to enrollment 
3. 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 
4. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected 
serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of 
bisphosphonate therapy or denosumab 
− Patients who are receiving bisphosphonate therapy or denosumab specifically to 
prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible 
− Patients who are receiving denosumab prior to enrollment must be willing and eligible to 
receive a bisphosphonate instead while on study 
5. History of treated asymptomatic or symptomatic CNS metastasis or presence of CNS 
metastases as determined by CT scan or MRI evaluation during screening or at prior 
radiographic assessments. 
6. Leptomeningeal disease 
7. Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for ≥ 2 weeks prior to Cycle 1, Day 1 
8. Any approved anticancer therapy, including chemotherapy, hormonal therapy or 
radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are 
allowed: 
− Hormone-replacement therapy or oral contraceptives 
− Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1 
9. Acute toxicities from previous therapy that have not resolved to Grade ≤ 1, except for 
alopecia 
10. Pregnant and lactating women 
11. Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome) 
12. Significant cardiovascular disease, such as New York Heart Association cardiac disease 
(Class II or greater), myocardial infarction within 3 months prior to Cycle 1, Day 1, unstable 
arrhythmias or unstable angina 
− Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded 
− Patients with known coronary artery disease, congestive heart failure not meeting the 
above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in 
the opinion of the treating physician, in consultation with a cardiologist if appropriate 
13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia or severe pneumonia 
14. Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 
− Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease) are eligible 
15. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a 
major surgical procedure during the course of the study 
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster 
ovary cells or to any component of the Atezolizumab formulation 


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18. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple 
sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a more comprehensive list of 
autoimmune diseases) 
− Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible 
− Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible  
− Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
o 
Rash must cover less than 10% of body surface area (BSA). 
o 
Disease is well controlled at baseline and only requiring low potency topical 
steroids. 
o 
No acute exacerbations of underlying condition within the previous 12 
months (not requiring PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids) 
19. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
20. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or 
evidence of active pneumonitis on screening chest CT scan 
− History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
21. Any other diseases, metabolic dysfunction, physical examination finding or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the patient at high risk from treatment complication 
22. Positive test for HIV 
23. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) or hepatitis C 
− Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as 
having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-
HBc] antibody test) are eligible 
− Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA 
24. Active tuberculosis 
25. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
26. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study.  
− Influenza vaccination should be given during influenza season only (example: 
approximately October to March in the Northern Hemisphere).  Patients must not 
receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to 
Cycle 1, Day 1 or at any time during the study treatment or within 5 months after the last 
dose of atezolizumab 
27. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD1, 
or anti− PD-L1 therapeutic antibodies 
- 
Patients who have received prior treatment with anti−CTLA-4 may be enrolled, provided 
at least 5 half-lives (approximately 75 days) have elapsed from the last dose of anti-
CTLA-4 to the first dose of Atezolizumab and there was no history of severe immune-
mediated adverse effects from anti−CTLA-4 (NCI CTCAE Grade 3 and 4) 


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28. Treatment with systemic immunostimulatory agents (including but not limited to interferon-
alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever 
is shorter) prior to Cycle 1, Day 1 
29. Treatment with an investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five 
half-lives of the investigational product, whichever is longer) 
30. Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti−tumor necrosis factor [TNF] agents) within 2 weeks 
prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive 
medications during the trial 
− Patients who have received acute, low-dose, systemic immunosuppressant medications 
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study  
− The use of inhaled corticosteroids for chronic obstructive pulmonary disease, 
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, low-
dose supplemental corticosteroids for adrenocortical insufficiency and topical steroids 
for cutaneous diseases are allowed 
 
Length of Study 
The study is expected to last approximately 5 years. 
 
End of Study 
The end of cohort will occur when all patients have been followed for survival for a minimum of 
24 months after the last patient has been enrolled in the cohort or until all patients have died, 
withdrawn consent or are lost to follow up, or the Sponsor decides to end the study, whichever 
occurs first.  
Recruitment/enrollment in any of the cohorts may present some challenges.  Therefore, a 
permanent stop rule may be applied if the recruitment rate is too low after any of the individual 
cohorts have been completely enrolled, which could result in stopping further enrolment in some 
of the remaining cohorts (Section 4.6.3), based on regular review of the recruitment rate After a 
cohort has been opened for at least 4 months, it may be closed early if the recruitment is less 
than 2 patients per month on average from the opening of the cohort. This decision will be made 
by the Sponsor. The overall end of study will occur when the end of cohort has occurred for all 
of the individual cohorts, as described above. 
 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
Non progression rate (NPR) at 18 weeks is defined as the percentage of patients with CR, 
PR or SD at 18 weeks, as determined by the Investigator using RECIST, v1.1 (except for 
prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for 
patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7).  Patients treated with Atezolizumab who have no post-baseline tumor 
assessment (per protocol mandated timelines), and enrolled patients who do not receive 
any dose of Atezolizumab will be replaced 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
Non progression rate (NPR) at 24 weeks is defined as the percentage of patients with CR, 
PR or SD at 24 weeks, as determined by the Investigator using RECIST, v1.1 (except for 
prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for 
patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7).  Patients treated with Atezolizumab who have no post-baseline tumor 
assessment (per protocol mandated timelines), and enrolled patients who do not receive 
any dose of Atezolizumab will be replaced 


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• 
Overall response rate (ORR) is defined as the proportion of patients with a CR or PR, as 
assessed by the Investigator using RECIST v1.1 (except for prostate cancer and malignant 
pleural mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7) 
• 
Best overall response (BOR) is defined as the proportion of patients with the best response 
obtained throughout the trial, as determined by the Investigator using RECIST v1.1 (except 
for prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for 
patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7) 
• 
Clinical benefit rate (CBR) is defined as the proportion of patients whose BOR, as 
determined by the Investigator using RECIST, v1.1 (except for prostate cancer and 
malignant pleural mesothelioma) and disease-specific criteria for patients with prostate 
cancer (see Appendix 6) and malignant pleural mesothelioma (see Appendix 7), is either 
CR, PR or SD lasting for at least 6 weeks 
• 
Duration of objective response (DOR) is defined as the time from the first occurrence of a 
documented objective response to the time of progression, as determined by the by the 
Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural 
mesothelioma) and disease-specific criteria for patients with prostate cancer (see Appendix 
6) and malignant pleural mesothelioma (see Appendix 7), or death from any cause, 
whichever occurs first.  For patients who do not die or experience disease progression 
before the end of the study or who are lost to follow-up, duration of objective response will 
be censored at the day of the last tumor assessment 
• 
Progression-free survival (PFS) is defined as the time from the first day of study treatment 
to the first occurrence of disease progression, as determined by the Investigator using 
RECIST, v1.1 (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Appendix 6) and malignant 
pleural mesothelioma (see Appendix 7), or death from any cause, whichever occurs first.  A 
patient without a PFS event will be censored at the time of the last evaluable tumor 
assessment. Patients with no tumor assessment after the baseline visit will be censored at 
the time of the first day of study treatment plus 1 day 
• 
Time to progression (TTP) is defined as time from the first day of study treatment to the first 
occurrence of progressive disease, as determined by the Investigator using RECIST, v1.1 
(except for prostate cancer and malignant pleural mesothelioma) and disease-specific 
criteria for patients with prostate cancer (see Appendix 6) and malignant pleural 
mesothelioma (see Appendix 7), or death due to reason of disease progression, whichever 
occurs first. Patients who have not progressed or died due to disease progression at the 
time of study completion or who are lost to follow-up will be censored at the date of the last 
evaluable tumor assessment. Patients with no tumor assessment after the baseline visit will 
be censored at the time of the first day of study treatment plus 1 day 
• 
Overall survival (OS) is defined as the time from the first day of study treatment to death 
from any cause. Patients for whom no death is captured on the clinical database will be 
censored at the most recent date they were known to be alive 
 
NPR at 18 and 24 weeks, ORR, BOR, CBR, PFS and TTP will also be determined by the by the 
Investigator using modified RECIST (see Appendix 3). 
 
Safety Outcome Measures 
The safety and tolerability of Atezolizumab will be assessed using the following safety outcome 
measures: 
• 
Incidence, nature, and severity of adverse events graded according to the NCI 
CTCAE, v4.0 
• 
Number of cycles and dose intensity 
• 
Incidence of anti-Atezolizumab antibodies and the potential correlation with 
pharmacokinetics and safety parameters 
 


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Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Maximum serum Atezolizumab concentration (Cmax) after infusion on Day 1 of Cycle 1 
• 
Minimum serum Atezolizumab concentration (Cmin) prior to infusion on Day 1 of Cycles 1, 2, 
3, 4, 8 and every eight cycles thereafter and at study termination 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Status of PD-L1 expression and other exploratory biomarkers (e.g. but not limited to protein 
and genetic markers)  in archival and/or freshly obtained tumor tissues and plasma  
collected pre-treatment and during treatment with Atezolizumab 
• 
Association of PD-L1 expression and other exploratory biomarkers (e.g. but not limited to 
protein and genetic markers) with disease status and/or response or resistance to 
Atezolizumab 
• 
Status of exploratory biomarkers in plasma (including but not limited to genetic markers and 
cytokines such as IFN-gamma) collected pre-treatment and during treatment/at 
progression/study discontinuation with Atezolizumab 
• 
Association of exploratory biomarkers in plasma with disease status and/or response or 
resistance to Atezolizumab, tumor immunobiology or tumor type 
 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The dose of Atezolizumab in this study will be 1200 mg (equivalent to an average body weight-
based dose of 15 mg/kg) administered by intravenous infusion every 3 weeks (21 [± 3] days). 
Administration of Atezolizumab will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
Atezolizumab will be delivered in 250 mL 0.9% NaCl IV infusion bags with product contacting 
surfaces of polyvinyl chloride (PVC) or polyolefin (PO) and IV infusion lines with product 
contacting surfaces of PVC or polyethylene (PE) and 0.2 µm in-line filters (filter membrane of 
polyethersulfone [PES]).  No incompatibilities have been observed between Atezolizumab and 
these infusion materials (bags and infusion lines).  
The initial dose of Atezolizumab will be delivered over 60 (± 15) minutes.  If the first infusion is 
tolerated without infusion-associated adverse events, the second infusion may be delivered 
over 30 (± 10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may 
be delivered over 30 (± 10) minutes. 
For first infusion of study treatment, the patient’s vital signs must be determined within 
60 minutes before the infusion; during, and after the infusion if clinically indicated.  For 
subsequent infusions, vital signs will be collected within 60 minutes before infusion and at the 
end of the infusion, if clinically indicated. 
Patients will be informed about the possibility of delayed post-infusion symptoms and instructed 
to contact their study physician if they develop such symptoms. 
No premedication will be allowed for the first dose of Atezolizumab. Premedication may be 
administered for Cycles ≥ 2 at the discretion of the treating physician.  The management of 
infusion-related reactions will be according to severity as described in section 5.1.4. 
 
For anaphylaxis precautions, see Appendix 4. 
Guidelines for dosage modification, treatment interruption or discontinuation and the 
management of specific adverse events are provided in Sections 5.1.3 and in the Atezolizumab 
Investigator’s Brochure. 
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  AEs associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 


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Please refer to the Pharmacy Manual for detailed instructions on drug preparation, storage and 
administration. 
 
Comparator 
Not applicable 
 
Non-Investigational Medicinal Products 
Not applicable 
 
Statistical Methods 
Primary Analysis 
The primary analysis will be based on NPR at 18 Weeks for each cohort, as assessed by the 
Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural 
mesothelioma) and disease-specific criteria for patients with prostate cancer (see Appendix 6) 
and malignant pleural mesothelioma (see Appendix 7).  This endpoint will be assessed at Stage 
I and Stage II.  
At the conclusion of this study, Atezolizumab will be declared effective or ineffective for each 
cohort based on rules for Stage II.  
The final analysis for each cohort will take place when all patients in that cohort have been 
followed for survival for a minimum of 24 months after the last patient has been enrolled or until 
all patients have died, withdrawn consent or are lost to follow up, or if the cohort is stopped due 
to safety or efficacy reasons or the Sponsor decides to end the cohort, whichever occurs first. 
Hypothesis Testing 
A Simon optimal two-stage design will be used to test whether Atezolizumab yields a NPR that 
is of clinical interest.  In this Phase II study, an NPR of 20% is a level of activity that is not of 
interest for further clinical development, whereas an NPR of 40% is of clinical interest.  
The study hypotheses are: 
• 
H0: π  ≤ π0 
• 
H1: π > π1 
 
Where π0 = 20% and the assumed NPR under the alternative is π1 = 40%. 
The type I error will be 10% and the study will have 80% power to reject the null hypothesis 
when the true NPR is 40%. 
The hypothesis and clinical assumptions will be applied to all cohorts separately.  
 
Determination of Sample Size   
The sample size for this phase II study is based on Simon’s optimal two-stage design (Simon 
1989). 
In this Phase II study, an NPR of 20% is a level of activity that is not of interest for further 
clinical development, whereas an NPR of 40% is of clinical interest.  The type I error will be 10% 
and the study will have 80% power to reject the null hypothesis when the true NPR is 40%. 
The Simon design in this study requires 12 fully evaluable patients for the first stage.  If at the 
end of the first stage there are 0, 1 or 2 patients with non-progressive disease at Week 18, the 
enrollment into this cohort will be terminated (or the cohort may be expanded as described 
below).  Otherwise, if more than 2 patients with non-progressive disease are observed at the 
end of Stage I, an additional 13 fully-evaluable patients may be enrolled into Stage II.  The 
study drug will be considered of clinical interest in this cohort if, at the end of the second stage, 
there are 8 or more patients with non-progressive disease out of 25 total fully-evaluable patients.  
It can be assumed that some patients will not be evaluable for NPR.  A patient will be 
considered evaluable for NPR if they received study drug, have a baseline tumor assessment 
and at least one tumor assessment post-baseline- (per protocol mandated timelines).  Thus, 


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more than 25 patients may be needed to be enrolled per cohort to obtain 25 fully-evaluable 
patients. 
The hypotheses and clinical assumptions will be applied to all cohorts individually.  
Statistical analyses will be based on patients with the same individual tumor type and may be 
based on pre-defined cohorts or on sub-cohorts. 
Allowing for expansion of cohorts into further sub-cohorts of individual tumor types and possible 
further expansion into subgroups of responders, the projected total number of patients enrolled 
in this study is approximately 725 (see Figure 2).   
If a clear clinical benefit has been observed for a defined subgroup of patients at the end of 
Stage I within a cohort that did not meet the criteria for continuation (as described in Section 
6.2.1), then enrolment into Stage II might still be allowed in this cohort for this specific subgroup 
after discussion with the Sponsor and the study Steering Committee. Similarly, if a clear clinical 
benefit has been observed for a defined subgroup of patients at the end of Stage II within a 
cohort that did not meet the criteria for success (as described in Section 6.2.2), then enrolment 
into Stage II might continue in this cohort for this specific subgroup after discussion with the 
Sponsor and the study Steering Committee. 
 
Synopsis Figure 2. 
Sample Size for Each Cohort in Stage I/II 
 
 
 
 
 
 
NP = non-progressors; NPR = non-progression rate. 
Assumptions: H0 = NPR 20%; H1 = NPR 40%; power = 80%; alpha = 10%. 
The sample size was estimated using Simon’s optimal two-stage design (Simon 1989). 
* 
And no additional clinical benefit in a subgroup.  
 
Interim Analyses 
The study will be analyzed for efficacy at Stage I and Stage II. All cohorts will also be analyzed 
at Week 24 (6 months) and at the end of cohort for each cohort. No additional interim analysis 
for efficacy will be performed in this study. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
+ 
censored value 
AC 
atypical carcinoids 
AE 
adverse event 
AESI 
adverse event of special interest 
ASA 
abnormal self antigen 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATA 
anti-therapeutic antibody 
BOR 
best overall response 
BRCA1/2 
breast cancer type 1/2 susceptibility protein 
BS 
bone sarcoma 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CHO 
Chinese hamster ovary 
CL 
mean apparent clearance 
ClinRO 
clinician-reported outcome 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common TerminologyCriteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DOR 
duration of response 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DTC 
differentiated thyroid cancers 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECG 
electrocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
ePRO 
electronic patient-reported outcome 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FOLFOX 
folinic acid/fluorouracil/oxaliplatin 
GEJ 
gastro-esophageal junction 
GEP-NETs 
neuroendocrine gastroenteropancreatic tumors 
GCT 
germ cell tumors 
GGT 
gamma-glutamyl transferase 
GIST 
gastrointestinal stromal tumors 
HBc 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA-DR 
human leukocyte antigen-DR 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papilloma virus 
HR 
hormone receptor 
IC 
PD-L1-positive tumor-infiltrating immune cell 
ICH 
International Conference on Harmonisation 
IFN-α 
interferon-alpha 
IFN-Ɣ 
interferon-gamma 
Ig 
immunoglobulin 
IGF-1R 
insulin-like growth-factor-1 receptor 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 


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LCNEC 
large-cell neuroendocrine carcinoma 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MFH 
malignant fibrous histiocytoma 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
high microsatellite instability 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
NA 
not applicable 
NCI 
 National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
NETs 
neuroendocrine tumors 
NPR 
non-progression rate 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
NSE 
neuron-specific enolase 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic or progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PI3K 
phosphoinositide 3-kinase 
PNECs 
pulmonary neuroendocrine cells 
PR 
partial response or partial receptor 
PRO 
patient-reported outcome 
PS 
performance status 
PT 
prothrombin time  
PTT 
partial thromboplastin time 


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PUVA 
psoralen and ultraviolet A 
QTcF 
QT interval corrected using Fridericia’s formula 
q3w 
every 3 weeks 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RCR 
Roche Clinical Repository 
RECIST, v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
RIS 
radiation induced sarcoma 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SAE 
serious adverse event 
SCFR 
stem cell factor receptor 
SEER 
Surveillance, Epidemiology and End Results 
SIA 
systemic immune activation 
STS 
soft tissue sarcoma 
T3 
triiodothyronine 
T4 
thyroxine 
TC 
tumor cells or typical carcinoids 
TGCT 
testicular germ cell tumors 
TILS 
tumor-infiltrating lymphocytes 
TNF 
tumor necrosis factor 
TSA 
tumor-specific antigen 
TSH 
thyroid-stimulating hormone 
TTP 
time to tumor progression 
UBC 
urothelial bladder cancer 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON ADVANCED SOLID TUMORS 
This study will assess the efficacy and safety of the anti-PD-L1 therapeutic antibody 
Atezolizumab for the treatment of a diverse array of advanced solid tumors.  The tumors 
were selected based on the characteristics of their pathology that suggest a potential 
susceptibility to immunotherapy with Atezolizumab.  Specifically, the tumors were 
chosen based on their potential for high immunogenicity, and on published evidence 
linking PD-L1 expression to pathogenesis. 
The tumors included in this study, as well as a brief description of their epidemiology and 
prognoses, are presented in Table 1. Full details of the histological types / subtypes and 
markers mandated for each cohort are described in Section 4.1.3. 
Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
Cervical cancer 
 
(Colombo et al. 2012) 
(http://globocan.iarc.fr) 
(http://www.cancer.org/cancer/
cervicalcancer/detailedguide/c
ervical-cancer-survival) 
 
• Cervical cancer is the fourth most common cancer in women, 
and the seventh overall 
• Around 528,000 new cases were diagnosed worldwide in 
2012, approximately 85% of which occurred in less 
developed regions.  Incidence in Europe ranged from 3.6 
(Switzerland) to 28.7 (Romania) per 100,000 women.  
Incidence rates in the  United States (US), Japan and China 
were 6.6, 10.9 and 7.5 per 100,000 women, respectively 
• Around 266,000 deaths occurred worldwide in 2012 due to 
cervical cancer.  Mortality rates in Europe ranged from 0.4 
(Iceland) to 10.8 (Romania) per 100,000 women.  Mortality 
rates in the US, Japan and China were 2.7, 2.8 and 3.4 per 
100,000 women, respectively 
• The 5-year survival rate is 32%–35% for Stage III disease 
and 15%–16% for Stage IV disease 
• Human papilloma virus (HPV) is detected in 99% of cervical 
tumors, in particular the oncogenic subtypes (e.g., HPV 16 
and 18) 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Nasopharyngeal cancer 
 
(Chan et al. 2012) 
(Lin et al. 2004) 
(http://globocan.iarc.fr/ia) 
(http://www.cancer.org/cancer/
nasopharyngealcancer/detaile
dguide/nasopharyngeal-
cancer-survival-rates) 
• Around 87,000 new cases of nasopharyngeal cancer were 
diagnosed worldwide in 2012.  Incidence rates in Europe 
ranged from 0 (Iceland) to 2.9 (Malta) per 100,000 men and 0 
(Iceland) to 0.6 (Malta) per 100,000 women.  Incidence rates 
were 0.7, 0.4 and 2.7 per 100,000 men and 0.3, 0.1 and 1.1 
per 100,000 women in the US, Japan and China, respectively 
• Around 51,000 deaths occurred worldwide in 2012 due to 
nasopharyngeal cancer.  Mortality rates in Europe ranged 
from 0 (Iceland) to 1 (Romania) per 100,000 men and 
0 (Iceland) to 0.3 (Albania) per 100,000 women.  Mortality 
rates were 0.2, 0.2 and 1.7 per 100,000 men and 0.1, 0.1 
and 0.6 per 100,000 women in the US, Japan and China, 
respectively 
• The 5-year survival rate is 62% for Stage III disease and 38% 
for Stage IV disease 
• Epstein-Barr virus (EBV) is detectable in approximately 95% 
of patients 
MSI-H or MMR-deficient 
colorectal cancer 
 
(Van Cutsem et al. 2010) 
(Poynter et al. 2008) 
(Sinicrope et al. 2011) 
(http://globocan.iarc.fr/ia) 
• Microsatellite instability (MSI) occurs in approximately 10% to 
20% of colorectal cancer cases 
• Magnetic resonance imaging (MMR)-deficient colon cancers 
have reduced rates of tumor recurrence, delayed time to 
recurrence and improved survival rates relative to MMR-
proficient disease 
• The 5-year survival rates are 23% for localized disease, 12% 
for intra-abdominal disease and 8% for distant disease 
BRCA 1/2 mutated cancers 
 
(Goodwin et al. 2012) 
(Bolton et al. 2012) 
(http://www.cancer.gov/cancer
topics/factsheet/Risk/BRCA) 
(http://www.ncbi.nlm.nih.gov/b
ooks/NBK1247/) 
(http://globocan.iarc.fr/ia) 
(http://www.cancer.org/cancer/
breastcancer/detailedguide/br
east-cancer-survival-by-stage) 
 
• BRCA1 and BRCA2 mutations have been identified in 
approximately 5% to 10% of all breast cancers 
• BRCA1 and BRCA2 mutations have been identified in 
approximately 15% of all ovarian cancers 
• In patients with breast cancer, mortality rates of patients with 
BRCA1/2 mutations and patients with sporadic disease were 
similar.  The 5-year survival rates are 72% for Stage III 
disease and 22% for Stage IV disease 
• In patients with ovarian cancer, BRCA1 and BRCA2 mutation 
carriers showed a more favorable survival than noncarriers 
(BRCA1: HR, 0.73; BRCA2: HR, 0.49).  The 5-year overall 
survival was 36% for noncarriers, 44% for BRCA1 carriers, 
and 52% for BRCA2 carriers 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Soft tissue visceral and 
bone sarcomas 
 
(Kasper et al, 2007) 
(van Glabekke et al, 2002) 
(WHO classification of tumors) 
(ESMO European Sarcoma N
etwork Working Group 2012) 
(Grimer et al. 2010) 
(http://www.cancer.org/cancer/
sarcoma-
adultsofttissuecancer/detailed
guide/sarcoma-adult-soft-
tissue-cancer-survival-rates) 
 
• Adult sarcomas comprise a heterogeneous group of rare 
tumors.  The most common soft tissue and visceral sarcoma 
types are malignant fibrous histiocytoma, liposarcoma and 
leiomyosarcoma and the most common types of bone and 
joint sarcoma are osteosarcoma and chondrosarcoma 
• The total estimated annual incidence of soft tissue and 
visceral sarcomas in Europe is 4–5/100,000 (approximately 
1% of all adult cancers).  In the US, the incidence of soft 
tissue and visceral sarcoma is 3.8 per 100,000 and the 
mortality rate is 1.5 per 100,000. The incidence of bone 
sarcoma is 0.9 per 100,000 and mortality is 0.4 per 100,000 
• About 12,020 new soft tissue and visceral sarcomas and 
about 2,300 new cases of bone sarcoma were diagnosed in 
the US in 2014 and about 4,740 and 1,500 people died from  
soft tissue and bone sarcomas, respectively 
• Approximately half of all patients with intermediate or high-
grade tumors develop metastatic disease requiring systemic 
treatment.  The 5-year survival rate is around 10% for soft 
tissue sarcoma (STS) that have metastasized.  After failure 
of first-line treatment the estimated 6-month progression-free 
survival rate is only 14% for agents deemed to be active in 
sarcoma 
• The 5-year survival rate for osteosarcoma with unresectable 
disease is between 7% and 19%. For chondrosarcoma the 
5-year survival is 89% for grade 1 and 53% for combined 
grade 2 and 3 
Pleural and Peritoneal 
Mesothelioma 
 
(Stahel et al. 2010) 
(Gregoire 2010) 
(Trupiano et al. 2004) 
(http://www.cancer.org/cancer/
malignantmesothelioma/detail
edguide/malignant-
mesothelioma-survival-
statistics) 
• Malignant mesothelioma has an incidence of 1.25 per 
100,000 in the UK, 1.1 per 100,000 in Germany and 1.0 per 
100,000 in the US 
• Incidence is expected to double in many countries within the 
next 20 years 
• Median survival time is 16 months for Stage III disease and 
12 months for Stage IV disease.  The 5-year survival rate is 
< 5%  
• Exposure to asbestos is a well-established etiological factor, 
with occupational exposure being documented in 70%–80% 
of those affected 
• Survival ranges from 9 to 18 months for peritoneal 
mesotheliomas and 4 to 12 months for pleural 
mesotheliomas 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Cholangiocarcinoma/cancer 
of the biliary tract 
 
(Bridgewater et al. 2014) 
(http://www.cancer.org/cancer/
bileductcancer/detailedguide/b
ile-duct-cancer-survival-by-
stage) 
• Cholangiocarcinoma, the second most common primary liver 
cancer after hepatocellular cancer, comprises a 
heterogeneous group of cancers with pathologic features of 
biliary tract differentiation  
• The incidence varies substantially worldwide, with the highest 
known rates in Northeast Thailand (> 80 per 100,000) and 
much lower rates in the Western world (e.g., Canada, 0.3 per 
100,000) 
• Incidence rates are rising around the world.  For example, 
incidence rates in the US increased from 0.3 per 100,000 in 
1975–79 to 0.9 per 100,000 in 1995–99 
• The 5-year survival rate is 30% for localized disease, 24% for 
regional disease and 2% for distant disease 
• Risk factors for cholangiocarcinoma, such as hepatobiliary 
flukes, primary sclerosing cholangitis, biliary tract cysts, 
hepatolithiasis and toxins, are associated with chronic biliary 
inflammation and increased cellular turnover 
Thyroid cancer 
 
(Pacini et al. 2012) 
(http://www.cancer.org/cancer/
thyroidcancer/detailedguide/th
yroid-cancer-survival-rates) 
• Thyroid cancer accounts for around 3.8% of all cancers in the 
US in 2016. The incidence was 13.9 per 100,000 per year 
and mortality was 0.5 per 100,000 per year in the US 
between 2009 and 2013. In Europe, incidence was 6.3 per 
100,000 and mortality was 0.6 per 100,000 in 2012 
• There are 4 types of thyroid cancers – papillary, follicular, 
medullar and anaplastic 
• Papillary and follicular thyroid cancers are differentiated 
tumors - Papillary thyroid cancer represents 70% to 80% of 
all thyroid cancers and follicular thyroid cancer represents 
10% to15%. Differentiated tumors (papillary or follicular) have 
a 10-year survival rate of 90 - 95% but survival decreases to 
50% at 5-year for metastatic disease 
• Medullary thyroid cancer makes up about 5 % to 10% of all 
thyroid cancers and has a 10-year survival rate of 75%; 
however, the 5-year survival rate is 5% for metastatic 
disease 
• Anaplastic thyroid cancer has an estimated incidence of 0.21 
per 100,000 person-years, and comprises < 2% of all thyroid 
cancers. More women than men are affected (2–3:1). The 5-
year survival rate is around 7% 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Gastric adenocarcinoma/ 
adenocarcinoma of the 
gastro-esophageal junction 
 
(http://globocan.iarc.fr/ia) 
(http://www.cancer.org/cancer/
stomachcancer/detailedguide/
stomach-cancer-survival-
rates) 
 
• Almost one million new cases of gastric cancer were 
estimated to have occurred in 2012 (952,000 cases, 6.8% of 
the total), making it the fifth most common malignancy in the 
world.  More than 70% of cases (677,000 cases) occurred in 
developing countries (456,000 in men, 221,000 in women), 
and half the world total occurs in Eastern Asia (mainly in 
China) 
• Age-standardized incidence rates are about twice as high in 
men as in women 
• Incidence rates in Europe ranged from 4.9 (Sweden) to 29.1 
(Belarus) per 100,000 men and 2.7 (Sweden) to 15.1 
(Albania) per 100,000 women.  Incidence rates were 5.3, 
45.8 and 32.8 per 100,000 men and 2.7, 16.5 and 13.1 per 
100,000 women in the US, Japan and China, respectively 
• Around 254,000 deaths occurred worldwide in 2012 due to 
gastric cancer.  Mortality rates in Europe ranged from 3.0 
(Iceland) to 24.6 (Belarus) per 100,000 men and 1.5 (Malta) 
to 12.6 (Albania) per 100,000 women.  Mortality rates were 
2.7, 18.8 and 25.5 per 100,000 men and 1.5, 7.3 and 10.7 
per 100,000 women in the US, Japan and China, respectively 
• Five-year survival rates are 9%–20% for Stage III and 4% for 
Stage IV 
• Infection with Helicobacter pylori is the primary identified risk 
factor for gastric cancer 
Other solid tumors  
• 
NA 
Germ cell tumors 
 
(Ferlay et al, 2004) 
(McGlynn et al. 2010) 
(Smith et al. 2006) 
(Oosterhuis et al, 2005) 
• Germ cell tumors (GCT) include a group of gonadal and 
extragonadal tumors that are considered as one disease with 
separate entities that can manifest themselves in different 
anatomical sites. In men testicular germ cell tumors (TGCT) 
are the most common GCTs, whilst in women the most 
common are of ovarian origin. GCTs occur mostly in young 
adults and children. Malignant GCTs are rare, comprising 
only 0.7% of all cancers 
• GCTs account for 95 percent of testicular cancers and the 
terms “testicular cancer” and TGCT are often used 
interchangeably. The global incidence rate of testicular 
cancer is 1.5 per 100,000 men. Incidence rates of TGCT 
have been increasing for at least 50 years, but mortality 
rates, at least in developed countries, have been declining. In 
the US, the 5-year survival rate is over 95% 
• Female GCTs are rare. They are mostly of ovarian origin. 
The estimated incidence rate is about 0.3 per 100,000 
women-years. The 5-year relative survival is about 84% 
• Extragonadal GCTs are very rare tumors that predominantly 
affect young males 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Estrogen receptor positive, 
HER2 negative breast 
cancer with > 100 mutations 
 
(Haricharan et al, 2014) 
(Stephens et al. 2012) 
(Disis et al, 2015) 
• 
Estrogen receptor (ER) positive, HER2 negative breast 
cancer represents 40 to 55% of breast cancers and the 
overall 5-year survival is estimated to be over 90%; 
however, this group of tumors is heterogeneous and 
prognosis and management varies based on criteria 
other than ER and HER2 
• 
Somatic mutation load (SML) may constitute an 
important immunogenic signature for a subset of ER 
positive, HER2 negative patients with a poorer 
prognosis. There are currently no epidemiologic data for 
the ER positive, HER2 negative breast cancer with a 
high mutation load 
Thymoma / Thymic cancer 
 
(PDQ®: Health Professional 
Version. Thymoma and 
Thymic CarcinomaTreatment - 
Cancer Information 
Summaries: NCI; 2002-2015 
(Rosai et al, 1999) 
(http://www.cancer.net/cancer-
types/) 
• 
Invasive thymoma and thymic cancer are relatively rare 
tumors, which together represent about 0.2% to 1.5% of 
all malignancies 
• 
The overall incidence of thymoma is 0.15 cases per 
100,000, based on SEER data. The 5-year overall 
survival of thymoma varies according to histological 
subtype but remains above 90% at 10 years for all 
subtypes 
• 
Thymic carcinoma accounts for only 0.06% of all thymic 
neoplasms. The 5-year overall survival is 30% to 50% 
for thymic carcinoma 
Gastroenteropancreatic 
(GEP) and lung 
neuroendocrine tumors  
(NETs) 
Low and intermediate 
grades (typical or atypical 
carcinoid) 
Poorly differentiated grade 
(excluding SCLC) 
 
(http://www.neuroendocrinetu
mor.com/health-care-
professional/mortality-
associated-with-nets.jsp) 
• 
Neuroendocrine gastroenteropancreatic tumors 
constitute a heterogeneous group of tumors with their 
origin in neuroendocrine cells of the embryological gut.  
Most commonly, the primary lesion is located in the 
gastric mucosa, the small and large intestine, the 
rectum and pancreas. The incidence has significantly 
increased over the last years and is estimated to be 
5.25/100,000/year 
• 
Neuroendocrine tumors (NETs) of the lung comprise a 
heterogeneous population of tumors ranging from well 
differentiated bronchial NETs to highly malignant such 
as large-cell neuroendocrine carcinoma (LCNEC). The 
incidence of pulmonary NETs is low, although reported 
to have increased over the past 30 years. According to 
the SEER database, in 2003, the combined incidence 
was 1.57/100,000 inhabitants 
• 
The 5-year survival rates for metastatic disease varies 
according to tumor characteristics with e.g. 35% for 
well-differentiated G1/G2 NETs and 4% for poorly 
differentiated disease 


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Table 1. 
Summary of the Advanced Solid Tumors Examined in This Study 
(Cont.) 
Known HPV induced 
squamous cell carcinoma 
Head and neck  
Penile cancer 
Vaginal cancer 
Vulvar cancer 
Anal cancer 
 
(De Vuyst et al, 2009) 
(http://www.cancer.net/cancer-
types/) 
• 
The prevailing evidence favors human papillomavirus 
(HPV) as a causative factor in many genital tract 
carcinomas 
• 
An estimated 50% of penile, 88% of anal, 43% of 
vulvar, 70% of vaginal, and 13–56% of oropharyngeal 
cancers are attributable to HPV, primarily HPV-16 
typically followed by HPV-18. 
• 
Head and neck squamous cell carcinoma (HNSCC) is 
the fifth most common cancer worldwide, with an annual 
incidence of about 60,000 cases annually in the US and 
Europe. The five-year survival rate is around 30% 
• 
Invasive penile cancer is a rare disease with an annual 
burden of 22,000 estimated cases. About 95% are 
squamous cell carcinoma 
• 
Carcinomas of the vagina are uncommon tumors 
comprising about 1% of the cancers that arise in the 
female genital system. About 85% are squamous cell 
carcinoma 
• 
Vulvar cancer accounts for about 5% of cancers of the 
female genital system in the US. About 90% are 
squamous cell carcinoma. The 5-year survival rate for 
women with vulvar cancer is 86% but decreases to 16% 
for metastatic tumors 
• 
Anal cancer accounts for about 4% of all cancers of the 
lower alimentary tract. Anal carcinomas are rare, with, 
an incidence of only 1 to 2.5 cases per 100,000 people 
per year in many countries; however, its incidence is 
growing.  In the US in 2016, there will be 8,080 new 
cases of anal cancer and 1,080 deaths from it. The 
overall 5-year survival is 65.7% however the 5-year 
survival decreases to 21% for metastatic tumors. The 
majority of anal cancer (98%) are related to HPV 
Known MSI high or MMR 
deficient tumors (excluding 
CRC and gastric cancer) 
 
(Hall et al, 2016) 
• 
MSI is a hypermutable phenotype caused by the loss of 
DNA mismatch repair (MMR) activity and is detected in 
a wide range of human solid tumors.  Its frequency is 
highly variable across tumor types and has not been 
evaluated for all tumor types.  Frequencies assessed 
include: uterine 14.1%, small bowel 8.6%, prostate 
6.2%, cancer of unknown primary origin 2.7%, 
hepatobiliary 2.3%, neuroendocrine 0.2%, pancreas 
0.2%, NSCLC 0.2%, and breast 0.1%. 
BRCA - breast cancer; CRC = colorectal cancer; HPV = human papilloma virus; MMR = 
mismatch repair; MSI-H = microsatellite instability, high; NA = not applicable; IV = intravenous; 
HER2 = human epidermal growth factor receptor 2 
 
Please refer to Section 1.3 (Study Rationale and Benefit-Risk Assessment) for further 
information on the specific cancers included in this study. 


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1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a phage-derived human immunoglobulin (Ig) G1 monoclonal antibody 
consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids).  
Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a 
non-glycosylated heavy chain that has minimal binding to Fc receptors and prevents Fc-
effector function at expected concentrations and eliminates the potential for antibody-
dependent cell-mediated cytotoxicity.  Atezolizumab targets human PD-L1 and inhibits 
its interaction with its receptors, programmed death−1 (PD-1) and B7.1 (CD80, B7-1).  
Both of these interactions are reported to provide inhibitory signals to T cells. 
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans. 
1.2.1 
Nonclinical Studies 
The safety, pharmacokinetic (PK) and toxicokinetics of Atezolizumab were investigated 
in mice and cynomolgus monkeys to support intravenous (IV) administration and to aid 
in predicting the appropriate starting dose in humans.  Given the similar binding of 
Atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey was 
selected as the primary and relevant nonclinical model for understanding the safety, PK 
and toxicokinetics of Atezolizumab. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for Atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of down-modulating the PD-L1/PD-1 pathway 
and supported entry into clinical trials in patients. 
Please refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical 
studies. 
1.2.2 
Ongoing Clinical Studies 
Atezolizumab is currently being tested in multiple Phase I, II and III studies, both as 
monotherapy and in combination with several anti-cancer therapies (see the 
Atezolizumab Investigator’s Brochure for study descriptions).  Much of the safety and 
efficacy data summarized below are from the Phase Ia Study PCD4989g, a multicenter, 
first-in-human, open-label, dose-escalation trial evaluating the safety, tolerability, 
immunogenicity, pharmacokinetics, exploratory pharmacodynamics and preliminary 
evidence of biologic activity of Atezolizumab administered as a single agent by IV 
infusion every 3 weeks (q3w) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies.  
 


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1.2.3 
Clinical Safety 
As of the cutoff date for the Investigator’s Brochure version 9, Atezolizumab, (August 
2016) has been administered to approximately 6053 patients with solid tumors and 
hematologic malignancies.  
Safety information for Atezolizumab is also gleaned from studies in the entire 
development program, including those where Atezolizumab is investigated in 
combination with other unapproved agents. 
Study PCD4989g, in which Atezolizumab is being used as a single agent in patients with 
locally advanced or metastatic solid tumors or hematologic malignancies, provides the 
majority of data (with 558 safety evaluable patients as of the data extraction date of 11 
May 2015) for the safety profile of Atezolizumab as monotherapy. Currently, no 
maximum tolerated dose, no dose-limiting toxicities and no clear dose-related trends in 
the incidence of AEs have been determined. Fatigue, decreased appetite, nausea and 
cough were commonly reported adverse events in single and combination therapy. The 
overall immune-mediated adverse events reported for Atezolizumab were considered 
moderate in severity and majority of patients were able to continue on Atezolizumab 
therapy. 
Adverse Events 
In PCD4989g of the 558 safety evaluable treated patients 376 patients (67.4%) reported 
at least one treatment-related adverse event, Grade 3 - 4 AEs were reported in 239 
patients (42.8%) of which 66 (11.8%) were considered related. Grade 3 and 4 AEs 
considered related by the investigator included dyspnea, pneumonitis, increased alanine 
aminotransferase (ALT), increased aspartate aminotransferase (AST), increased 
gamma-glutamyl transferase (GGT), lymphocyte count decreased, cardiac tamponade, 
asthenia, autoimmune hepatitis, pneumonia, influenza, and hypoxia. More detailed 
information is provided in the latest version of the IB.  
Immune-mediated Adverse Events 
Given the mechanism of action of Atezolizumab, events associated with inflammation 
and/or immune-mediated adverse events have been closely monitored during the 
Atezolizumab clinical program.  These include potential dermatologic, hepatic, endocrine 
and respiratory events.  Events of immune-related hepatitis, pneumonitis, colitis, 
pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis, Guillain-Barré syndrome, myasthenic syndrome / myasthenia gravis, 
meningoencephalitis and infusion-related reactions are considered adverse drug 
reactions associated with Atezolizumab. 
Please refer to the Atezolizumab Investigator’s Brochure for details regarding immune-
mediated adverse events observed in patients treated with Atezolizumab. 


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1.2.4 
Clinical Activity 
1.2.4.1 
Study PCD4989g 
Anti-tumor activity, including Response Evaluation Criteria in Solid Tumors 
(RECIST)−based responses (i.e., RECIST v1.1 responses), have been observed in 
patients with different tumor types treated with Atezolizumab monotherapy in 
Study PCD4989g. 
Among 345 evaluable patients treated by 21 October 2013 (data cutoff of 21 April 2014) 
with a median 30.4 weeks of follow-up, 62 experienced objective responses per RECIST 
v1.1 at an ORR of 18% (95% CI: 14.1%−22.3%).  Objective responses with 
Atezolizumab monotherapy were observed in a broad range of malignancies including 
NSCLC, RCC, melanoma, bladder cancer, colorectal cancer, head and neck cancer, 
gastric cancer, breast cancer, and sarcoma.  The majority of the responses have been 
durable, with a median DOR of 77.6 weeks (range: 6.4+ to 97.9+ weeks, where “+” 
denotes a censored value); 72.6% (45 of 62 patients) of these responses were ongoing 
as of the clinical cutoff date. 
Please refer to the Atezolizumab Investigator’s Brochure for details on clinical activity in 
all patients treated to date regardless of tumor type. 
NSCLC 
As of the 21 April 2014 cutoff, 88 patients with NSCLC who enrolled into 
Study PCD4989g and received their first dose of Atezolizumab by 21 October 2013 were 
evaluable for efficacy.  The median age was 60.5 years.  The group represented a 
heavily pre-treated patient population in that 84.1% of the patients had received ≥ 2 prior 
systemic therapies.  Patients had a median duration of follow-up of 36.1 weeks.  
RECIST responses (confirmed) were observed in a total of 18 patients, inclusive of 
squamous and non-squamous histologies, and across all treatment cohorts (treatment 
dose levels of 1 to 20 mg/kg). 
Preliminary results suggest that PD-L1 expression in tumor tissue is likely to be 
associated with response to Atezolizumab.  A prototype IHC assay was used to measure 
specific PD-L1 signals in TCs and ICs.  PD-L1 staining categories in TCs were defined 
as TC0, TC1, TC2, and TC3, and in ICs were defined as IC0, IC1, IC2, and IC3.  Of note, 
an ORR of 50% (11 of 22 patients, 95% CI: 28.2%− 71.8%) and an ORR of 31.6% (12 of 
38, 95% CI: 17.5%−48.6%) were observed in patients whose tumors were characterized 
by high levels of PD-L1 staining in TCs or ICs (TC3 or IC3 group and TC3 or IC2/3 group, 
respectively) compared with an ORR of 12.1% (7 of 58 patients, 95% CI: 5.7%−22.5%) 
in patients with low or no PD-L1 staining in TCs and ICs (TC0/1/2 and IC0/1/2 group) 
(Table 2). 
As of the data cutoff of 21 April 2014, 11 of the 18 responding patients have continued to 
respond after 13.0+ weeks to 97.9+ weeks.  The median DOR is 66.9 weeks.  See the 


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Atezolizumab Investigator’s Brochure for details on clinical activity in patients with 
NSCLC treated to date. 
Table 2. 
Efficacy-Evaluable NSCLC Patients in Study PCD4989g: ORR by 
Tumor PD-L1 Expression and Objective Response Rate (per 
RECIST, Version 1.1) 
PD-L1 IHC 
Expression Category 
ORR 
(n=88) 
PR 
SD 
TC3 or IC3 
50% (11 of 22) 
95% CI: 28.2%−71.8% 
50% 
(11 of 22) 
18.2% 
(4 of 22) 
TC3 or IC2/3 
31.6% (12 of 38) 
95% CI: 17.5%−48.6% 
31.6% 
(12 of 38) 
28.9% 
(11 of 38) 
TC0/1/2 and IC0/1/2 
12.1% (7 of 58) 
95% CI: 5.7%−22.5% 
12.1% 
(7 of 58) 
36.2% 
(21 of 58) 
TC0/1/2 and IC0/1 
14.3% (6 of 42) 
95% CI: 6.4%−27.7% 
14.3% 
(6 of 42) 
33.3% 
(14 of 42) 
IC = tumor-infiltrating immune cells; IHC = immunohistochemistry; TC = tumor cells; NSCLC = 
non−small cell lung cancer; ORR = objective response rate; PR = partial response; SD = stable 
disease; PD-L1 = programmed death− ligand 1; RECIST = Response Evaluation Criteria in Solid 
Tumors.  
Note: This table is based on a data cutoff of 21 April 2014 of patients with NSCLC dosed by 21 
October 2013. Objective response is per RECIST v1.1. 
 
Urothelial Bladder Cancer  
As of the clinical cut-off date of 21 April 2014, efficacy analyses had been performed on 
70 patients (33 IHC 2/3, 36 IHC 0/1 and 1 unknown) with locally-advanced or metastatic 
urothelial bladder cancer (UBC) (all patients were dosed by 27 January 2014 and had a 
minimum of 12 weeks of follow-up).  In these 70 patients, the median age was 65 years 
(range: 36−89 years).  Sixty-four patients (91%) had received prior platinum-based 
chemotherapy.  The majority of patients had at least one or more poor prognostic 
features (i.e., hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group [ECOG] 
performance status [PS] ≥ 1, liver involvement) at baseline, with 52 patients (74%) 
having visceral metastases. 
Among the 33 efficacy-evaluable IHC 2/3 patients, median follow-up was 6 months 
(range: 1+ – 12 months).  The investigator-assessed ORR (unconfirmed) per Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST, v1.1]) was 52% (95% CI: 34%, 
69%), with 3 complete responses (CRs) (Table 5).  Among the 36 efficacy-evaluable IHC 
0/1 patients, median follow-up was 4 months (range: 1+ to 7 months).  The ORR was 14% 
(95% CI: 6%, 28%) (Table 3).   
 


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Table 3. 
Efficacy-Evaluable UBC Patients in Study PCD4989g: ORR per 
RECIST v1.1 According to PD-L1 Tumor Expression 
IHC Score 
ORR, Best Response 
% (95% CI) 
PD-L1+ vs. PD-L1– 
ORR, Best Response 
% (95% CI) 
IHC 3 (IC ≥ 10%) 
60 (2, 85) 
52 (34, 69) 
IHC 2 (10% > IC ≥ 5%) 
48 (27, 68)  
IHC 1 (5% > IC ≥ 1%) 
17 (6, 37) 
14 (6, 28) 
IHC 0 (IC < 1%) 
8 (0, 35) 
IC = PD-L1−positive tumor-infiltrating immune cell; IHC = immunohistochemistry; ORR, overall 
response rate; PD-L1 = programmed death−ligand 1; UBC = urothelial bladder cancer. 
Note: This table is based on a data cutoff of 21 April 2014 of UBC patients dosed by 
27 January 2014. 
 
Median PFS was 24 weeks (range: 5 to 50+) in the IHC 2/3 cohort and 8 weeks (range: 
0.1+ to 30+ weeks) in the IHC 0/1 cohort.  Overall, median PFS appeared to be 
associated with PD-L1 expression.  For the entire UBC population, 19 of 22 patients had 
ongoing responses at the time of data cut-off, and the median duration of response had 
not been reached.   
Renal Cell Carcinoma 
As of the clinical cut-off date of 21 April 2014, efficacy analyses had been performed on 
69 patients with RCC (all patients were dosed by 21 October 2013).  In these 69 patients, 
the median age was 61 years (range: 33−81 years).  Sixty patients (87%) had received 
prior systemic therapies, including cytokine-based therapies (39%), tyrosine kinase 
inhibitors (58%) and mTOR inhibitors (25%).  Eighteen patients (26%) were in the 
Memorial Sloan-Kettering Cancer Center (MSKCC) poor risk stratification group, while 
71%, 23%, 35% and 4% of patients at enrolment had metastases in the lung, liver, bone 
and brain, respectively.  
Among the 69 efficacy-evaluable patients, the median follow-up was 239 days (range: 
21 to 834 days).  The investigator-assessed ORR (confirmed) per RECIST, v1.1, was 15% 
(95% CI: 8%, 25%), including 1 CR.  The ORRs in the IHC 1/2/3 and IHC 0 groups were 
20% (95% CI: 9%, 37%) and 10% (95% CI: 2%, 30%), respectively.  The PFS was 24 
weeks (range: 5 to 98+ weeks), with a 24-week PFS rate of 51% (95% CI: 38%, 63%).  
The ORR for Fuhrman Grade 4 or sarcomatoid clear cell RCC (n=18) was 22% (95% CI: 
8%, 47%).   
Further analysis indicated that higher response rates were observed in MSKCC poor-risk 
patients with PD-L1 IHC 1/2/3 expression (Table 4).  
 


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Table 4. 
Efficacy-Evaluable RCC Patients in Study PCD4989g: ORR per 
MSKCC Risk Stratification and PD-L1 Tumor Expression 
 
All Patients 
IHC 1/2/3 a 
MSKCC Risk Category 
n 
ORR, n (%) 
95% CI 
n 
ORR, n (%) 
95% CI 
Overall 
62 
9 (15%) 
CI: 8%, 25%  
[1 CR and 8 PRs] 
35 
7 (20%) 
CI: 9%, 37% 
[1 CR and 6 PRs] 
Favorable 
10 
2 (20%) 
CI: 4%, 56% 
3 
0% 
CI: 0%, 63% 
Intermediate 
36 
3 (8%) 
CI: 2%, 21% 
24 
3 (13%) 
CI: 4%, 31% 
Poor 
15 
4 (27%) 
CI: 10%, 55% 
7 
4 (57%) 
CI: 23%, 87% 
MSKCC = Memorial Sloan-Kettering Cancer Center; IHC = immunohistochemistry; ORR, overall 
response rate; PD-L1 = programmed death−ligand 1; RCC = renal cell carcinoma. 
a. One patient had unknown PD-L1 status. 
Note: This table is based on a data cutoff of 21 April 2014 of RCC patients dosed by 
21 October 2013. 
 
1.2.4.2 
Study GP28328 
Study GP28328 is an ongoing Phase Ib study evaluating the safety and pharmacology of 
Atezolizumab administered with bevacizumab alone (Arm A) or with bevacizumab plus 
folinic acid/fluorouracil/oxaliplatin (FOLFOX) (Arm B) in patients with advanced solid 
tumors.  As of the clinical cut-off date of 7 July 2014, 35 patients had enrolled in Arm A 
and 36 had enrolled in Arm B (safety-evaluable population).  Sixty percent of patients in 
Arm A and 22% of patients in Arm B had received ≥ 3 prior systemic regimens.   
Responses in the RCC and CRC cohorts are shown in Table 5. 
 


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Table 5. 
Efficacy-Evaluable RCC and CRC Patients in Study GP28328: 
Summary of Responses 
 
n 
ORR 
Atezolizumab + bevacizumab (Arm A) 
 
 
 
First-line RCC 
10 
40% 
 
CRC 
13 
8% 
Atezolizumab + bevacizumab + FOLFOX (Arm B) 
 
 
 
First-line CRC 
18 
44% 
 
CRC 
25 
36% 
CRC = colorectal cancer; RCC = renal cell carcinoma. 
Note: This table is based on a data cutoff of 7 July 2014 of RCC and CRC patients dosed by 
7 April 2013. 
 
In Arm A, responses were also observed in melanoma (1/4 PR) and breast cancer 
(1/1 PR).  In Arm B, responses were also observed in RCC (1/1 CR) and breast cancer 
(1/2 PR). 
1.2.5 
Clinical Pharmacokinetics 
On the basis of available preliminary PK data (0.03−20 mg/kg), Atezolizumab appeared 
to show linear pharmacokinetics at doses ≥ 1 mg/kg.  For the 1-mg/kg and 20-mg/kg 
dose groups, the mean apparent clearance (CL) and the mean volume of distribution at 
steady state (Vss) had a range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 mL/kg, 
respectively, which is consistent with the expected profile of an IgG1 antibody in humans. 
The development of anti-therapeutic antibodies (ATAs) has been observed in patients in 
all dose cohorts and was associated with changes in pharmacokinetics for some patients 
in the lower dose cohorts (0.3, 1, and 3 mg/kg).  The development of detectable ATAs 
has not had a significant impact on pharmacokinetics for doses from 10 to 20 mg/kg.  
Patients dosed at the 10-, 15-, and 20-mg/kg dose levels have maintained the expected 
target trough levels of drug despite the detection of ATAs.  To date, no clear relationship 
between detection of ATAs and adverse events or infusion reactions has been observed. 
See the Atezolizumab Investigator's Brochure for additional details on clinical 
pharmacokinetics. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Rationale 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012). 


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PD-L1 is an extracellular protein that down-regulates immune responses primarily in 
peripheral tissues through binding to its two receptors PD-1 and B7.1.  Many human 
tumors have been found to overexpress PD-L1, which acts to suppress anti-tumor 
immunity.  PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, 
which is sustained in states of chronic stimulation such as in chronic infection or cancer 
(Blank et al. 2005; Keir et al. 2008).  Ligation of PD-L1 with PD-1 inhibits T-cell 
proliferation, cytokine production and cytolytic activity, leading to the functional 
inactivation or exhaustion of T cells.  B7.1 is a molecule expressed on antigen-
presenting cells and activated T cells.  PD-L1 binding to B7.1 on T cells and antigen-
presenting cells can mediate down-regulation of immune responses, including inhibition 
of T-cell activation and cytokine production (Butte et al. 2007; Yang et al. 2011). 
Overexpression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity, resulting in immune evasion (Blank and Mackensen 2007).  Therefore, 
interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate 
tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with Atezolizumab has demonstrated activity in patients 
with advanced malignancies in patients who have failed standard of care therapies.  In 
the PCD4989g Phase Ia dose-escalation and expansion study of 345 evaluable patients 
treated by 21 October 2013 (data cutoff of 21 April 2014) with a median 30.4 weeks of 
follow-up, 62 patients experienced objective responses per RECIST, v1.1, at an ORR of 
18% (95% CI: 14.1%−22.3%).  Objective responses with Atezolizumab monotherapy 
were observed in a broad range of malignancies including NSCLC, RCC, melanoma, 
bladder cancer, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, 
and sarcoma.  The median DOR was 77.6 weeks (range: 6.4+ to 97.9+ weeks, where “+ ” 
denotes a censored value). The majority of these responses have been durable, with 
72.6% (45 of 62) of responses ongoing as of the clinical cutoff date. 
Preliminary results from the Phase Ia Study PCD4989g suggest that PD-L1 expression 
in tumor tissue is likely to be associated with response to Atezolizumab.  A prototype 
immunohistochemistry (IHC) assay was used to measure specific PD-L1 signals in 
tumor cells (TCs) and tumor-filtrating immune cells (ICs). 
The basic approach of the study will be to examine the efficacy and safety of 
Atezolizumab patients with different advanced solid tumors.  The cancer subtypes were 
chosen based on input from academic experts and relevant published literature.  Two 
types of evidence were considered to be particularly relevant in the choice: 
1. 
Does evidence exist that the tumor is immunogenic?  Two basic categories of tumor 
antigens are thought to trigger anticancer immune surveillance: abnormal self 
antigens (ASAs), and tumor-specific antigens (TSAs) (Schreiber et al. 2010).  ASAs 
are generated in a variety of ways, including induction of embryonal and 
developmental genes not normally expressed in adult tissues, expression of normal 
proteins with abnormal sugar moieties or expression of self proteins at abnormally 


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high levels.  TSAs result from spontaneous somatic mutations or breaks in germline 
DNA that lead to missense mutations, frameshift errors or fusion proteins.  Thus, 
advanced solid tumors having potentially high levels of ASAs and/or TSAs were 
considered to be suitable for inclusion in this study.  A high level of tumor-infiltrating 
lymphocytes was also used as evidence of inherent immunogenicity, as it indicates 
a tumor microenvironment permissive for leukocyte trafficking and extravasation. 
2. 
Does evidence exist that the PD-L1 checkpoint may play a role in the development 
of the tumor?  Thus, tumors that have been shown in published reports to express 
PD-L1 in vivo were considered for inclusion in the study.  This evidence was 
considered to be especially relevant if evidence also existed that the level of PD-L1 
expression correlated with cancer grade and/or prognosis, implying a direct role for 
the PD-L1 pathway in tumor immunity. 
 
Based on these considerations, as well as other tumor-specific issues that might suggest 
potential activity for Atezolizumab (see below), the solid cancers described in the 
following sections were chosen for study. 
1.3.1.1 
Cervical Cancer 
A key step in an antitumor immune response is the production and recognition of ASAs 
and TSAs that are recognized by lymphocytes as foreign (non-self).  Breaking 
self-tolerance is not as great of an obstacle for virally-induced cancers because viral 
antigens are inherently non-self, and virally-induced cancers are thus potentially highly 
immunogenic (Schreiber et al. 2010).   
Human papilloma virus (HPV) is detected in 99% of cervical tumors, in particular 
oncogenic subtypes such as HPV 16 and 18 (Colombo et al. 2012).  In addition, cervical 
cancer progression is associated with deregulated viral gene expression, which leads to 
(among other things) deficient DNA repair and the accumulation of genetic damage in 
the infected cell, both of which may increase the levels of TSAs (Doorbar et al. 2012). 
Evidence in the literature also suggests that PD-L1-mediated immune checkpoints may 
play a role in cervical cancer progression.  PD-L1 was found to be expressed on tumor 
cells in 19% to 29% of patients with cervical cancer (Karim et al. 2009; Grosso et al. 
2013).  PD-L1 expression on cervical T cells and dendritic cells, respectively, correlated 
positively with increasing grade (Yang et al. 2013) and inversely with spontaneous 
regression (Kojima et al. 2013). 
1.3.1.2 
Nasopharyngeal Carcinoma 
As with cervical cancer, nasopharyngeal carcinoma is highly associated with viral 
infection, in this case Epstein-Barr virus (EBV), and thus has the potential to be highly 
immunogenic.  In one study, plasma EBV was detectable before treatment in 94 of 99 
patients with nasopharyngeal carcinoma, but not in 40 healthy controls or 20 cured 
patients (Lin et al. 2004).  Median plasma EBV levels also correlated with disease stage. 


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Consistent with a role for immune checkpoints in the disease, PD-L1 was expressed on 
tumor cells in 68% to 100% of patients (Hsu et al. 2010; Yang et al. 2011).  PD-L1 has 
also been shown to be highly expressed on tumor-infiltrating macrophages in patients 
with nasopharyngeal carcinoma (Chen et al. 2013).  Finally, higher expression rate of 
PD-1 in intratumoral CD8+ T cells significantly correlated with poorer OS, disease-free 
survival and locoregional recurrence-free survival (Hsu et al. 2010).  
1.3.1.3 
MSI-H or MMR-Deficient Colorectal Cancer 
In MSI-H colorectal cancer, the accumulation of errors in microsatellites that reside in 
gene exons leads to the generation of a large number of abnormal peptides due to 
frameshift mutations: the so-called "mutator phenotype" (Bodmer et al. 1994).  Such an 
array of abnormal peptides represents a pool of potential TSAs that render MSI-H 
tumors inherently more detectable by the host immune system.  In fact, epitope mapping 
based on results of The Cancer Genome Atlas (TCGA) estimated that approximately 7 
TSAs are generated on average in individual colorectal tumors with appropriate anchor 
residues for MHC loading (Segal et al. 2008).   
Consistent with potentially high immunogenicity, MSI-H colorectal cancer is associated 
with high numbers of tumor-infiltrating lymphocytes and a Crohn-like host response 
(Hutchins et al. 2011).  PD-L1 immune checkpoint regulation has also been directly 
implicated in CRC pathogenesis.  Thus, PD-L1 was expressed on tumor cells in 53% of 
patients with colon adenocarcinoma (Dong et al. 2002).  A case report has been 
published describing a patient with PD-L1-positive MSI-H colorectal cancer who 
exhibited a long-term response with the anti-PD-1 antibody BMS-936558 (Lipson et al. 
2013).  Finally, the anti-PD-L1 antibody Atezolizumab demonstrated preliminary activity 
against colorectal cancer in Study PCD4989g as a single agent and in Study GP28328 
in combination with bevacizumab ± FOLFOX (Section 1.2.4). 
1.3.1.4 
BRCA 1/2 Mutated Cancers 
The BRCA 1/2 gene products play a central role in another DNA repair pathway, double-
strand break repair (DSBR) (O'Donovan and Livingston 2010).  While not as mutagenic 
as mismatch-repair mutants (see previous section), DSBR mutants do exhibit some 
increase in mutator activity, as well as a dramatic rise in genomic instability.  This implies 
that BRCA 1/2 tumors may have high frequencies of induced TSAs (Schreiber et al. 
2010).  Consistent with this, it has been estimated that breast cancers accumulate on 
average 10 novel and unique TSAs (Segal et al. 2008).  Furthermore, extensive tumor 
infiltration by cytotoxic CD8+ T cells was strongly associated with patient survival and 
response to therapy (Salgado et al. 2014).  Thus, growth of these tumors may require a 
bypass of normal tumor immunity. 
Evidence in the literature also suggests that PD-L1-mediated immune checkpoints may 
play a role in cancers commonly associated with BRCA 1/2 mutations.  In one case 
series study (Ghebeh et al. 2006), PD-L1 was expressed in 22 of 44 breast cancer 
patients in both epithelial cells and tumor-infiltrating lymphocytes.  Intra-tumor 


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expression of PD-L1 was significantly associated with histologic grade, while expression 
of PD-L1 in tumor-infiltrating lymphocytes was associated with large tumor size and 
histologic grade.  In another case series study, PD-L1 was expressed in 152 (23.4%) of 
650 breast cancer specimens; PD-L1 expression was associated with a significantly 
worse OS (Muenst et al. 2014).    
In patients with ovarian cancer, higher expression of PD-L1 on tumor cells correlated 
with a significantly poorer prognosis than lower expression, while a significant inverse 
correlation was observed between PD-L1 expression and the intraepithelial CD8+ T 
lymphocyte count (Hamanishi et al. 2007).  Ovarian cancer-infiltrating dendritic cells 
progressively expressed increased levels of PD-L1 over time.  Accumulation of PD-L1 in 
the tumor was associated with suppression of T cell activity and decreased infiltrating T 
cells in advancing tumors (Krempski et al. 2011).  Finally, in a Phase I dose-escalation 
study of 207 patients treated with the anti-PD-L1 antibody BMS-936559, a response rate 
of 6% was observed in patients with ovarian cancer (Brahmer et al. 2012).  
1.3.1.5 
Soft Tissue, Visceral and Bone Sarcomas 
Adult soft tissue sarcoma (STS) and bone and joint sarcoma (BS) constitute a rare group 
of heterogeneous mesenchymal cancers originating from connective tissue.  There are 
multiple histological subtypes of STS and BS. 
Soft-tissue sarcoma comprises a generally aggressive set of diseases characterized by 
multiple histological subtypes generally categorized according to the normal tissue they 
mimic and the most common types are malignant fibrous histiocytoma, liposarcoma and 
leiomyosarcoma.  Genomic profiling indicates that many soft tissue sarcomas contain 
translocations, mutations, amplifications or other more complex and chaotic karyotypes 
(Maki 2001; Linch et al. 2014).  Consequently, this broad class of tumors may be rich 
sources of TSAs, implying a bypass of tumor immunity may be necessary for 
progression.  Moreover, dendritic cells have been shown to induce an effective antitumor 
immune response in both animal models and human sarcoma trials, suggesting that 
boosting immune responses may have therapeutic value in this setting (Indelicato and 
Finkelstein 2012). 
Radiation induced sarcomas (RIS) are well-characterized and constitute about 3% of all 
sarcomas.  They are more aggressive than other sarcomas.  One of the most significant 
effects of radiation therapy on normal tissues is mutagenesis and genomic instability 
which is the basis for radiation-induced malignancies.  A high frequency of MYC 
amplifications has been described in radiation-induced angiosarcomas, but not in 
primary angiosarcomas and other somatic mutations have been described.  Many 
tumors that respond to PD-1/PD-L1 inhibitors are those with a high mutation load or that 
are commonly associated with mutations. 


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The most common types of bone sarcoma are osteosarcoma and chondrosarcoma. 
PD-L1 expression in osteosarcoma has been described as 36% in 161 patients with 
osteosarcoma (Raj et al. 2014). 
Evidence that PD-L1 specifically plays a role in inhibiting immune surveillance in soft 
tissue sarcoma comes from the observation that the protein was expressed on tumor 
cells in 58% of patients with the disease (Kim et al. 2013).  Moreover, PD-L1 expression 
was significantly associated with higher clinical stage, presence of distant metastasis, 
higher histological grade, poor differentiation of tumor and tumor necrosis, suggesting 
the protein is playing an active role in inducing immune checkpoints (Kim et al. 2013).  
1.3.1.6 
Mesothelioma 
Chronic exposure to asbestos, a Group I carcinogen, induces genetic alterations in lung 
epithelial cells via at least two known mechanisms: direct DNA damage, and mutagenic 
asbestos-driven escape from apoptosis (Otsuki et al. 2007).  The resulting genetic 
alterations are thought to drive the development of malignant mesothelioma.  The same 
process might be expected to result in an increased rate of TSA production, as well, 
making mesothelioma a potentially good target for immunotherapeutic approaches. 
Many of the epidemiologic associations pertaining to malignant pleural mesothelioma 
apply to malignant mesothelioma arising in the peritoneum.  There are, however, several 
important site-specific differences in the demographic features, genetics, and distribution 
of histological subtypes between mesotheliomas arising in the pleural and peritoneal 
cavities that suggest fundamental biological disparities between tumors at these sites 
(Husain et al. 2013).  Due to differences in biology and prognosis, two different cohorts 
have been implemented in this study: pleural mesothelioma and peritoneal 
mesothelioma. 
Evidence that mesothelioma tumors are indeed immunogenic comes from studies 
demonstrating high levels of immune cell infiltration in mesothelioma tumors (Gregoire 
2010).  However, the relative levels of lymphocyte subtypes, as well as the cytokine 
levels, indicate that the immune infiltrate is in a relatively tolerogenic state (Hegmans et 
al. 2006; Gregoire 2010), i.e., that immune checkpoints may be required for 
tumorigenesis.  PD-L1 may play a role in forming this tolerogenic state, as the protein 
has been found to be highly expressed on mesothelioma tumor cells and within the 
tumor stroma (Currie et al. 2009). 
1.3.1.7 
Cholangiocarcinoma/Cancer of the Biliary Tract 
Long established risk factors for cholangiocarcinoma include hepatobiliary flukes, 
primary sclerosing cholangitis, biliary tract cysts, hepatolithiasis and toxins (Bridgewater 
et al. 2014).  All of these etiologic factors are thought to lead to a chronic state of biliary 
inflammation and increased cellular turnover (Bridgewater et al. 2014).  The chronic 
inflammation might be expected to down-regulate immune responses via immune 
checkpoint mechanisms, which in turn might help to promote carcinogenesis.   


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Several published studies support this model.  For instance, resting human 
cholangiocytes in culture have been shown to induce PD-L1 protein expression following 
administration of interferon-gamma, which is known to be up-regulated in many tumor 
microenvironments (Gong et al. 2009).  Expression of PD-L1 was also up-regulated in 
cholangiocarcinoma tissues compared with adjacent tissues (Ye et al. 2009).  Tumor-
related PD-L1 expression was significantly correlated with both tumor differentiation and 
stage and was inversely correlated with CD8+ tumor-infiltrating lymphocytes. 
1.3.1.8 
Thyroid Cancer 
There are 4 types of thyroid cancers – papillary, follicular, medullar and anaplastic. 
Papillary and follicular thyroid cancers are usually considered together as differentiated 
thyroid cancer. 
Most patients with differentiated thyroid cancer will evolve favorably with current therapy, 
which mostly includes surgery and radio-iodine treatment; however, 10–30% will present 
recurrent disease and may metastasize.  Medullary thyroid cancer (MTC) usually 
presents low chemosensitivity and radiosensitivity and does not concentrate iodine. 
1.3.1.8.1 
Anaplastic thyroid cancer 
Anaplastic thyroid cancer, one of the most aggressive human tumors, is characterized 
by multiple genetic mutations and chromosomal aberrations (Smallridge et al. 2009). 
DNA copy number changes were found in 11 out of the 13 patients with anaplastic 
thyroid cancer; gains were noted in 10 out of the 13, deletions in 3 out of the 13, both 
gains and deletions in two, and chromosome deletion in one (Hemmer et al. 1999).  This 
high degree of genetic heterogeneity might be expected to associate with high numbers 
of TSAs, but the highly aggressive course indicates that the immune system is 
nonetheless unable to check the uncontrolled growth.   
The inability of the immune system to slow anaplastic thyroid cancer might be 
attributable, at least in part, to the PD-L1/PD-1 pathway and is supported by several 
observations.  First, in a study of 407 thyroid nodule tissue samples, including 293 
differentiated thyroid carcinoma samples, malignant tissues displayed more intense PD-
L1 staining levels than benign tissues (both p<0.0001) (Cunha et al. 2013).  Second, 
elevated levels of PD-L1 protein were associated with the presence of CD4+ and CD8+, 
lymphocytes (p<0.05); tumor-associated macrophages (P<0.0001); and the presence of 
myeloid-derived suppressor cells (P=0.03256) (Cunha et al. 2013).  Finally, Stage II–IV 
thyroid cancer patients presented with higher PD-L1 mRNA levels than stage I cases 
(p=0.03522) (Cunha et al. 2013). 
1.3.1.8.2 
Follicular and papillary thyroid cancers 
Associations between inflammation and differentiated thyroid cancers have been 
reported and evidenced by a mixture of immune cells frequently found within, inside, or 
even surrounding primary thyroid tumors (Ward et al. 2014).  In papillary thyroid cancer, 
PD-L1 expression correlates with a greater risk of recurrence, poorer prognosis and 


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shortened disease free survival (Chowdhury et al, 2016).  Preliminary results of a study 
of pembrolizumab in a cohort of 22 patients with advanced papillary or follicular thyroid 
cancer, who failed standard therapy, reported 2 partial responses and a stable disease 
rate of 54.5% (Mehnert et al, 2016). 
1.3.1.8.3 
Medullary thyroid cancer and mixed medullary and follicular or 
papillary carcinoma 
Medullary thyroid carcinoma (MTC), arising from parafollicular, calcitonin-producing C 
cells, represents an aggressive, usually slow-growing tumor occurring in both sporadic 
and familial forms.  Sporadic MTC harbors RET gene somatic mutations in up to 50% of 
cases, and RAS family gene mutations occur in about 10%. 
The immune system has been shown to play a role in MTC as evidenced by an increase 
of FoxP3+ lymphocytes in peripheral blood of patients with MTC, which correlated with 
prognosis (Ward et al, 2014). 
1.3.1.9 
Gastric Adenocarcinoma/Adenocarcinoma of the Gastro-
Esophageal Junction 
Infection with Helicobacter pylori (H. pylori), a type of bacterium found in the stomach of 
about two-thirds of the world’s population, is a major cause of gastric cancer.  A 2001 
combined analysis of 12 case-control studies estimated that the risk of non-cardia 
gastric cancer (cancer in all areas of the stomach, except for the top portion near the 
esophagus) was nearly six times higher for H. pylori-infected people than for uninfected 
people (Helicobacter and Cancer Collaborative 2001).  Similarly, in prospective cohort 
studies, H. pylori-infected individuals had a nearly eight-fold increased risk for non-cardia 
gastric cancer (Kamangar et al. 2006).  A general atrophy of the stomach lining caused 
by H. pylori is thought to be the root cause of carcinogenesis in gastric cancer, although 
more direct interactions mediated by the bacterium have also been posited (Atherton 
2006). 
As with other bacterial infections, H. pylori induces a robust immune reaction in the host 
(Atherton 2006; Kusters et al. 2006).  Unlike other bacterial infections, however, the 
immune response is primarily cellular, rather than humoral.  Moreover, the cell-mediated 
immune reactions mounted by the host generally fail to clear the infection, due to 
H. pylori-induced products that interfere with local immune responses.  Thus, gastric 
cancer develops in the presence of an induced cell-mediated immune response, but one 
which immune subtypes and cytokine levels indicate to be in a tolerogenic state.  It is 
reasonable to hypothesize that the PD-L1/PD-1 pathway may be co-opted by the 
bacterium to help generate this anergy.  
Consistent with this hypothesis, a number of studies have indicated a role for PD-L1 in 
gastric carcinogenesis.  In case studies, PD-L1 was expressed on tumor cells in 42% to 
65% of patients with gastric cancer (Wu et al. 2006; Geng et al. 2014; Wei et al. 2014).  
PD-L1 immunodetection was significantly correlated to tumor size, invasion, lymph node 


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metastasis and survival time of patients.  PD-L1 immunolabeling was significantly 
enhanced (P<0.01) when the tumor infiltrated into the deep muscular layers, with lymph 
node metastasis or survival time of less than 2 years (Wu et al. 2006; Geng et al. 2014).  
High expression of PD-L1 was associated with poor prognosis (Geng et al. 2014).  
Finally, the anti-PD-L1 antibody Atezolizumab demonstrated preliminary activity against 
gastric cancer in Study PCD4989g. 
1.3.1.10 
Other Solid Tumors 
This cohort has been closed to recruitment from Protocol Version 4 onwards.  
Immune checkpoints and their involvement in tumor surveillance are highly complex, and 
many details of their regulation remain to be determined.  Thus, other cancers than the 
ones included in the previous 9 cohorts are good targets for Atezolizumab, but might not 
be predicted to be so based on our current knowledge.  In an effort to potentially capture 
other targetable cancers, the cohort enrolled patients with advanced solid tumors not 
included in the other cohorts.  Any positive signals in Cohort 10 may be followed up in 
future clinical studies.  
1.3.1.11 
Malignant Germ Cell Tumors 
Malignant germ cell tumors form a heterogeneous entity that is described by their 
histology. The tumors derive from embryonal cells and are located in the majority of 
cases in gonads (testis and ovary), but also in head and neck and mediastinum. 
Gonocytes have almost completely demethylated DNA, which facilitates the 
accumulation of mutations during cell replication and the development of intratubular 
germ cell neoplasia (Hanna et al. NEJM 2014). Frankhauser et al. have published PD-L1 
expression in testicular germ cell tumors. They found 73% of all seminomas and 64% of 
all non-seminomas exhibited PD-L1 expression by multi-tissue microarray using a cut-off 
value of 5% (Frankhauser et al. BJC 2015). 
1.3.1.12 
ER+/HER2- Metastatic Breast Cancer with Known High 
Mutation Load (>100 mutations) by Local Test 
Although several advances have been achieved, most of the patients with metastatic 
ER+/HER2- breast cancer will die after 4 years. One of the challenges is to identify new 
treatment for patients with ER+/HER2- mBC. 
Whole exome sequencing of metastatic breast cancers has revealed that a subset of 
ER+/Her2- mBC present with high mutational load (Stephens et al. Nature 2012, M. 
Disis, ASCO 2015). This subset of patients might be more likely to benefit from 
immunotherapy due to increased number of mutations and neoantigens. Haricharan et al. 
demonstrated that ER+, but not ER-, tumors with a high somatic mutational load are 
associated with poor overall survival (HR = 2.02). These high mutation load tumors are 
enriched for coincident mutations in both DNA damage repair and ER signature genes 
(Haricharan et al. Breast Cancer Res Treat, 2014). 


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1.3.1.13 
Thymoma and Thymic Cancer 
Epithelial thymomas and thymic carcinomas include a variety of subtypes, well described 
in the World Health Organization (WHO) classification and must be differentiated from a 
number of nonepithelial thymic neoplasms, including (but not limited to) neuroendocrine 
tumors (NETs), germ cell tumors and lymphomas. In general, thymomas are indolent 
tumors with a tendency toward local recurrence rather than metastasis.  Thymic 
carcinomas, however, are typically invasive, with a higher risk of relapse and a poorer 
prognosis. 
Thymic carcinoma is often associated with an overexpression of growth factor receptors 
like epidermal growth factor receptor (EGFR), stem cell factor receptor (SCFR) and 
Insulin-like growth-factor-1 receptor (IGF-1R) and have been found to frequently harbor 
mutations in epigenetic regulatory genes.  
In a sample of 38 thymic carcinoma patients, 70% stained positive for PD-L1 and in a 
sample of 101 thymomas, 23% stained positive for PD-L1 (Katsuyo et al. 2015). 
1.3.1.14 
Gastroenteropancreatic (GEP) and Lung Neuroendocrine 
Tumors (NETs) 
Neuroendocrine tumors (NETs) are generally classified based on their anatomic site of 
origin.  NETs can arise in many different areas of the body, and are most often located in 
the intestine, pancreas or the lungs.  Due to the different etiology and biology, two 
different cohorts are implemented in this study: neuroendocrine gastroenteropancreatic 
tumors and neuroendocrine tumors of the lung (excluding small cell lung cancer, SCLC). 
The WHO classification scheme places neuroendocrine tumors into three main 
categories, which emphasize the tumor grade rather than the anatomical origin: well-
differentiated NETs (low grade), neuroendocrine carcinomas with low-grade malignant 
behavior and poorly differentiated (high grade) and neuroendocrine carcinomas, which 
are the large cell neuroendocrine and small cell carcinomas. 
Neuroendocrine gastroenteropancreatic tumors (GEP-NETs) share a common 
phenotype with immunoreactivity for the so-called ‘pan-neuroendocrine’ markers 
including chromogranin A and synaptophysin.  Neuron-specific enolase (NSE) and CD56 
are often positive in GEP-NETs, but are not specific for this tumor entity. Pulmonary 
neuroendocrine cells (PNECs) express serotonin and NSE and also gastrin-releasing 
peptide (GRP) (Öberg et al. 2012). 
In a cohort of 32 patients with metastatic GEP-NET, PD-L1 expression was reported in 
21.9% of the patients (Kim et al. 2016). 
1.3.1.15 
HPV Induced Squamous Cell Carcinomas 
As described for cervical cancer, HPV induced tumors have the potential to be highly 
immunogenic.  An estimated 50% of penile, 88% of anal, 43% of vulvar, 70% of vaginal, 


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and 13–56% oropharyngeal cancers are attributable to HPV, primarily HPV-16 typically 
followed by HPV-18 (De Vuyst et al, 2009). 
1.3.1.15.1 
Head and Neck Squamous Cell Carcinoma (HNSCC) 
During the past decade, infection with HPVs, in particular HPV16 has emerged as a risk 
factor for HNSCCs, specifically HNSCCs arising in the oropharynx (tonsil, base of 
tongue, and soft palate). Currently, up to 70% of oropharyngeal cancers in the US are 
HPV-mediated oropharyngeal squamous cell carcinomas. HPV-16 is detected in over 90% 
of HPV-induced HNSCC and data suggests that HPV-16 cancers may present more 
frequently with lymph node metastases and may have a poorer outcome compared with 
other HPV types (Nichols et al, 2013).  
Recently several studies of PD-1–pathway inhibitors have reported overall response 
rates in the 20% range in relapsed HNSCC (Seiwert et al, 2015; Fury et al. 2014). 
Responses were observed in both HPV positive and HPV negative patients, 
1.3.1.15.2 
Penile Cancer 
Penile carcinoma is mostly a squamous cell carcinoma (SCC) with several histological 
subtypes. In this study only HPV positive squamous cell penile carcinoma will be 
included. The current treatment of HPV-positive penile SCC is identical to other penile 
SCCs. 
HPV DNA has been detected in approximately 40% to 50% of invasive penile cancer 
cases and in up to 90% of high-grade squamous intraepithelial lesions.  The high-risk 
oncogenic subtypes 16 and 18 were detected in over 60% of HPV-positive specimens. 
1.3.1.15.3 
Vaginal and Vulvar Cancers 
SCC accounts for approximately 85% of vaginal cancer cases and about 90% of vulvar 
carcinomas.  In this study only HPV positive squamous cell carcinoma of the vagina and 
the vulva will be included. Both HPV 16 and 18 are commonly detected in HPV-induced 
vaginal or vulvar cancers. The treatment of HPV positive or negative SCC of the vagina 
and vulva are identical. 
1.3.1.15.4 
Anal Cancer 
HPV infection is strongly associated with anal cancer development and may be a 
necessary step in its carcinogenesis. HPV16 is the most prevalent HPV subtype in anal 
carcinoma and is present in up to 89% of all patients with anal carcinoma 
(Serup-Hansen et al, 2014). 
1.3.1.16 
Known MSI High or MMR Deficient Tumors (excluding CRC and 
gastric cancers) 
Microsatellite instability (MSI) is a hypermutable phenotype caused by the loss of DNA 
MMR activity and is detected in a wide range of human solid tumors.  Its frequency is 
highly variable across tumor types and has not been evaluated for all tumor types.  
Frequencies assessed include: uterine 14.1%, small bowel 8.6%, prostate 6.2%, cancer 


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of unknown primary origin 2.7%, hepatobiliary 2.3%, neuroendocrine 0.2%, pancreas 
0.2%, NSCLC 0.2% and breast 0.1% (Hall et al, 2016). 
MSI has been linked to a number of phenotypic characteristics and clinicopathological 
features of tumors and its predictive relevance has been primarily studied in colorectal 
cancer.  Recent data are suggestive of more pronounced efficacy of checkpoint 
inhibitors in patients with colorectal or gastric cancer whose tumors are MSI-high.  
MSI-H CRC is known to have an exceptionally high mutation burden.  There is an 
increased presence of tumor-specific neoantigens in hypermutated tumors which is 
associated with an increased quantity of tumor-infiltrating lymphocytes (TILs) and 
overexpression of immune checkpoint receptors and ligands such as PD-1 and PD-L1 
(Overman et al. 2016). 
Overall the MSI status appears predictive of anti-PD-1/L1 therapy efficacy independently 
of tumor histology (Le et al., 2015). 
1.3.2 
Benefit-Risk 
Prior to enrolment, most patients in this study will have received previous treatment 
including surgery, radiation therapy and/or systemic cytotoxic chemotherapy for the 
treatment of their solid tumor(s).  Moreover, it is likely that all standard therapeutic 
options for their advancing, treatment-refractory disease will have been exhausted, 
necessitating enrolment into a clinical trial, and that their overall prognosis is 
consequently bleak.   
Immunotherapy with Atezolizumab could provide substantial benefit to the advanced 
solid tumor patients enrolling in this study.  In the ongoing Study PCD4989g, 
Atezolizumab has exhibited efficacy in a variety of solid tumors.  For instance, in 
advanced NSCLC patients with IC ≥ 5%, the confirmed ORR was 26.5% (95% CI: 14.3%, 
43.6%) and the 24-week PFS rate was 36.4% (95% CI: 19.95%, 52.74%).  The DOR 
ranged from 12.3+ to 85.9+ weeks.  In advanced NSCLC patients with IC < 5%, the 
confirmed ORR was 15.9% (95% CI: 7.2%, 29.0%) and the 24-week PFS rate was 41.1% 
(95% CI: 26.18%, 56.07%).  The DOR ranged from 25.4+ to 70.6+ weeks.   
Significant efficacy was also observed in Study PCD4989g in patients with advanced 
urothelial cancer (IHC 2/3, ORR = 52% [95% CI: 34%, 69%]; IHC 0/1, ORR =  4% [95% 
CI: 6%, 28%]) and advanced RCC (IHC 1/2/3, ORR = 20% [95% CI: 9%, 37%]; IHC 0, 
ORR = 10% [95% CI: 2%, 30%]) (Section 1.2.4.1).  Thus, consistent with other studies in 
the literature (Brahmer et al. 2012), the anti-PD-L1 antibody Atezolizumab may act as a 
general anticancer immunotherapy that works across multiple solid tumor types.  
Nonetheless, in order to maximize potential patient benefit, substantial effort has been 
made to choose patients for enrolment who are most likely to benefit from Atezolizumab 
therapy.  To do so, academic experts were queried and relevant published literature was 
reviewed to identify solid tumors that: 1) were likely to have high immunogenicity and, 


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thus, to respond to therapies that increase antitumor immunity; and 2) had published 
evidence indicating a direct role of PD-L1 expression on clinical outcomes, including 
prognosis and treatment outcomes.  Further detail on the reasons for choosing the 
included tumors in this study are presented in the previous section (Section 1.3.1).  
Although Atezolizumab has been generally well tolerated (see Section 1.2.3), adverse 
events with potentially immune-mediated causes, including rash, hypothyroidism, 
hepatitis/transaminitis, colitis, and myasthenia gravis have been observed in 
Study PCD4989g.  To date, these events have been monitorable and treatable (see 
Section 5.1.4 and the Atezolizumab Investigator’s Brochure for more information on 
managing adverse events associated with Atezolizumab therapy). 
In summary, then, treatment with Atezolizumab offers the potential for clinical benefit in 
many advanced solid tumors.  Because most Atezolizumab-related toxicities observed to 
date have been mild, transient, and do not overlap with those of chemotherapy, patients 
who do not respond to study treatment are considered likely to be able to subsequently 
receive further therapies.  Patients will be fully informed of the risk of continuing study 
treatment in spite of apparent radiographic progression, and investigators should make a 
careful assessment of the potential benefit of doing so, considering radiographic data 
and the clinical status of the patient. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective for this study is as follows: 
• 
To evaluate non-progression rate (NPR) at 18 weeks in patients with advanced solid 
tumors treated with Atezolizumab, defined as the percentage of patients with CR, 
PR or SD as assessed by the Investigator according to RECIST, v1.1 (except for 
prostate cancer and malignant pleural mesothelioma) and disease-specific criteria 
for patients with prostate cancer (see  Appendix 6) and malignant pleural 
mesothelioma (see Appendix 7). 
 
The secondary efficacy objectives for this study are as follows: 
• 
To evaluate NPR at 24 weeks, overall response rate (ORR), best overall response 
(BOR), clinical benefit rate (CBR), duration of response (DOR), time to tumor 
progression (TTP) and progression-free survival (PFS), as assessed by the 
Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural 
mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7) 
• 
To evaluate NPR at 18 and 24 weeks, ORR, BOR, CBR, DOR, TTP and PFS, as 
assessed by the Investigator using modified RECIST (Appendix 3)  
• 
To evaluate overall survival (OS) 
 


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2.2 
SAFETY OBJECTIVES 
The safety objectives for this study are as follows: 
• 
To evaluate the safety and tolerability of Atezolizumab in patients with advanced 
solid tumors 
• 
To characterize the immunogenic potential of Atezolizumab by measuring anti-
Atezolizumab antibodies and to explore the potential relationship of the 
immunogenicity response with safety and efficacy 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The PK objectives for thi s study are as follows: 
• 
To characterize the pharmacokinetics of Atezolizumab 
 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To evaluate the relationship between tumor tissue PD-L1 expression and measures 
of efficacy, including NPR at 18 weeks and 24 weeks, ORR, BOR, CBR, DOR, TTP, 
PFS and OS. 
• 
To assess predictive and prognostic exploratory biomarkers (e.g. but not limited to 
protein and genetic markers on DNA and RNA) in archival and/or fresh tumor tissue 
and plasma and their association with disease status and/or response to study 
treatment 
• 
To evaluate exploratory pharmacodynamic (PD) biomarkers (e.g., genetic markers, 
T, B and NK cell enumeration, T cell subpopulations like CD8+ T, effector/memory T 
cells, regulatory T cells, changes in expression of CD25 or human leukocyte 
antigen-DR [HLA-DR], interferon [IFN]-gamma production, IL-2 and other 
exploratory biomarkers) in tumor tissue, tumor microenvironment and plasma and 
their association with disease status, and/or response to study treatment, tumor 
immunobiology or tumor type 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This will be an open-label, multicenter, multinational, multicohort, phase II study. For 
each cohort, the study will consist of a Screening Period (Day –35 to −1), a Treatment 
Period, a Treatment Discontinuation Visit occurring ≤ 30 days after the last dose of study 
medication and a 24-month Survival Follow-up Period (Figure 1).  Day 1 (baseline) will 
be defined as the first day a patient receives study medication. 




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The study will include 16 cohorts of patients with the following solid cancers: 
1. 
Cervical cancer 
2. 
Nasopharyngeal carcinoma 
3. 
Known MSI-H- or MMR-deficient colorectal cancer 
4. 
Known BRCA 1/2 mutated cancers 
a. BRCA mutated ovarian cancer 
b. BRCA mutated breast cancer 
5. 
Soft tissue, visceral and bone sarcomas:  
a. Liposarcoma  
b. Leiomyosarcoma 
c. Gastrointestinal stromal tumors (GIST) 
d. Undifferentiated pleomorphic sarcoma  
e. Known translocation-related sarcomas 
f. Radiation induced sarcoma 
g. Osteosarcoma 
h Chondrosarcoma 
6. 
Mesothelioma 
a. Pleural mesothelioma 
b. Peritoneal mesothelioma 
7. 
Cholangiocarcinoma/cancer of the biliary tract 
8. 
Thyroid cancer 
a. Anaplastic thyroid cancer 
b. Follicular or papillary thyroid cancer 
c. Medullary thyroid cancer and mixed medullary and follicular or papillary 
thyroid cancer 
9. 
Gastric adenocarcinoma/adenocarcinoma of the gastro-esophageal junction 
10. Other solid tumors – closed to recruitment from Protocol Version 4 onwards   
11. Malignant germ cell tumors 
12. ER+/HER2- metastatic breast cancer with known high mutation load (>100 
mutations) by local test 


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13. Thymoma and thymic cancer 
a. Thymoma 
b. Thymic cancer 
14. Gastroenteropancreatic (GEP) and lung neuroendocrine tumors (NETs) 
a. Low and intermediate grades (typical or atypical carcinoid) 
b. Poorly differentiated grade (excluding SCLC) 
15. Known HPV induced squamous cell carcinomas 
a. Head and neck 
b. Penile cancer 
c. Vaginal cancer / vulvar cancer 
d. Anal cancer 
16. Known MSI high or MMR deficient tumors (excluding colorectal and gastric cancers) 
 
Full details of the histological types / subtypes and markers mandated for each cohort 
are described in Section 4.1.3. 
In addition, only patients whose tissue is available for biomarker assessment testing will 
be eligible.  
Enrolled patients will receive Atezolizumab at a fixed dose of 1200 mg administered 
intravenously on the first day of each cycle.  One cycle of therapy will be defined as 
21 days (± 3 days).   
Patients treated with Atezolizumab who have no post-baseline tumor assessment (per 
protocol mandated timelines), and enrolled patients who do not receive any dose of 
Atezolizumab will be replaced. 
Atezolizumab treatment may be continued as long as patients are experiencing clinical 
benefit, as assessed by an investigator, in the absence of unacceptable toxicity or 
symptomatic deterioration attributed to disease progression after an integrated 
assessment of radiographic data, biopsy results (if available) and clinical status. 
Patients will be permitted to continue Atezolizumab treatment after RECIST v1.1 criteria 
(or disease-specific criteria for patients with prostate cancer [Appendix 6] and malignant 
pleural mesothelioma [Appendix 7]) for progressive disease are met if they meet all of 
the following criteria: 
• 
Evidence of clinical benefit as assessed by the Investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g., 
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• 
No decline in ECOG performance status that can be attributed to disease 
progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients treated with Atezolizumab in whom radiographic disease progression is 
confirmed at a subsequent tumor assessment may be considered for continued study 
treatment at the discretion of the Investigator if they continue to meet the above criteria. 
If an individual patient continues to experience clinical benefit beyond 2 years of 
radiologic progressive disease, it lies within the discretion of each investigator to 
continue study treatment based on a positive risk benefit assessment by the investigator. 
The primary objective of this study is to evaluate Investigator-determined non-
progression rate (NPR) at 18 weeks in the individual cohorts using RECIST, v1.1 (except 
for prostate cancer and malignant pleural mesothelioma) and disease-specific criteria for 
patients with prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7).  Secondary efficacy variables (including ORR, BOR, CBR, DOR, TTP and 
PFS) will be recorded using RECIST, v1.1, (except for prostate cancer and malignant 
pleural mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7), and modified 
RECIST (see Appendix 3). 
Safety will be monitored by assessing AEs, SAEs, AEs of special interest (AESIs), 
laboratory findings and electrocardiogram.  The National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE, v4.0) will be used to 
quantify the intensity of AEs occurring during treatment.  Incidence, type and severity of 
AEs, SAEs, incidence of AEs and SAEs leading to Atezolizumab interruption or 
discontinuation and cause of death will be reported.  In addition, to characterize the 
immunogenic potential and PK of Atezolizumab, blood samples will be taken at various 
time points before and after study treatment administration (see Appendix 2 for a 
detailed description of the assessments). 
This study will also have an exploratory analysis examining biomarkers.  These analyses 
will be conducted on archival tissue specimens (required for patient inclusion), as well as 
prospectively-collected plasma/blood samples and freshly obtained tumor specimens.  
Collected samples will be analyzed at a central laboratory for PD-L1 expression, as well 
as other potential markers, to assess relationships between biomarker expression and 
patient outcomes including, but not limited to, response and disease progression.  
All patients will be monitored for survival for a minimum period of 24 months after the 
last patient has been enrolled in each cohort or until all patients have died, withdrawn 
consent or are lost to follow up, or the Sponsor decides to end the study, whichever 
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calls and/or review of patient medical records approximately every 3 months from study 
treatment discontinuation until patient death, loss to follow-up, withdrawal of consent or 
until the study is terminated by the Sponsor.  Patients who discontinue study treatment 
for reasons other than disease progression (e.g., toxicity) should continue to undergo 
scheduled tumor assessments approximately every 3 months until death, disease 
progression, initiation of further systemic cancer therapy or study closure, whichever 
occurs first. 
Enrollment in this study will be based on Simon's optimal two-stage design (Simon 1989).  
Accordingly, 12 fully-evaluable patients will be enrolled in each cohort in the first stage.  
If 3 or more of these patients exhibit non-progressive disease at the end of Stage I, then 
an additional 13 fully-evaluable patients will be enrolled in Stage II.  Thus, approximately 
725 patients are expected to participate in the study.  However, if positive efficacy 
signals are observed in any of the other cohorts that include different tumor types or in a 
specific subgroup of patients within other cohorts (e.g. biomarker positive subgroup), the 
Sponsor in discussion with the Steering Committee may decide to extend the enrolment 
of the individual tumor type or subgroup of patients based on methodology explained in 
the Determination of Sample Size (Section 6.1).  
Please refer to the Schedule of Assessments (Appendix 1) for more detail on the timing 
and nature of assessments to be carried out in this study. 
3.2 
END OF STUDY 
The end of cohort will occur when all patients have been followed for survival for a 
minimum of 24 months after the last patient has been enrolled in the cohort or until all 
patients have died, withdrawn consent or are lost to follow up, or the Sponsor decides to 
end the study, whichever occurs first. 
Recruitment/enrollment in any of the cohorts may present some challenges. Therefore, a 
permanent stop rule may be applied if the recruitment rate is too low after any of the 
individual cohorts have been completely enrolled, which could result in stopping further 
enrolment in some of the remaining cohorts (Section 4.6.3).  This decision will be made 
by the Sponsor based on regular review of the recruitment rate. After a cohort has been 
opened for at least 4 months, it may be closed early if the recruitment is less than 2 
patients per month on average from the opening of the cohort. The overall end of study 
will occur when the end of cohort has occurred for all of the individual cohorts, as 
described above. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Dose and Schedule 
The fixed dose of 1200 mg (equivalent to an average body weight−based dose of 
15 mg/kg) was selected on the basis of both nonclinical studies and available clinical 
data from Study PCD4989g as described below. 


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The target exposure for Atezolizumab was projected on the basis of nonclinical tissue 
distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the 
observed Atezolizumab interim pharmacokinetics in humans, and other factors.  The 
target trough concentration (Ctrough) was projected to be 6 μg/mL on the basis of several 
assumptions, including: 1) 95% tumor-receptor saturation is needed for efficacy and 2) 
the tumor-interstitial concentration to plasma ratio is 0.30 based on tissue distribution 
data in tumor-bearing mice. 
The Atezolizumab dose is also informed by available efficacy, safety, PK and 
immunogenicity data in humans.  Thus, anti-tumor activity has been observed across 
doses from 1 mg/kg to 20 mg/kg.  The MTD of Atezolizumab was not reached and no 
DLTs have been observed at any tested dose (0.03–20 mg/kg).  Preliminary PK data 
from Study PCD4989g suggest that Atezolizumab exhibits pharmacokinetics that are 
both linear and consistent with typical IgG1 antibodies at doses ≥ 1 mg/kg.  Patients 
dosed at 10-, 15-, and 20-mg/kg have maintained the expected target trough levels 
(6 µg/mL), despite the detection of some ATAs.  To date, no relationship between the 
development of measurable ATAs and safety or efficacy has been observed. 
Currently available PK and ATA data suggest that the 15-mg/kg Atezolizumab q3w 
regimen (or fixed-dose equivalent) for Phase II and Phase III studies would be sufficient 
to both maintain Ctrough 6 μg/mL and further safeguard against both interpatient variability 
and the potential effect of ATAs that might lead to subtherapeutic levels of Atezolizumab 
at the 10-mg/kg q3w dose level (or fixed-dose equivalent).  From inspection of available 
observed Ctrough data, moving further to the 20-mg/kg Atezolizumab q3w regimen does 
not appear to be warranted to maintain targeted Ctrough levels relative to the proposed 15-
mg/kg Atezolizumab q3w level.  
Finally, simulations do not suggest any clinically meaningful differences in exposure 
following a fixed dose or a dose adjusted for weight (Bai et al. 2012).  On the basis of the 
preceding analysis, a fixed dose of 1200 mg has been selected in this study (equivalent 
to an average body weight-based dose of 15 mg/kg). 
Selection of an every-21-day dosing interval is supported by this preliminary 
pharmacokinetics evaluation and allows for a convenient integration with common 
chemotherapeutic regimens. 
All available PK, ATA, safety, and efficacy data for Atezolizumab will continue to be 
evaluated as described above to support the proposed 1200-mg fixed dose. 
3.3.2 
Rationale for Patient Population and Analysis Groups 
This study will assess the safety and efficacy of Atezolizumab in patients with a diverse 
array of advanced solid tumors.  An increasing pool of data indicates that anti-PD-L1 
therapy, by reinvigorating tumor-specific T-cell activity, has the potential to boost 
antitumor immunity against multiple cancers.  A Phase I dose-escalation study of 207 


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patients treated with the anti-PD-L1 antibody BMS-936559 reported an ORR of 
approximately 17% in patients with melanoma, 12% in patients with renal cell carcinoma, 
10% in patients with NSCLC and 6% in patients with ovarian cancer (Brahmer et al. 
2012).  Several durable responses were observed in this study, with partial responses 
and complete responses ongoing at over 18 months.   
Similarly, in the ongoing Study PCD4989g, Atezolizumab exhibited efficacy in a variety 
of solid tumors, including NSCLC, bladder cancer and RCC (Section 1.2.4.1). 
Although the response rate appears to correlate with PD-L1 expression in Phase I study 
PCD4989g, responses per RECIST v1.1 and prolonged stable disease have been 
observed in the subgroup of patients with low PD-L1 expression.  Therefore, this trial will 
include patients with all levels of PD-L1 expression.  
In order to maximize potential patient benefit, substantial effort has been made to 
choose patients for enrolment who are most likely to benefit from Atezolizumab therapy.  
To do so, academic experts were queried and relevant published literature was reviewed 
to identify solid tumors that: 1) were likely to have high immunogenicity and, thus, to 
respond to therapies that increase antitumor immunity; and 2) had published evidence 
indicating a direct role of PD-L1 expression on clinical outcomes, including prognosis 
and treatment outcomes.  Further detail on the rationale for choosing the included 
tumors in this study are presented in Section 1.3.1. 
3.3.3 
Rationale for Biomarker Assessments 
The development of advanced cancers is thought to occur by a complex, multi-step 
process involving diverse cell-biological functionalities.  These include sustaining 
proliferative signaling, evading growth suppressors, resisting cell death, enabling 
replicative immortality, inducing angiogenesis, reprogramming of energy metabolism, 
evading immune destruction and activating invasion and metastasis (Hanahan and 
Weinberg 2011).  Therefore, all patients may not be equally likely to benefit from 
treatment with Atezolizumab.  Thus, this study will collect various tumor and blood 
samples at baseline in an effort to identify those patients with advanced solid tumors 
who respond most actively to Atezolizumab.  Furthermore longitudinal sampling of both 
tumor and blood may help identifying changes induced by Atezolizumab and might help 
to understand potential escape mechanisms.  Analysis and comparison of tumor and 
blood samples might additionally help to (further) develop diagnostic tools and 
techniques.  
3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
The primary efficacy outcome measure for this study is as follows: 
• 
Non progression rate (NPR) at 18 weeks is defined as the percentage of patients 
with CR, PR or SD at 18 weeks, as determined by the Investigator using RECIST, 


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v1.1 (except for prostate cancer and malignant pleural mesothelioma) and disease-
specific criteria for patients with prostate cancer (see Appendix 6) and malignant 
pleural mesothelioma (see Appendix 7).  Patients treated with Atezolizumab who 
have no post-baseline tumor assessment (per protocol mandated timelines), and 
enrolled patients who did not receive any dose of Atezolizumab will be replaced 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
Non progression rate (NPR) at 24 weeks is defined as the percentage of patients 
with CR, PR or SD at 24 weeks, as determined by the Investigator using RECIST, 
v1.1 (except for prostate cancer and malignant pleural mesothelioma) and disease-
specific criteria for patients with prostate cancer (see Appendix 6) and malignant 
pleural mesothelioma (see Appendix 7).  Patients treated with Atezolizumab who 
have no post-baseline tumor assessment (per protocol mandated timelines), and 
enrolled patients who did not receive any dose of Atezolizumab will be replaced 
• 
Overall response rate (ORR) is defined as the proportion of patients with a CR or 
PR, as assessed by the Investigator using RECIST v1.1 (except for prostate cancer 
and malignant pleural mesothelioma) and disease-specific criteria for patients with 
prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7) 
• 
Best overall response (BOR) is defined as the proportion of patients with the best 
response obtained throughout the trial, as determined by the Investigator using 
RECIST v1.1 (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Appendix 6) and 
malignant pleural mesothelioma (see Appendix 7) 
• 
Clinical benefit rate (CBR) is defined as the proportion of patients whose BOR, as 
determined by the Investigator using RECIST, v1.1 (except for prostate cancer and 
malignant pleural mesothelioma) and disease-specific criteria for patients with 
prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7), is either CR, PR or SD lasting for at least 6 weeks 
• 
Duration of objective response (DOR) is defined as the time from the first 
occurrence of a documented objective response to the time of progression, as 
determined by the Investigator using RECIST, v1.1 (except for prostate cancer and 
malignant pleural mesothelioma) and disease-specific criteria for patients with 
prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7), or death from any cause, whichever occurs first.  For patients who do 
not die or experience disease progression before the end of the study or who are 
lost to follow-up, duration of objective response will be censored at the day of the 
last tumor assessment 
• 
Progression-free survival (PFS) is defined as the time from the first day of study 
treatment to the first occurrence of disease progression, as determined by the 
Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural 
mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7), or death from 
any cause, whichever occurs first.  A patient without a PFS event will be censored at 
the time of the last evaluable tumor assessment.  Patients with no tumor 
assessment after the baseline visit will be censored at the time of the first day of 
study treatment plus 1 day 


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• 
Time to progression (TTP) is defined as time from the first day of study treatment to 
the first occurrence of progressive disease, as determined by the Investigator using 
RECIST, v1.1 (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Appendix 6) and 
malignant pleural mesothelioma (see Appendix 7), or death due to reason of 
disease progression, whichever occurs first. Patients who have not progressed or 
died due to disease progression at the time of study completion or who are lost to 
follow-up will be censored at the date of the last evaluable tumor assessment.  
Patients with no tumor assessment after the baseline visit will be censored at the 
time of the first day of study treatment plus 1 day 
• 
Overall survival (OS) is defined as the time from the first day of study treatment to 
death from any cause.  Patients for whom no death is captured on the clinical 
database will be censored at the most recent date they were known to be alive 
 
NPR at 18 and 24 weeks, ORR, BOR, CBR, DOR, PFS and TTP will also be determined 
by the Investigator using modified RECIST (see Appendix 3). 
3.4.2 
Safety Outcome Measures 
The safety and tolerability of Atezolizumab will be assessed using the following safety 
outcome measures: 
• 
Incidence, nature, and severity of adverse events graded according to the NCI 
CTCAE, v4.0 
• 
Number of cycles and dose intensity 
• 
Incidence of anti-Atezolizumab antibodies and the potential correlation with 
pharmacokinetics and safety parameters 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Maximum serum Atezolizumab concentration (Cmax) after infusion on Day 1 of 
Cycle 1 
• 
Minimum serum Atezolizumab concentration (Cmin) prior to infusion on Day 1 of 
Cycles 1, 2, 3, 4, 8 and every eight cycles thereafter and at study termination 
 
3.4.4 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Status of PD-L1 expression and other exploratory biomarkers (e.g. but not limited to 
protein and genetic markers) in archival and/or freshly obtained tumor tissues and 
plasma  collected pre-treatment and during treatment with Atezolizumab 
• 
Association of PD-L1 expression and other exploratory biomarkers (e.g. but not 
limited to protein and genetic markers) with disease status and/or response or 
resistance to Atezolizumab 
• 
Status of exploratory biomarkers in plasma (including but not limited to genetic 
markers and cytokines such as IFN-gamma) collected pre-treatment and during 
treatment/at progression/study discontinuation with Atezolizumab 


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Association of exploratory biomarkers in plasma with disease status and/or 
response or resistance to Atezolizumab, tumor immunobiology or tumor type 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed Informed Consent Form 
2. 
Ability to comply with protocol 
3. 
Male or female, 18 years of age or older. 
4. 
Histologically documented solid tumors that are advanced (i.e. Stages III or IV 
disease) and: 
– 
meet one of the cohort specifications in Section 4.1.3 
- 
have progressive disease at study entry 
- 
have received at least one line of prior systemic therapy or for which alternative 
therapy does not exist which is known to prolong survival.  
5. 
Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in 
paraffin blocks (preferred) or, in exceptional cases, 15 freshly cut and unstained 
slides, with an associated pathology report (in local language), for central testing. 
Detection of tumor in the provided block (or slide) needs to be confirmed by the 
central pathology laboratory prior to study enrollment. 
– 
Only tissue from core needle, punch or excisional biopsy sample collection will 
be accepted.  For core-needle biopsy specimens, at least three cores should be 
submitted for evaluation.  Fine-needle aspiration, brushing, bone tissue, and 
lavage samples are not acceptable 
– 
Patients who do not have tissue specimens meeting eligibility requirements 
must undergo a biopsy during the screening period.  Acceptable samples 
include core needle biopsies for deep tumor tissue (minimum three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, 
or mucosal lesions 
6. 
Measurable disease as defined by RECIST, v1.1. (except for prostate cancer and 
malignant pleural mesothelioma) and disease-specific criteria for patients with 
prostate cancer (see Appendix 6) and malignant pleural mesothelioma (see 
Appendix 7) 
7. 
ECOG Performance Status of 0 or 1 
8. 
Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 3 days prior to the first study treatment (Cycle 1, Day 1): 
– 
Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without granulocyte colony-
stimulating factor support within 2 weeks before Cycle 1, Day 1) 


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– 
Lymphocyte count ≥ 500/µL 
– 
White blood cell counts > 2500/μL 
– 
Platelet count ≥ 100,000/µL (without transfusion within 2 weeks before Cycle 1, 
Day 1) 
– 
Hemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic 
treatment to meet this criterion) 
– 
Serum bilirubin < 1.5 × upper limit of normal (ULN), with the following exception: 
Patients with known Gilbert disease who have serum bilirubin level 
≤ 3 × ULN may be enrolled 
– 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and 
alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions: 
Patients with liver involvement: AST and/or ALT ≤ 5 × ULN 
Patients with liver or bone metastases: alkaline phosphatase ≤ 5 × ULN 
– 
Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min on the basis 
of the Cockcroft-Gault glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL) 
– 
International normalized ratio (INR) and activated partial thromboplastin time 
(aPTT) ≤ 1.5 × ULN.  This applies only to patients who do not receive 
therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such 
as low−molecular weight heparin or warfarin) should be on a stable dose 
– 
Serum albumin level > 3.2 g/dL 
9. 
Women who are not postmenopausal (≥ 12 months of non-therapy-induced 
amenorrhea) or surgically sterile must have a negative serum pregnancy test result 
within 14 days prior to initiation of study drug 
10. For female patients of childbearing potential, agreement (by patient) to use a highly 
effective form(s) of contraception that results in a low failure rate (< 1% per year) 
when used consistently and correctly, and to continue its use for 5 months after the 
last dose of Atezolizumab.  Such methods include: combined (estrogen and 
progestogen containing) hormonal contraception, progestogen-only hormonal 
contraception associated with inhibition of ovulation together with another additional 
barrier method always containing a spermicide, intrauterine device (IUD): 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner (on the understanding that this is the only one partner during the whole 
study duration), and sexual abstinence. Oral contraception should always be 
combined with an additional contraceptive method because of a potential interaction 
with the study drug.   
11. Life expectancy > 3 months 
 


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4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1.  Malignancies other than disease under study within 5 years prior to Cycle 1 Day 1, 
with the exception of those with a negligible risk of metastasis or death (e.g., 
expected 5-year OS > 90%) treated with expected curative outcome (such as 
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin 
cancer, localized prostate cancer treated surgically with curative intent, ductal 
carcinoma in situ treated surgically with curative intent) 
2.  Uncontrolled tumor-related pain 
– 
Patients requiring pain medication must be on a stable regimen at study entry 
– 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone 
metastases or metastases causing nerve impingement) should be treated prior 
to enrollment 
– 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not 
presently associated with spinal cord compression) should be considered for 
loco-regional therapy if appropriate prior to enrollment 
3.   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 
4.  Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca >12 mg/dL or 
corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued 
use of bisphosphonate therapy or denosumab 
– 
Patients who are receiving bisphosphonate therapy or denosumab specifically 
to prevent skeletal events and who do not have a history of clinically significant 
hypercalcemia are eligible 
– 
Patients who are receiving denosumab prior to enrollment must be willing and 
eligible to receive a bisphosphonate instead while on study 
5.  History of treated asymptomatic or symptomatic CNS metastasis or presence of 
CNS metastases as determined by CT scan or MRI evaluation during screening or 
at prior radiographic assessments. 
6.  Leptomeningeal disease 
7.  Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for ≥ 2 weeks prior to Cycle 1, Day 1 
8.  Any approved anticancer therapy, including chemotherapy, hormonal therapy or 
radiotherapy, within 3 weeks prior to initiation of study treatment; however, the 
following are allowed: 
– 
Hormone-replacement therapy or oral contraceptives 
– 
Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1 


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9.  Acute toxicities from previous therapy that have not resolved to Grade ≤ 1, except 
for alopecia 
10.  Pregnant and lactating women 
11. Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant liver 
disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena 
cava syndrome) 
12. Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction within 3 months prior to Cycle 1, 
Day 1, unstable arrhythmias or unstable angina 
– 
Patients with a known left ventricular ejection fraction (LVEF) < 40% will be 
excluded 
– 
Patients with known coronary artery disease, congestive heart failure not 
meeting the above criteria, or LVEF < 50% must be on a stable medical 
regimen that is optimized in the opinion of the treating physician, in consultation 
with a cardiologist if appropriate 
13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to 
hospitalization for complications of infection, bacteremia or severe pneumonia 
14. Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 
– 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or chronic obstructive pulmonary disease) are eligible 
15. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of 
need for a major surgical procedure during the course of the study 
16. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
17. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese 
hamster ovary cells or to any component of the Atezolizumab formulation 
18. History of autoimmune disease, including but not limited to myasthenia gravis, 
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a 
more comprehensive list of autoimmune diseases) 
– 
Patients with a history of autoimmune hypothyroidism on a stable dose of 
thyroid replacement hormone are eligible 
– 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are 
eligible 


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– 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
o Rash must cover less than 10% of body surface area (BSA). 
o Disease is well controlled at baseline and only requiring low potency 
topical steroids. 
o No acute exacerbations of underlying condition within the previous 
12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], 
methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
high-potency or oral steroids) 
19. Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
20. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), or evidence of active pneumonitis on screening chest CT 
scan 
– 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
21. Any other diseases, metabolic dysfunction, physical examination finding or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the patient at high risk from treatment 
complication 
22. Positive test for HIV 
23. Patients with active hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) or hepatitis C 
– 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(defined as having a negative HBsAg test and a positive antibody to hepatitis B 
core antigen [anti-HBc] antibody test) are eligible 
– 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA 
24. Active tuberculosis 
25. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 
26. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study  
– 
Influenza vaccination should be given during influenza season only (example: 
approximately October to March in the Northern Hemisphere).  Patients must 
not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks 
prior to Cycle 1, Day 1 or at any time during the study treatment or within 5 
months after the last dose of atezolizumab 
27. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
anti−PD-1, or anti−PD-L1 therapeutic antibodies 












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4.3.2 
Atezolizumab Dosage, Administration, and Compliance 
The dose of Atezolizumab in this study will be 1200 mg administered by intravenous 
infusion every 3 weeks (21 [± 3] days). 
Administration of Atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
Atezolizumab will be delivered in 250 mL 0.9% NaCl IV infusion bags with product 
contacting surfaces of polyvinyl chloride (PVC) or polyolefin (PO) and IV infusion lines 
with product contacting surfaces of PVC or polyethylene (PE) and 0.2 µm in-line filters 
(filter membrane of polyethersulfone [PES]).  No incompatibilities have been observed 
between Atezolizumab and these infusion materials (bags and infusion lines). 
The initial dose of Atezolizumab will be delivered over 60 (± 15) minutes.  If the first 
infusion is tolerated without infusion-associated adverse events, the second infusion 
may be delivered over 30 (± 10) minutes.  If the 30-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 (± 10) minutes.   
For first infusion of study treatment, the patient’s vital signs must be determined within 
60 minutes before the infusion; during, and after the infusion if clinically indicated. For 
subsequent infusions, vital signs will be collected within 60 minutes before infusion and 
at the end of the infusion, if clinically indicated.  
Patients will be informed about the possibility of delayed post-infusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
No premedication will be allowed for the first dose of Atezolizumab.  Premedication may 
be administered for Cycles ≥ 2 at the discretion of the treating physician.  The 
management of infusion-related reactions will be according to severity as follows: 
• 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related 
event, the infusion rate should be reduced to half the rate being given at the time of 
event onset.  Once the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate.  If tolerated, the infusion 
rate may then be increased to the original rate 
• 
In the event that a patient experiences a moderate infusion-related event (NCI 
CTCAE Grade 2) or flushing, fever, or throat pain, the patient should have his or her 
infusion immediately interrupted and should receive aggressive symptomatic 
treatment.  The infusion should be restarted only after the symptoms have 
adequately resolved to baseline grade. The infusion rate at restart should be half of 
the infusion rate that was in progress at the time of the onset of the infusion-related 
event 
• 
For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), 
the infusion should be stopped immediately, and aggressive resuscitation and 
supportive measures should be initiated.  Patients experiencing severe or life-


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threatening infusion-related events will not receive further infusion and will be further 
managed as clinically indicated until the event resolves 
 
For anaphylaxis precautions, see Appendix 4. 
Guidelines for dosage modification, treatment interruption or discontinuation, and the 
management of specific adverse events are provided in Section 5.1.3 and the 
Atezolizumab Investigator’s Brochure. 
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF).  AEs associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse 
Event eCRF. 
Please refer to the Pharmacy Manual for detailed instructions on drug preparation, 
storage and administration. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(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 will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Atezolizumab 
The Sponsor will offer post-trial access to the study drug (Atezolizumab) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 


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A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for the cohort of advanced solid tumor into which the 
patient had enrolled 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for the cohort of advanced solid tumor into which the patient had enrolled 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
Patients may also take part in an extension study if the patient is still benefiting from 
treatment (defined as no registered PD) at the time of planned Last Patient Last Visit 
date. If the extension study is not set-up in time for the patient to roll over by the planned 
protocol LPLV date, nor is there a Post-Trial Access Program available, the patient can 
continue treatment in the study until the extension study is opened at the patient’s site. 
During the interim period between LPLV and a patient rolling over to the extension study, 
only safety data (AE including SAE and AESI) will continue to be collected in the eCRF. 
Other assessments (e.g. tumor assessment) can be performed as per standard of care. 
 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening evaluation 
and the treatment discontinuation visit. 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine and/or famotidine or another H2 
receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious infusion-
associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, 
tachycardia, reduced oxygen saturation or respiratory distress should be managed with 
supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists). 


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Systemic corticosteroids and tumor necrosis factor−α inhibitors may attenuate potential 
beneficial immunologic effects of treatment with Atezolizumab but may be administered 
at the discretion of the treating physician.  If feasible, alternatives to corticosteroids 
should be considered.  Premedication may be administered for Cycles ≥ 2 at the 
discretion of the treating physician after consultation with the Medical Monitor.  The use 
of inhaled corticosteroids for COPD and mineralocorticoids (e.g., fludrocortisone) and 
low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical 
insufficiency is allowed.  Megestrol administered as an appetite stimulant is acceptable 
while the patient is enrolled in the study. 
Colony-stimulating factors, such as granulocyte colony-stimulating factor and 
erythropoietin, should only be used according to the ASCO and ASCO/ASH guidelines, 
respectively (Smith et al. 2006; Rizzo et al. 2010).  Influenza vaccination should be given 
during influenza season only (approximately October to March).  Patients must not 
receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, 
Day 1 or at any time during the study treatment, or within 5 months after the last dose of 
Atezolizumab, but may receive inactivated vaccine. 
Patients who use hormonal therapy with gonadotropin-releasing hormone agonists or 
antagonists for prostate cancer, oral contraceptives, hormone-replacement therapy, 
prophylactic or therapeutic anticoagulation therapy (such as low molecular weight 
heparin or warfarin at a stable dose level), or other allowed maintenance therapy (see 
Section 4.1.2) should continue their use. 
Females of reproductive potential should use a highly effective means of contraception. 
All concomitant medications should be reported to the investigator and recorded on the 
appropriate eCRF. 
 
4.4.2 
Prohibited Therapy 
Any concomitant therapy intended for the treatment of cancer, whether health authority-
approved or experimental, is prohibited.  This includes but is not limited to the following: 
• 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents or herbal therapy (except for maintenance therapies outlined in Section 4.1.1, 
and 4.1.2) 
– 
After Cycle 2, certain forms of radiotherapy may be considered for pain 
palliation if patients are deriving benefit (e.g., treatment of known bone 
metastases). Please contact the Medical Monitor prior to initiating radiotherapy.  
– 
Patients experiencing a mixed response requiring local therapy (e.g., surgery, 
stereotactic radiosurgery, radiotherapy, radiofrequency ablation) for control of 
three or fewer lesions may still be eligible to continue study treatment.  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 Sponsor 


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• 
The concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, their use for patients on study is allowed at the discretion of the 
investigator, provided that there are no known interactions with any study treatment.  
As noted above, herbal therapies intended for the treatment of cancer are prohibited 
• 
Patients who are receiving a receptor activator of nuclear factor kappa B ligand 
inhibitor (denosumab) prior to enrollment must be willing and eligible to receive a 
bisphosphonate instead while on study; denosumab could potentially alter the 
activity and the safety of Atezolizumab 
 
Patients should not receive any live, attenuated vaccine (e.g., FluMist®) at any time 
during the study while the patient is receiving Atezolizumab and for a period of 5 months 
after the discontinuation of Atezolizumab. 
Patients are not allowed to receive immunostimulatory agents, including but not limited 
to interferon (IFN)-α, IFN-γ, or IL-2, during the entire study.  These agents, in 
combination with Atezolizumab, could potentially increase the risk for autoimmune 
conditions. 
Patients should also not receive immunosuppressive medications, including but not 
limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide.  These 
agents could potentially alter the activity and the safety of Atezolizumab.  Systemic 
corticosteroids and anti−TNF-α agents may attenuate potential beneficial immunologic 
effects of treatment with Atezolizumab, but may be administered at the discretion of the 
treating physician. If feasible, alternatives to these agents should be considered. 
In addition, all patients should not receive other immunostimulatory agents for 10 weeks 
after the last dose of Atezolizumab. 
The above list of medications is not necessarily comprehensive.  The investigator should 
consult the prescribing information for any concomitant medication and contact the 
Medical Monitor if questions arise regarding medications not listed above. 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the Schedule of Assessments performed during the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before Cycle 1 Day 1.  The investigator will maintain a screening log 


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to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History, Disease History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including but not limited to cancer histology, grade, stage, prior cancer therapies and 
procedures, smoking history, asbestos exposure). The following must be reported: 
results of HPV determination on tumor tissue using in situ hybridization (ISH) or a 
polymerase chain reaction (PCR)-based test (results from existing tests must be 
available at baseline for patients who are candidates for the HPV induced tumors cohort), 
results of determination of microsatellite instability (MSI) or MMR deficiency on tumor 
tissue and corresponding normal tissue per institution’s standard practice (results from 
existing tests must be available at  baseline for patients who are candidates for the MSI-
high or MMR deficient tumor cohorts), results of BRCA mutations (results from existing 
tests must be provided at baseline for patients candidates for the BRCA positive breast 
or ovarian cancer cohort), results of ER and HER2 status and documentation of number 
of mutations detected by local test (results from existing tests are mandatory at baseline 
for patients who are candidates for the breast cancer with > 100 mutations cohort), 
results of EBV determination on tumor tissue per local institutional practice 
(nasopharyngeal and gastric cancer cohorts).  Associated syndromes, Helicobacter 
pylori infection, and relevant mutations (such as RET/PTC, PTEN, BRAF, RAS, PI3KCA, 
TP53, etc.), reproductive status, and all medications (e.g., prescription drugs, over-the-
counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 7 days prior to the screening visit must also be reported. A history of 
pleural or pericardial effusion or of ascites requiring intervention should be entered in the 
medical history.  
An anonymized copy or transcript of screening test results or medical history may be 
collected by the Sponsor for data interpretation, either for a specific cohort or for specific 
cases. A review of histopathology may be performed by the Sponsor or their delegates 
for individual cases or for specific cohorts to ascertain cancer histology - this will be 
performed using tissue/slides collected for biomarkers. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF.  Height and 
weight should be measured and recorded in the eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 


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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 pressures while the patient is in a seated position and temperature. 
 For first infusion of study treatment, the patient’s vital signs must be determined within 
60 minutes before the infusion; during, and after the infusion if clinically indicated. For 
subsequent infusions, vital signs will be collected within 60 minutes before infusion and 
at the end of the infusion, if clinically indicated. Patients will be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. 
Blood oxygen saturation will be measured at time points specified in the Schedule of 
Assessments (see Appendix 1) by pulse oximetry. 
4.5.5 
Tumor and Response Evaluations 
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or magnetic resonance imaging (MRI) of the chest, abdomen, and 
pelvis.  A spiral CT scan of the chest may be obtained but is not a requirement. 
A CT (with contrast) or MRI scan of the head must be done at screening to evaluate 
CNS metastasis in all patients.  An MRI scan of the brain is required to confirm or refute 
the diagnosis of CNS metastases at baseline in the event of an equivocal scan (see 
Section 4.1.2 for CNS-related exclusions). 
Bone scans and CT scans of the neck should also be performed if clinically indicated.  At 
the investigator’s discretion, other methods of assessment of measurable disease as per 
RECIST v1.1 (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Appendix 6) and malignant 
pleural mesothelioma (see Appendix 7) may be used. 
For subsequent tumor assessments, procedures should be performed as indicated in 
Appendix 1.  The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for CT 
scans).  All known sites of disease must be documented at screening and reassessed at 
each subsequent tumor evaluation.  Response will be assessed by the investigator using 
RECIST v1.1 (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Appendix 6) and malignant 
pleural mesothelioma (see Appendix 7), and modified RECIST criteria (see Appendix 3).  
The same evaluator should perform assessments if possible to ensure internal 
consistency across visits. 


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Computed tomography (CT) scans and other data supporting efficacy measurements 
may be collected by the Sponsor in case an independent review is required, either for a 
specific cohort or for specific cases (e.g. to validate responses). 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Local laboratory assessments will include the following: 
• 
Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count with 
automated differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells], and platelet count). A manual differential can be done if clinically 
indicated. 
• 
Serum chemistries (includes BUN, creatinine/creatinine clearance, sodium, 
potassium, magnesium, chloride, bicarbonate ([if routinely performed on venous 
blood samples]), calcium, phosphorus, glucose, total bilirubin with fractionation into 
direct and indirect (if total bilirubin elevated during the study), ALT, AST, alkaline 
phosphatase, lactate dehydrogenase, total protein and albumin) 
• 
Coagulation (aPTT and INR) 
• 
Serum pregnancy test for women of childbearing potential, including women who 
have had a tubal ligation; childbearing potential is defined as not having undergone 
surgical sterilization, hysterectomy, and/or bilateral oophorectomy, or not being 
postmenopausal (≥ 12 months of amenorrhea) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood; dipstick 
permitted) 
• 
Thyroid function testing (thyroid-stimulating hormone [TSH], free T3, free T4) 
• 
HBV serology (HBsAg, antibodies against HBsAg, hepatitis B core antigen) HBV 
DNA  must be obtained prior to Cycle 1, Day 1 if patient has positive serology for 
anti-HBc Ab 
• 
C-reactive protein (CRP) 
• 
HCV serology – prior to inclusion only. Patients positive for hepatitis C virus (HCV) 
antibody must be tested for HCV using RNA polymerase chain reaction 
• 
All patients will be tested for HIV prior to the inclusion into the study and HIV-
positive patients will be excluded from the clinical trial 
• 
Patients with ovarian cancer: CA125 level 
• 
Patients with colon cancer: CEA level 
• 
Patients with prostate cancer: PSA level 
• 
Patients with breast cancer: CA153 level 
• 
Patients with pancreatic cancer: CA 19.9 levels  
• 
Other tumor biomarkers as clinically indicated 
 


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• 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
o 
Serum sample for ATA assessment using validated immunoassays (see 
Appendix 1 and 2 for details)  
o 
Serum sample for PK assessments using validated immunoassays (see 
Appendix 1 and 2 for details) 
• 
Plasma samples for biomarkers (see Appendix 1 and 2 for details) 
 
Any remaining samples collected for PK, biomarker assays, and ATAs may be used for 
exploratory biomarker profiling, identification, and pharmacodynamic assay development 
purposes and additional safety assessments (e.g., ATA assay), as appropriate. 
• 
Archival or fresh biopsy samples for eligibility:  
o Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in 
paraffin blocks (preferred) or, in exceptional cases, 15 freshly cut and unstained 
slides, with an associated pathology report (in local language), for central 
testing. Detection of tumor in the provided block (or slide) needs to be 
confirmed by the central pathology laboratory prior to study enrollment. 
o Only tissue from core needle, punch or excisional biopsy sample collection will 
be accepted.  For core-needle biopsy specimens, at least three cores should be 
submitted for evaluation.  Fine-needle aspiration, brushing, bone tissue, and 
lavage samples are not acceptable 
o Patients who do not have tissue specimens meeting eligibility requirements 
must undergo a biopsy during the screening period.  Acceptable samples 
include core needle biopsies for deep tumor tissue (minimum three cores) or 
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, 
or mucosal lesions 
• 
Optional biopsies 
o For patients who have agreed to provide optional tumor tissue samples and 
have signed the Consent for Optional Biopsies Form.  
o Tumor tissue will be freshly obtained by core needle or excisional/punch biopsy.  
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.  
o The pre-treatment specimen will be obtained after eligibility criteria have been 
fulfilled.  Alternatively, the pre-treatment biopsy can be replaced by a biopsy 
which was taken no more than 12 months before Cycle 1, Day 1.   


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o A subsequent biopsy will then be performed approximately 3 weeks (Cycle 2, 
Day 1) after the first Atezolizumab administration.  (For logistical reasons, the 
subsequent biopsy may be performed with a time window of 1 week.) 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biopsies shall be performed with discernment as this traumatic surgical gesture will not 
in all cases benefit intrinsically the individual patient, but hypothetically medical research. 
4.5.7 
Electrocardiograms 
Twelve-lead ECG is required at screening and as indicated in Appendix 1.  ECGs should 
be obtained on the same machine whenever possible.  Lead placement should be as 
consistent as possible.  ECG recordings should be performed after the patient has been 
resting in a supine position for at least 10 minutes. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings. Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.8 
Samples for Roche Clinical Repository 
4.5.8.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.  
RCR specimens will be used to achieve the following objectives: 
• 
To further study the association of biomarkers with efficacy, adverse events, or 
disease progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.8.2 
Approval by the Institutional Review Board or Ethics Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 


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and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.8) will not be 
applicable at that site. 
4.5.8.3 
Sample Collection 
All blood and tissue samples collected in this study and derivatives thereof will be 
destroyed no later than 5 years after the date of final closure of the clinical study 
database.  However, patients who enroll in this study will have the option, at the time of 
enrolment, to consent to RCR sampling to allow the remainder of these samples and 
derivatives thereof to be stored and used for exploratory research.  If the patient 
provides consent for this optional exploratory research, these samples will be sent to 
and stored in the RCR and will be destroyed no later than 15 years after the date of final 
closure of the clinical study database. 
These specimens will be used for research purposes to identify biomarkers that are 
predictive of response to study treatment (in terms of dose, safety, and tolerability) and 
will help to better understand the pathogenesis, course, and outcome of advanced solid 
tumors.  Specimens for non-inherited biomarker discovery will be single coded like any 
other clinical sample (labeled and tracked using the patient’s study identification number 
(see Section 8.4 and 4.5.8.4).  Genetic specimens will undergo additional processes to 
maintain confidentiality upon receipt by the RCR (Section 4.5.8.4)   
Tumor tissue, plasma samples and derivatives thereof are collected throughout the 
study for purposes of biomarker assessment (Section 2.4 and Schedule of Assessments 
[Appendix 1 and 2]).  Residual samples will be collected and stored for research 
purposes, including tumor samples (archival material and freshly obtained biopsies) and 
plasma samples.  Archival tumor tissue blocks from the initial diagnosis will be returned 
to the site. 
The specimens in the RCR will be made available for future biomarker research toward 
further understanding of study treatment, solid tumors and related diseases, adverse 
events and toward development of potential associated diagnostic assays.  The 
implementation and use of the RCR specimens is governed by the RCR policy to ensure 
the appropriate use of the RCR specimens. 
For all samples, dates of consent and specimen collection should be recorded on the 
associated RCR page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Laboratory Manual.  
4.5.8.4 
Confidentiality 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described in the section below. 


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Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study Investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.8.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form administered at study enrolment will contain a separate 
section that addresses participation in the RCR.  The Investigator or authorized 
designee will explain to each patient the objectives, methods, and potential hazards of 
participation in the RCR.  Patients will be told that they are free to refuse to participate 
and may withdraw their specimens at any time and for any reason during the storage 
period.  A separate, specific signature will be required to document a patient's 
agreement to participate in the optional RCR research.  Patients who decline to 
participate will not provide a separate signature. 
The Investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 


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In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.  
4.5.8.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to RCR research have the right to withdraw their specimens 
from the RCR at any time for any reason.  If a patient wishes to withdraw consent to the 
testing of his or her specimens, the Investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from Study 
MO29518 does not, by itself, constitute withdrawal of specimens from the RCR.  
Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study MO29518. 
4.5.8.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the Investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study must be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study prior to receiving study drug 
will be replaced. 


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4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Symptomatic deterioration attributed to disease progression as determined by the 
Investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status 
• 
Intolerable toxicity related to Atezolizumab, including development of an immune-
mediated adverse event determined by the investigator to be unacceptable given 
the individual patient’s potential response to therapy and severity of the event 
• 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment 
• 
Use of another non-protocol anti-cancer therapy (see Section 4.4.2) 
• 
Pregnancy 
 
Atezolizumab treatment may be continued as long as patients are experiencing clinical 
benefit as assessed by an investigator in the absence of unacceptable toxicity or 
symptomatic deterioration attributed to disease progression after an integrated 
assessment of radiographic data, biopsy results (if available), and clinical status. 
Patients will be permitted to continue Atezolizumab treatment after RECIST v1.1 (or 
disease-specific criteria for patients with prostate cancer [see Appendix 6] and malignant 
pleural mesothelioma [see Appendix 7]) criteria for progressive disease are met if they 
meet all of the following criteria:  
• 
Evidence of clinical benefit as assessed by the Investigator 
• 
Absence of symptoms and signs (including worsening of laboratory values, e.g., 
new or worsening hypercalcemia) indicating unequivocal progression of disease  
• 
No decline in ECOG performance status that can be attributed to disease 
progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients treated with Atezolizumab in whom radiographic disease progression is 
confirmed at a subsequent tumor assessment may be considered for continued study 
treatment at the discretion of the Investigator if they continue to meet the above criteria. 
If an individual patient continues to experience clinical benefit beyond 2 years of 
radiologic progressive disease, it lies within the discretion of each investigator to 
continue study treatment based on a positive risk benefit assessment by the investigator. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Anticancer therapies received after Atezolizumab discontinuation will 
be collected.   


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Patients who withdraw from the study prior to receiving study drug will be replaced.  
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study or any cohort 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 – Recruitment in each cohort will be monitored 
regularly. After a cohort has been opened for at least 4 months, it may be closed 
early if the recruitment is less than 2 patients per month on average from the 
opening of the cohort. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study or 
close a cohort.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Atezolizumab (TECENTRIQ®) is approved for the treatment of urothelial carcinoma, 
NSCLC, small cell lung cancer (SCLC) and triple-negative breast cancer (TNBC). 
Human experience is currently ongoing and the entire safety profile is not known at this 
time.  The following information is based on results from nonclinical and clinical studies 
and published data on similar molecules. 
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Section 4.1.1 and 4.1.2) and 
close monitoring (as indicated below and in Section 4.5). 
Administration of Atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
All adverse events and serious adverse events will be recorded during the trial and for 
up to 90 days after the last dose of study drug or until the initiation of another anti-cancer 
therapy, whichever occurs first.  To mitigate potential unknown risks, at least in part, 


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dosing beyond Cycle 1 will be limited to patients who have not developed unacceptable 
toxicity or disease progression or who have evidence of potential 
pseudoprogression/tumor immune infiltration.  The potential safety issues anticipated in 
this trial, as well as measures intended to avoid or minimize such toxicities, are outlined 
in the following sections. 
5.1.1 
Risks Associated With Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy 
may increase the risk of immune-mediated adverse events, specifically the induction or 
enhancement of autoimmune conditions.   
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, 
and myositis.  Immune-mediated reactions may involve any organ system and may lead 
to hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  
Refer to Appendix 8 and Section 6 of the Atezolizumab Investigator's Brochure for a 
detailed description of anticipated safety risks for atezolizumab. 
5.1.2 
General Plan to Manage Safety Concerns 
5.1.2.1 
Eligibility Criteria 
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from 
the nonclinical toxicology studies with Atezolizumab, as well as the nonclinical/clinical 
data from other PD-L1/PD-1 inhibitors, were taken into account.  Specifically, patients at 
risk for study-emergent autoimmune conditions or with a prior diagnosis of autoimmune 
disease, patients with evidence of acute infections, and patients who have received a 
live-attenuated viral vaccine within 4 weeks of Cycle 1 Day 1 are excluded from the 
study (see Section 4.1.2 for additional details). 
5.1.2.2 
Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and non-
serious adverse events defined and graded according to NCI CTCAE, v4.0.  Patients will 
be assessed for safety (including laboratory values) according to the Schedule of 
Assessments (Appendix 1).  Laboratory values must be reviewed prior to each infusion. 
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts (see 
Appendix 1 and Appendix 2 for the list and timing of study assessments). 
During the study, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions and infection. 


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All serious adverse events and protocol-defined events of special interest (see  
Sections 5.2.2 and 5.2.3) will be reported in an expedited fashion (see Section 5.4.2).   
Patients will be followed for safety for 90 days following their last dose of study drug or 
until they receive another anti-cancer therapy, whichever comes first. 
Patients who have an ongoing study drug−related adverse event upon study completion 
or at discontinuation from the study will be followed until the event has resolved to 
baseline grade, the event is assessed by the investigator as stable, new anti-cancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it 
has been determined that study treatment or participation is not the cause of the adverse 
event. 
5.1.3 
Atezolizumab Dose Modification 
There will be no dose reduction for Atezolizumab in this study.  Patients may temporarily 
suspend study treatment if they experience adverse events that require a dose to be 
held.  If Atezolizumab is held because of adverse events for > 105 days beyond when 
the next dose would have been given, then the patient will be discontinued from 
Atezolizumab treatment and will be followed for safety and efficacy as specified in the 
Schedule of Assessments (Appendix 1). 
If a patient must be tapered off steroids used to treat adverse events, Atezolizumab may 
be held for additional time beyond 105 days. The acceptable length of interruption will 
depend on an agreement between the investigator and the Medical Monitor.   
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, 
may be allowed with Medical Monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 
5.1.4 
Management of Specific Adverse Events 
 Refer to Appendix 8 and Section 6 of the Atezolizumab Investigator's Brochure for a 
detailed description of anticipated safety risks for atezolizumab. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious 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. 


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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 5.3.5.8 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria; 


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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 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions).  Adverse events of special interest 
for this study include the following: 
• 
The following are confirmed treatment-emergent autoimmune conditions: 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency or 
hyperthyroidism 
• 
Hepatitis 
• 
Transaminitis: Grade ≥ 2 (AST or ALT > 3 × ULN and bilirubin > 2 × ULN ) or 
 
 
AST/ALT > 10 × ULN 
– 
Systemic lupus erythematosus 
– 
Neurological: Guillain-Barré syndrome, Myasthenia Gravis, 
Meningoencephalitis 
• 
Events suggestive of hypersensitivity, cytokine release,SIRS (influenza-like illness, 
systemic inflammatory response syndrome), SIA ( systemic inflammatory activation) 
or infusion-reaction syndromes" 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 
may be suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product.  This 
term applies only when a contamination of the study drug is suspected." 


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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 drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see  Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 90 days after the 
last dose of study drug or until they receive another anti-cancer therapy, whichever 
comes first.  After this period, the investigator should report any serious adverse events 
that are believed to be related to prior study drug treatment (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of nondirective 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


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Table 6. 
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 or 
not 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 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions, a diagnosis (if known) should 
be recorded on the Adverse Event eCRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases).  However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
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. 


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5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints. Such events should only be recorded once on the Adverse 
Event eCRF. The initial severity (intensity or grade) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme severity should also be recorded on the Adverse Event eCRF.  If the event 
becomes serious, it should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions).  The Adverse Event eCRF should be updated by changing the event from 
"non-serious" to "serious," providing the date that the event became serious, and 
completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
− Change from baseline and one of the following: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 


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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). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
- 
Change from baseline and one of the following: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 x baseline value) in combination with either 
an elevated total bilirubin (> 2xULN) 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 x baseline value in combination with total 
bilirubin > 2 x ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 x 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 


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the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
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 one of the advanced solid tumors included in this 
study should be recorded only on the Study Completion/Early Discontinuation eCRF.  All 
other on-study deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2), 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of one of the advanced solid 
tumors included in this study should be recorded only on the Survival eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
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"). 


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5.3.5.9 
Lack of Efficacy or Worsening of the Advanced Solid Tumors 
Included in This Study 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 (except for prostate cancer and malignant 
pleural mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7) and modified 
RECIST (see Appendix 3). 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. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or to perform an efficacy measurement for the study) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
− The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of 
the expected normal progression of the disease 
− The patient has not experienced an adverse event 
 
• 
Hospitalization due solely to progression of the underlying cancer (including 
symptoms) 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.11 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 


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associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
5.3.5.12 
Adverse Events in Individuals Not Enrolled in the Study 
If an adverse event inadvertently occurs in an individual not enrolled in the study 
(e.g., during administration of study drug), the Adverse Event Form provided to 
investigators should be completed and submitted to the Sponsor or its designee, either 
by faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators. 
5.3.5.13 
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 
infusion-related reaction on the Adverse Event eCRF.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences both a local 
and systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF. 
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) 
• 
Non-serious adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious 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 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. 
5.4.2.2 
Events That Occur After Study Drug Initiation 
After initiation of study drug, serious adverse events and non-serious adverse events of 
special interest will be reported until 90 days after the last dose of study drug or until they 
receive another anti-cancer therapy, whichever comes first.  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 Roche Drug Safety by the 
EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event / Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 


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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 eCRFA pregnancy report will automatically be generated 
and sent to Roche Drug Safety.  The investigator should discontinue study drug and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF. 
In the event that the EDC system is unavailable, the Clinical Trial Pregnancy Reporting 
Form provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Once the EDC system is available, all information will 
need to be entered and submitted via the EDC system. 
5.4.3.2 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug 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). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, the patient withdraws consent or until the patient receives another anti-cancer 
therapy, whichever comes first.  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. 


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All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious 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 
POST-STUDY ADVERSE EVENTS 
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.   
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. During survival follow-up, deaths attributed to progression of the advanced 
solid tumor should be recorded on the Survival eCRF and details should be recorded on 
the Study Completion/Early Termination eCRF. 
 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Atezolizumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 


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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Statistical analyses will be based on patients with the same individual tumor type and 
may be based on pre-defined cohorts or on sub-cohorts. Furthermore, if during the 
conduct of the study, a specific subgroup of patients in a cohort/sub-cohort is identified 
(e.g. a biomarker positive subgroup) then statistical analysis may be performed based 
on this subgroup of patients. In general, within section 6, the term cohort is used to refer 
to a group of patients to be analyzed together (whether this is a cohort, a sub-cohort or a 
subgroup). 
The safety population will be the main population for all analyses (demographics, 
efficacy and safety) unless otherwise stated. For each cohort, the safety population will 
include all patients who have received at least one dose of study medication.  
For each cohort, the intent-to-treat (ITT) population will include all patients enrolled in the 
study irrespective of whether they have received study medication or not. The ITT 
population will be used to summarize disposition data.  
The evaluation of each cohort at the end of Stage I and Stage II will be based only on 
data from fully evaluable patients, defined as patients receiving at least one dose of 
Atezolizumab and having at least one tumor assessment post-baseline (per protocol 
mandated timelines). 
The per-protocol (PP) population will not be defined due to the small number of patients 
per cohort, but major protocol deviations will be listed. 
The study will be analyzed for the primary efficacy variable at the end of Stage I and 
Stage II.  All cohorts will also be analyzed at Week 24 (6months) and at the end of 
cohort. In case a cohort is closed before reaching 12 patients (e.g., due to accrual 
problems), data for that cohort will be listed only or pooled with cohort 10. The end of 
cohort analysis for each cohort will take place when all patients in that cohort have been 
followed for survival for a minimum of 24 months after the last patient has been enrolled 
in the cohort or until all patients have died, withdrawn consent or are lost to follow up, or 
if the cohort is stopped due to safety or efficacy reasons, or the Sponsor decides to end 
the cohort, whichever occurs first. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size for this phase II study is based on Simon’s optimal two-stage design 
(Simon 1989). 
In this Phase II study, an NPR of 20% is a level of activity that is not of interest for further 
clinical development, whereas an NPR of 40% is of clinical interest.  The type I error will 
be 10% and the study will have 80% power to reject the null hypothesis when the true 
NPR is 40%. 


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The Simon design in this study requires 12 fully evaluable patients for the first stage.  If 
at the end of the first stage there are 0, 1 or 2 patients with non-progressive disease at 
Week 18, the enrollment into this cohort will be terminated (or the cohort may be 
expanded as described below).  Otherwise, if more than 2 patients with non-progressive 
disease are observed at the end of Stage I, an additional 13 fully-evaluable patients may 
be enrolled into Stage II.  The study drug will be considered of clinical interest in this 
cohort if, at the end of the second stage, there are 8 or more patients with non-
progressive disease out of 25 total fully-evaluable patients.  
It can be assumed that some patients will not be evaluable for NPR.  A patient will be 
considered evaluable for NPR if they received study drug, have a baseline tumor 
assessment and at least one tumor assessment post-baseline (per protocol mandated 
timelines).  Thus, more than 25 patients may be needed to be enrolled per cohort to 
obtain 25 fully-evaluable patients. 
The hypotheses and clinical assumptions will be applied to all cohorts individually. 
Statistical analyses will be based on patients with the same individual tumor type and 
may be based on pre-defined cohorts or on sub-cohorts  
If a clear clinical benefit has been observed for a defined subgroup of patients at the end 
of Stage I within a cohort that did not meet the criteria for continuation (as described in 
Section 6.2.1), then enrolment into Stage II might still be allowed in this cohort for this 
specific subgroup after discussion with the Sponsor and the study Steering Committee. 
Similarly, if a clear clinical benefit has been observed for a defined subgroup of patients 
at the end of Stage II within a cohort that did not meet the criteria for success (as 
described in Section 6.2.2), then enrolment into Stage II might continue in this cohort for 
this specific subgroup after discussion with the Sponsor and the study Steering 
Committee. 


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Figure 2. Sample Size for Each Cohort in Stage I/II 
 
 
NP = non-progressors; NPR = non-progression rate. 
Assumptions: H0 = NPR 20%; H1 = NPR 40%; power = 80%; alpha = 10%. 
The sample size was estimated using Simon’s optimal two-stage design (Simon 1989). 
* And no additional clinical benefit in a subgroup.  
 
6.2 
STOPPING RULES FOR EACH COHORT 
6.2.1 
Rules for Stage I 
• 
Enrolment into the cohort may continue into Stage II if more than 2 patients (out of 
12) with non-progressive disease at Week 18 are observed at the end of Stage I. 
• 
Enrolment into the cohort will stop at the end of Stage I if the number of patients 
with non-progressive disease (confirmed or unconfirmed) is 2, 1 or 0 out of 12 patients. 
However, if the overall patient population does not meet requirements at Stage I, but a 
clinical benefit is observed in a specific subgroup (e.g. biomarker positive subgroup) of 
patients, then only this subgroup may be added for Stage I and Stage II to reach 
numbers as explained in the Sample Size Estimation.  
All decisions above will be made by the Sponsor in discussion with the study Steering 
Committee members.   


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6.2.2 
Rules for Stage II 
A study treatment will be considered to be promising for a given cohort in Stage II if: 
• 
there is no unacceptable toxicity, and 
• 
at 18 weeks, there are 8 or more patients with non-progressive disease out of 25 
fully-evaluable patients. 
 
If the overall patient population does not meet the Stage II criteria, but a clinical benefit is 
observed in a specific subgroup (e.g. biomarker positive subgroup) of patients, then 
Stage II may be expanded to include additional patients from this specific subgroup in 
order to re-evaluate the Stage II criteria in this patient subgroup. 
Additionally, other efficacy endpoints and safety may also be evaluated for a final 
decision at the end of Stage II. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment criteria exceptions, study treatment administration, reasons for patient 
discontinuations from the study and duration of follow-up will be described and 
summarized. Major protocol violations will be listed. 
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
This is an open-label phase 2 study that will assess Atezolizumab administered at a 
single dosage (1200 mg q3w). Consequently, no formal treatment group comparability 
analyses will be conducted.  Demographics and medical history will be summarized for 
each cohort. 
6.5 
EFFICACY ANALYSES 
6.5.1 
Primary Efficacy Endpoint 
The primary analysis will be based on NPR at 18 Weeks for each cohort, as assessed 
by the Investigator using RECIST, v1.1 (except for prostate cancer and malignant pleural 
mesothelioma) and disease-specific criteria for patients with prostate cancer (see 
Appendix 6) and malignant pleural mesothelioma (see Appendix 7).  This endpoint will 
be assessed at Stage I and Stage II. The number and percentage of progression-free 
patients will be presented along with the corresponding Clopper-Pearson 95% 
confidence interval.  
Hypothesis Testing 
A Simon optimal two-stage design will be used to test whether Atezolizumab yields a 
NPR that is of clinical interest.  In this Phase II study, an NPR of 20% is a level of activity 
that is not of interest for further clinical development, whereas an NPR of 40% is of 
clinical interest.  


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The study hypotheses are: 
• 
H0: π ≤ π0 
• 
H1: π > π1 
 
Where π0 = 20% and the assumed NPR under the alternative is π1 = 40%. 
The type I error will be 10% and the study will have 80% power to reject the null 
hypothesis when the true NPR is 40%. 
The hypothesis and clinical assumptions will be applied to all cohorts separately. This is 
an early phase II study and cohorts are independent, hence there will be no adjustment 
for multiplicity. 
6.5.2 
Secondary Efficacy Endpoints 
The number and percentage of progression-free patients at 24 weeks will be presented 
along with the corresponding Clopper-Pearson 95% confidence interval. The ORR, BOR 
and CBR will be analyzed in a similar way.   
The time-to-event variables, DOR, PFS, TTP and OS, will be presented graphically 
using the Kaplan-Meier (KM) approach. Estimates together with the associated 95% 
confidence interval will be reported for the median and for the 1-year and 2-year survival 
rates. Duration of response will be summarized only for responders.  
NPR, ORR, BOR, DOR, CBR, PFS and TTP as assessed by the by the Investigator 
using modified RECIST (see Appendix 3) will also be analyzed as described above. 
6.6 
SAFETY ANALYSES 
The safety variables will be summarized for the safety population.  All safety variables 
will be summarized for each cohort. 
Safety will be assessed through summaries of AEs, changes in laboratory test results, 
changes in vital signs and ECGs, and exposure to Atezolizumab. 
Verbatim descriptions of AEs will be mapped to thesaurus terms.  Adverse event data 
will be listed by cohort, study site, patient number and study day.  Events occurring on or 
after treatment on Day 1 will be summarized by mapped term, appropriate thesaurus 
levels, and NCI CTCAE v4.0 grade.  In addition, SAEs, deaths, and AESIs will be listed 
separately and summarized.  AEs leading to treatment discontinuation will be listed.  
Relevant laboratory and vital signs data will be displayed by time, with NCI CTCAE 
Grade 3 and 4 values identified, where appropriate.  Additionally, all laboratory data will 
be summarized by grade with use of NCI CTCAE v4.0. 


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Number of cycles and duration on study medication will be summarized by means of 
frequency tables and descriptive statistics for continuous variable (N, median, inter-
quartile range, mean, SD, minimum, maximum). 
6.7 
PHARMACOKINETIC ANALYSES 
Atezolizumab serum concentration data (Cmin and Cmax) will be tabulated and 
summarized for each cycle at which pharmacokinetics are measured (Cmax will be 
reported for Cycle 1 only; Cmin will be evaluated at Cycles 1, 2, 3, 4, 8, every eight cycles 
thereafter and at treatment discontinuation).  Descriptive statistics will include means, 
medians, ranges and SDs, as appropriate. 
6.8 
EXPLORATORY ANALYSES 
Exploratory biomarker analyses (e.g. but not limited to protein and genetic markers) in 
tumor and plasma samples (both baseline and on treatment) will be performed in an 
effort to understand the association of these markers with study drug response.  
Biomarkers will be summarized using descriptive statistics: N, medians, inter-quartile 
range, mean, standard deviation, minimum and maximum for continuous variables and 
frequency counts and percentages for categorical variables.  The relationship between 
biomarkers and efficacy variables will be assessed using appropriate models.  More 
details will be provided in the Statistical Analysis Plan. 
6.9 
INTERIM ANALYSES 
The study will be analyzed for efficacy at Stage I and Stage II.  All cohorts will also be 
analyzed at Week 24 (6 months) and at the end of cohort for each cohort. No additional 
interim analysis for efficacy will be performed in this study. 
7. 
DATA COLLECTION AND MANAGEMENT  
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data.  Data entered manually will be collected via 
EDC using eCRFs.  Sites will be responsible for data entry into the EDC system.  In the 
event of discrepant data, the CRO will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.  Central laboratory data will be sent directly to the Sponsor using 
the Sponsor's standard procedures to handle and process the electronic transfer of 
these data. 
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 


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standard procedures will be used to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the CRO and records retention for the study data will 
be consistent with the CRO’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for 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, ePRO 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 
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 (E.U.) 
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 


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8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 


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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. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 


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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 50 sites globally will participate in the study, and approximately 
725 patients will be enrolled. 
Enrollment will occur through an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., PDL1 testing, ATA and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
A Steering Committee will be the advisory committee, and study status will be discussed 
at an ongoing basis.  
Global CRO will support coordination and medical monitoring activities. 


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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: 
https://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.p
df 
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 
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. 


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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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APPENDICES


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Appendix 1 Schedule of Assessments
Screening1
Treatment
(All cycles, 
unless 
otherwise 
indicated) 2
Treatment 
discontinuation 
visit
Follow-Up
End of Study 
Visit
Day (Window)
Days -35 to -1
Day 1 (± 3 days 
for cycles ≥2)
≤ 30days 
after last dose
Every 3 months 
from study 
treatment 
discontinuation 
(+/- 30 days)
24 months
Informed consent 1
X
Review of eligibility criteria
X
Medical history and demographics 3
X
Cancer history 4
X
Concomitant medications 5
X
X
X
Tumor assessment
RECIST 1.1 and modified RECIST per 
Appendix 3 6
X
Every 6 weeks, ± 5 days (2 cycles) for the first 24 weeks and every 
12 weeks, ± 5 days (4 cycles) thereafter until loss of clinical benefit, 
withdrawal of consent, death, or study termination by the Sponsor, 
whichever occurs first
Brain MRI/CT Scan with contrast 6
X
Specific tumor markers 7
X
As clinically indicated, but at least every 6 weeks, ± 5 days (2 cycles) for 
the first 24 weeks and every 12 weeks , ± 5 days (4 cycles) thereafter until 
loss of clinical benefit, withdrawal of consent, death, or study termination 
by the Sponsor, whichever occurs first
Collection of results from specific markers 
assessed on tumor tissue 8
X


Appendix 1
Schedule of Assessments (cont.)
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Screening1
Treatment
(All cycles, 
unless 
otherwise 
indicated) 2
Treatment 
discontinuation 
visit
Follow-Up
End of Study 
Visit
Day (Window)
Days –35 to –
1
Day 1 (± 3 days 
for cycles ≥2)
≤ 30 days after 
last dose
Every 3 months 
from study 
treatment 
discontinuation 
(+/- 30 days)
24 months
Physical examination 9
X
X
X
ECOG performance status
X
X(-3 days from 
treatment start)
X
Vital signs 10
X
X
X
Oxygen saturation (pulse oximetry)
X
X
X
12-lead electrocardiogram 11
X
X
X
Weight
X
Height
X


Appendix 1
Schedule of Assessments (cont.)
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Screening1
Treatment
(All cycles, 
unless 
otherwise 
indicated) 2
Treatment 
discontinuation 
visit
Follow-Up
End of Study 
Visit
Day (Window)
Days –35 to –
1
Day 1 (± 3 days 
for cycles ≥2)
≤ 30days 
after last dose
Every 3 months 
from study 
treatment 
discontinuation 
(+/- 30 days)
24 months
Local laboratory assessments
Hematology 12, 13
X
X
X
Serum chemistry -13
X
X
X
Coagulation panel (aPTT, INR)
X
X
C-reactive protein 
X
X
X
Urinalysis 14
X
X15
X
Serum pregnancy test 16
X
TSH, free T3, free T4
X
Every 3rd cycle 
(starting at C3, 
C6, C9 ctd.)
X
HIV, HBV and HCV serology 17
X


Appendix 1
Schedule of Assessments (cont.)
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Screening1
Treatment
(All cycles, 
unless 
otherwise 
indicated) 2
Treatment 
discontinuation 
visit
Follow-Up
End of Study 
Visit24
Day (Window)
Days –35 to –
1
Day 1 (± 3 days 
for cycles ≥2)
≤ 30 days 
after last dose
Every 3 months 
from study 
treatment 
discontinuation 
(+/- 30 days)
24 months
Central laboratory assessments 18
Serum sample for ATA assessment
X
X
120 (±30) days 
after last dose
Serum sample for PK assessments
X
X
120 (±30) days 
after last dose
        Plasma sample for biomarkers
X
X
Adverse events19
X
X
X
X
X
Atezolizumab infusion 20
X
Archival tissue specimen (tumor block 
preferred) 21
X
Freshly obtained tumor specimen (optional) 22
X 
X 
Survival follow-up 23
X
X
ATA = anti-therapeutic antibody; ECOG = Eastern Cooperative Oncology Group; FDG =18fluorodeoxyglucose; HBV = hepatitis B virus; HCV = 
hepatitis C virus; PET = positron emission tomography; RECIST = Response Evaluation Criteria in Solid Tumors; TSH = thyroid-stimulating 
hormone; PSA = prostate-specific antigen.
1.
Written informed consent is required for performing any study-specific tests or procedures. Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 35 days prior to study entry may be used for screening assessments rather than 
repeating such tests.


Appendix 1
Schedule of Assessments (cont.)
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2.
Visits during the Treatment Period are to be completed on Day 1 (± 3 days for cycles ≥2) of every 3-week cycle until study drug 
discontinuation.
3.
Demographic information includes sex, age, and self-reported race/ethnicity.
4.
Cancer history including but not limited to cancer histology, grade, stage, prior cancer therapies and procedures, smoking history, asbestos 
exposure, HPV infection and HPV subtypes, associated syndromes, Helicobacter Pylori infection, and relevant mutations such as RET/PTC, 
PTEN, BRAF, RAS, PI3KCA, TP53, etc.
5.
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 screening visit should be documented.  At subsequent visits, changes to current medications or medications 
used since the last documentation of medications will be recorded.
6.
Examinations performed as standard of care prior to obtaining informed consent and within 35 days of Cycle 1, Day 1 may be used rather than 
repeating tests.  All measurable and evaluable lesions should be assessed and documented at this visit, with use of physical examination and 
image-based evaluation.  Screening assessments should include CT scans with oral and intravenous contrast or magnetic resonance imaging 
(MRI) of the chest, abdomen, and pelvis, and a brain scan (CT or MRI).  Bone scans and CT scan of neck should also be performed if 
clinically indicated.  If a CT scan for tumor assessment is performed in a PET/CT scanner, the CT acquisition must be consistent with 
standards of a full-contrast CT scan.  CT scans must be used to measure lesions selected for response assessment.  The same radiographic 
procedure used to define measurable lesions at baseline must be used throughout the study for each patient.  
7.
CA125 level for patients with ovarian cancer, CEA level for patients with colorectal cancer, PSA for patients with prostate cancer, CA153 levels 
for patients with breast cancer, CA 19.9 levels for patients with pancreatic cancer, or other tumor marker (as appropriate) should be obtained 
as clinically indicated or with each tumor assessment.
8.
Results of local tests performed to meet eligibility criteria must be submitted at baseline and recorded in the eCRF as specified: -1) Known 
HPV induced tumors: HPV determination on tumor tissue using in situ hybridization (ISH) or a polymerase chain reaction (PCR) must be 
provided at baseline and recorded in the eCRF (results of HPV determination in cervical cancer cohort must be recorded in the eCRF) -2) MSI-
high or MMR deficient cohorts: microsatellite instability or MMR deficiency on tumor tissue and corresponding normal tissue must be provided 
at baseline and recorded in the eCRF -3) Nasopharyngeal carcinoma or gastric adenocarcinoma / adenocarcinoma of the gastro-esophageal 
junction: EBV determination on tumor tissue per institution’s standard practice (recorded in the eCRF). -4) BRCA positive breast or ovarian 
cancer cohort – BRCA testing must be provided at baseline and recorded in the eCRF - 5) ER positive, HER2 negative breast cancer with 
> 100 mutations: ER and HER2 test and determination of mutational load per local test must be provided at baseline and recorded in the 
eCRF.
9
Complete physical examination at screening and treatment discontinuation visit and limited physical examination during treatment. At baseline, 
physical examination should be done within 3 days prior to the first drug administration (Day 1) See Section 4.5.3.
10. Vital signs include heart rate, respiratory rate, blood pressures, and temperature. At baseline, vital signs should be done within 3 days prior to 
the first drug administration (Day 1). For first infusion of study treatment, the patient’s vital signs should be determined within 60 minutes 
before the infusion; during, and after the infusion if clinically indicated. For subsequent infusions, vital signs will be collected within 60 minutes 


Appendix 1
Schedule of Assessments (cont.)
Atezolizumab—F. Hoffmann-La Roche Ltd
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before infusion and at the end of the infusion, if clinically indicated. Patients will be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop such symptoms.
11. ECG recordings will be obtained during screening and as clinically indicated at other time points. ECG should be done during screening period 
(within 35 day from Day 1), not needed to be repeated at D1. Patients should be resting and in a supine position for at least 10 minutes prior to 
each ECG collection.
12. Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils, and other cells), and platelet count.  A manual differential can be done if clinically indicated. See 
Section 4.1.1 for a list of laboratory results obtained within 3 days prior to the first study treatment.
13.
Laboratory tests that should be done within 3 days prior to the first drug administration ( Day 1): Absolute neutrophil count (ANC), lymphocyte 
count, white blood cell counts, platelet count, hemoglobin, serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) 
and alkaline phosphatase, serum albumin, serum creatinine, international normalized ratio (INR) and activated partial thromboplastin time 
(aPTT). These tests must meet the eligibility criteria.
The other biochemistry test sodium, potassium, magnesium, chloride, bicarbonate ([if routinely performed on venous blood samples]), calcium, 
phosphorus, glucose, lactate dehydrogenase and total protein can be done within 35 days from D1.
14. Urinalysis includes specific gravity, pH, glucose, protein, ketones and blood; dipstick permitted. Urinary analysis should be done during 
screening period (within 35 day from day 1, not needed to be repeated at D1)
15. On Day 1 of Cycle 3 and every two cycles thereafter.
16. Serum pregnancy test for women of childbearing potential must be performed and documented as negative within 14 days prior to Day 1.
17. All patients will be tested for HIV prior to the inclusion into the study and HIV-positive patients will be excluded from the clinical trial.  
Hepatitis B surface antigen, anti-HBc antibody, anti-HBs antibody, and anti-HCV antibody should be collected during screening.  In patients 
who have positive serology for the anti-HBc antibody, HBV DNA should be done during screening and the results should be available prior to 
Cycle 1, Day 1.
18. See Section 4.5.6 and Appendix 2 for details.
19. After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until 90 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever occurs first. After this period, investigators should report any deaths, 
serious adverse events, or other adverse events of concern that are believed to be related to prior treatment with study drug. The investigator 
should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow up, or the patient withdraws consent. Every effort should be made to follow all serious adverse events considered to 
be related to study drug or trial-related procedures until a final outcome can be reported.
20. The initial dose of study treatment will be delivered over 60 (± 15) minutes.  If the first infusion is tolerated without infusion-associated adverse 
events, the second infusion may be delivered over 30 (± 10) minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may 
be delivered over 30 (± 10) minutes.


Appendix 1
Schedule of Assessments (cont.)
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21. Archival tumor tissue specimen may be obtained from any prior tumor excision or biopsy performed at any time during the course of the 
patient's illness.  Tumor blocks are preferred; 15 freshly cut and unstained slides can be provided in exceptional circumstances if tumor blocks 
are unavailable.  Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion 
with the Sponsor.  Patients who do not have tissue specimens meeting eligibility requirements must undergo a biopsy during the screening 
period. Alternatively, the biopsy during screening can be replaced by a biopsy which was taken no more than 12 months before Cycle 1, Day 1.  
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. 
22. For patients who have signed the Consent for Optional Biopsies Form. Tumor tissue will be freshly obtained by core needle or 
excisional/punch biopsy.  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.    The pre-treatment specimen will be obtained after 
eligibility criteria have been fulfilled.  Alternatively, the pre-treatment biopsy can be replaced by a biopsy which was taken no more than 12 
months before Cycle 1, Day 1.  A subsequent biopsy will then be performed approximately 3 weeks (Cycle 2, Day 1) after the first 
Atezolizumab administration (for logistical reasons, the subsequent biopsy may be performed with a time window of 1 week.)
23. Will also include new anticancer drug(s) received after treatment discontinuation, responses and duration of responses to them, and other 
cancer information.  Survival follow-up information will be collected via clinic visits, telephone calls, and/or review of patient medical records 
approximately every 3 months and this period will last for a minimum of 24 months after the last patient has been enrolled or until all patients 
have died, withdrawn consent or are lost to follow-up or the Sponsor decides to end the study (whichever occurs first).
24. During the interim period between LPLV and a patient rolling over to the extension study, only safety data (AE including SAE and AESI) will 
continue to be collected in the eCRF. Other assessments (e.g. tumor assessment) can be performed as per standard of care.


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Appendix 2
Schedule of Anti-Therapeutic Antibody, 
Pharmacodynamic and Pharmacokinetic Assessments
Visit
Time
Sample Type
Cycle 1,
Day 1
Pre-dose
Atezolizumab PD  1
Serum Atezolizumab PK  Serum Atezolizumab ATA 
30 min (± 10 min) after end of Atezolizumab infusion
Serum Atezolizumab PK  
Cycle 2, 
Day 1 (± 1 day)
Pre-dose
Atezolizumab PD 1
Serum Atezolizumab ATA  Serum Atezolizumab PK 
Cycle 3, 
Day 1 (± 1 day)
Pre-dose
Serum Atezolizumab ATA Serum Atezolizumab PK 
Cycle 4, 
Day 1 (± 1 day)
Pre-dose
Atezolizumab PD 1
Serum Atezolizumab ATA 
Serum Atezolizumab PK  
Cycle 8 and every 8 cycles thereafter
Day 1 (± 1 day)
Pre-dose
Serum Atezolizumab ATA  
Serum Atezolizumab PK 
At progression of disease (RECIST)
Atezolizumab PD 1
Treatment discontinuation visit (≤30 days 
after last dose) 4
At visit
Atezolizumab PD 1,3
Serum Atezolizumab ATA  
Serum Atezolizumab PK  
Post-treatment discontinuation visit (120 
[± 30 days] after last dose) 4
At visit
Serum Atezolizumab ATA 2
Serum Atezolizumab PK 2
PD = plasma PD (pharmacodynamic) biomarkers; PK = pharmacokinetics; ATA = anti-therapeutic antibody
1. Plasma 
2. For patients who discontinue the study treatment, ATA and PK samples are to be obtained at 120 days ± 30 days after the last dose of study 
treatment unless the patient dies or withdraws consent or the study closes (during the interim period between LPLV and a patient rolling over 
to the extension study, ATA and PK samples do not need to be collected).
3. Plasma sample at treatment discontinuation visit only required if radiologic progression sample is taken outside a ±4 week window of the 
treatment discontinuation visit.


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents like Atezolizumab, which can produce delayed responses that may be 
preceded by initial apparent radiological progression, including the appearance of new lesions.  
Therefore, modified response criteria have been developed that account for the possible 
appearance of new lesions and allow radiological progression to be confirmed at a subsequent 
assessment.  In this protocol, patients will be permitted to continue study treatment even after 
modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease 
are met if the risk/benefit ratio is judged to be favorable.  
Modified RECIST is derived from RECIST, Version 1.1 conventions 1 and immune-related 
response criteria 2 (irRC). When not otherwise specified, RECIST v1.1 conventions will apply.
Modified RECIST and RECIST, Version 1.1:  Summary of Changes
RECIST v1.1
Modified RECIST
New lesions after baseline
Define progression.
New measurable lesions are 
added into the total tumor 
burden and followed.
Non-target lesions
May contribute to the 
designation of overall 
progression
Contribute only in the 
assessment of a complete 
response
Radiographic progression
First instance of 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease
Determined only on the basis 
of measurable disease;  must 
be confirmed by a consecutive 
assessment 4 weeks from 
the date first documented 
RECIST Response Evaluation Criteria in Solid Tumors.
DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS
All measurable and non-measurable lesions should be assessed at screening and at the protocol-
specified tumor assessment timepoints.  Additional assessments may be performed. 
                                           
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
antiPD-1 antibody in cancer. N Engl J Med 2012;366:244354.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Can Res 2009;15:741220.


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
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: 
1.
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT/MRI 
scan slice thickness/interval no greater than 5 mm)
2.
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable)
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  
NON-MEASURABLE LESIONS
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with short axis 10 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 disease, lymphangitic involvement of skin or 
lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below.
BONE LESIONS
Bone scan, positron emission tomography (PET) scan, or plain films are not considered adequate 
imaging techniques for measuring bone lesions.  However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.Lytic bone lesions or mixed lytic–blastic 
lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging 
techniques such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone lesions are non-
measurable.
CYSTIC LESIONS
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  However, if 
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 usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Study protocols should detail the conditions under which such lesions 
would be considered measurable.


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When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.  This means 
that, for instances in which patients have only one or two organ sites involved, a maximum of two 
lesions (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions (albeit 
measurable) in those organs will be recorded as non-measurable lesions (even if the size is 
# 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but in addition, should lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance, the next largest lesion 
that can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of % 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT, this is almost always the axial plane; for MRI, the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node that is reported as being 20 mm ∋30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis % 10 mm 
but & 15 mm) should be considered non-target lesions.  Nodes that have a short axis of & 10 mm 
are considered non-pathological and should not be recorded or followed. Lesions irradiated within 
3 weeks prior to Cycle 1, Day 1 may not be counted as target lesions.
1RQ7DUJHW/HVLRQV
All other lesions (or sites of disease), 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”). 
After baseline, changes in non-target lesions will contribute only in the assessment of complete 
response (i.e., a complete response is attained only with the complete disappearance of all tumor 
lesions, including non-target lesions) and will not be used to assess progressive disease. 
1HZ/HVLRQV
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., nonlymph node lesions must be  10mm; see note for 
new lymph node lesions below).  Up to a maximum of five new lesions total (and a 
maximum of two lesions per organ), all with measurements at all timepoints, can be 


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
included in the tumor response evaluation.  New lesion types that would not qualify as 
target lesions per RECIST cannot be included in the tumor response evaluation.
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the 
sum of longest diameters (SLD), if the maximum number of 5 measurable new lesions
being followed has not been reached.
CALCULATION OF SUM OF THE DIAMETERS 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated as a measure of tumor burden.  
The sum of the diameters is calculated at baseline and at each tumor assessment for the purpose 
of classification of tumor responses.
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions identified at 
baseline prior to treatment on Day 1.
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment collected 
per protocol or as clinically indicated, the sum of the diameters at tumor assessment will be 
calculated using tumor imaging scans.  All target lesions and all new measurable lesions that 
have emerged after baseline will contribute to the sum of the diameters at tumor assessment.  
Hence, each net percentage change in tumor burden per assessment with use of modified 
RECIST accounts for the size and growth kinetics of both old and new lesions as they appear. 
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability (equivalent to baseline 
target lesion selection) will be followed.  That is, if at first appearance the short axis of a new lymph node 
lesion 15 mm, it will be considered a measureable new lesion and will be tracked and included in the 
SLD.  Thereafter, the lymph node lesion will be measured at subsequent timepoints and measurements will 
be included in the SLD, even if the short axis diameter decreases to 15 mm (or even 10 mm).  However, 
if it subsequently decreases to 10 mm, and all other lesions are no longer detectable (or have also 
decreased to a short axis diameter of 10 mm if lymph nodes), then a response assessment of CR may be 
assigned.
If at first appearance the short axis of a new lymph node is 10 mm and 15 mm, the lymph node will not 
be considered measurable but will still be considered a new lesion. It will not be included in the SLD unless 
it subsequently becomes measurable (short axis diameter 15 mm).
The appearance of new lymph nodes with diameter 10 mm should not be considered pathological and not 
considered a new lesion.
RESPONSE CRITERIA
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Lymph nodes that shrink to 
10 mm short axis are considered normal.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all target and all 
new measurable lesions, taking as reference the baseline sum of diameters, in the absence of 
CR.
Note:  The appearance of new measurable lesions is factored into the overall tumor burden but 
does not automatically qualify as progressive disease until the sum of the diameters increases by 
20% when compared with the sum of the diameters at nadir.


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of the diameters while on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all target and all 
new measurable lesions, taking as reference the smallest sum on study (nadir SlD; this includes 
the baseline sum if that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST
New lesions alone do not qualify as progressive disease.  However, their contribution to total 
tumor burden is included in the sum of the diameters, which is used to determine the overall 
modified RECIST tumor response. 
EVALUATION OF BEST OVERALL RESPONSE USING MODIFIED RECIST
TIMEPOINT RESPONSE
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  Table 1
provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline.
MISSING ASSESSMENTS AND NOT EVALUABLE DESIGNATION
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable 
(NE) at that timepoint.  If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered NE at that timepoint, unless a convincing argument can be 
made that the contribution of the individual missing lesion(s) would not change the assigned time 
point response.  This would be most likely to happen in the case of PD.  For example, if a patient 
had a baseline sum of 50 mm with three measured lesions and at follow-up only two lesions were 
assessed but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of 
the contribution of the missing lesion.


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Appendix 3
Modified Response Evaluation Criteria in Solid Tumors (cont.)
Table 1  Modified RECIST Timepoint Response Definitions
% Change in 
Sum of the 
Diameters 
(Including 
Measurable New 
Lesions When 
Present)
Target 
Lesion 
Definition
Non-Target 
Lesion 
Definition
New 
Measurable 
Lesions
New 
Unmeasurable 
Lesions
Overall 
Modified 
RECIST 
Timepoint 
Response
100% a
CR
CR
No
No
CR
100% a
CR
Non-CR or 
not all 
evaluated
No
No
PR
30%
PR
Any
Yes or no
Yes or no
PR
30% to 
20%
SD
Any
Yes or no
Yes or no
SD
Not all evaluated
Not 
evaluated
Any
Yes or no
Yes or no
NE
20%
PD
Any
Yes or no
Yes or no
PD
CR complete response; NE not evaluable; PD progressive disease; PR partial 
response; RECIST Response Evaluation Criteria in Solid Tumors; SD stable disease.
a When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met since a normal 
lymph node is defined as having a short axis of 10 mm.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 10 mm in order to meet 
the definition of CR.
BEST OVERALL RESPONSE:  ALL TIMEPOINTS
The best overall response is determined once all the data for the patient are known.
The best overall response according to modified RECIST is interpreted as below:
3.
CR:  Complete disappearance of all tumor lesions (target and non-target) and no new 
measurable or unmeasurable lesions, confirmed by a consecutive assessment 4 weeks 
from the date first documented.  All lymph nodes short axes must be 10 mm.
4.
PR:  Decrease in the sum of the diameters of all target and all new measurable lesions 30% 
relative to baseline, in the absence of CR, confirmed by a consecutive assessment 4 
weeks from the date first documented.  
5.
SD: Criteria for CR, PR, and PD are not met. 


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Modified Response Evaluation Criteria in Solid Tumors (cont.)
6.
PD:  Increase in the sum of the diameters of all target and all new measurable lesions 20% 
relative to the nadir, which mustbe confirmed by a consecutive assessment 4 weeks from 
the date first documented as follows: 
The confirmatory assessment shows an additional measurable increase in tumor 
burden as measured by the sum of the diameters of all target and all new measurable 
lesions.


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


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Appendix 5
Preexisting Autoimmune Diseases
Subjects should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease. 
Subjects with any history of immune deficiencies or autoimmune disease listed in the 
table below are excluded from participating in the study
Possible exceptions to this exclusion could be subjects with a medical history of such 
entities as atopic disease or childhood arthralgias where the clinical suspicion of 
autoimmune disease is low.  Patients with a history of autoimmune-related 
hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this 
study.  In addition, transient autoimmune manifestations of an acute infectious disease 
that resolved upon treatment of the infectious agent are not excluded (e.g., acute Lyme 
arthritis). –
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions:
1.
Rash must cover less than 10% of body surface area (BSA).
2.
Disease is well controlled at baseline and only requiring low potency topical 
steroids.
3.
No acute exacerbations of underlying condition within the previous 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, high potency or oral steroids) 
Please contact the Medical Monitor regarding any uncertainty over autoimmune 
exclusions.


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Appendix 5
Preexisting Autoimmune Diseases (cont.)
Autoimmune Diseases and Immune Deficiencies
Acute disseminated
encephalomyelitis
Addison’s disease
ANCA positive vasculitis
Ankylosing spondylitis
Antiphospholipid antibody
syndrome
Aplastic anemia
Autoimmune hemolytic anemia
Autoimmune hepatitis
Autoimmune
hypoparathyroidism
Autoimmune hypophysitis
Autoimmune myocarditis
Autoimmune oophoritis
Autoimmune orchitis
Autoimmune 
thrombocytopenic
purpura
Behcet’s disease
Bullous pemphigold
Celiac disease
Chronic fatigue syndrome
Chronic inflammatory
demyelinating
polyneuropathy
Chung-Strauss syndrome
Crohn’s disease
Dermatomyositis
Dysautonomia
Epidermolysis bullosa acquista
Gestational pemphigoid
Giant cell arteritis
Glomerulonephritis
Goodpasture’s syndrome
Graves’ disease
Guillain-Barré syndrome
Hashimoto’s disease
IgA nephropathy
Inflammatory bowel disease
Interstitial cystitis
Kawasaki’s disease
Lambert-Eaton myasthenia
syndrome
Lupus erythematosus
Lyme disease - chronic
Meniere’s syndrome
Mooren’s ulcer
Morphea
Multiple sclerosis
Myasthenia gravis
Neuromyotonia
Opsoclonus myoclonus
syndrome
Optic neuritis
Ord’s thyroiditis
Pemphigus
Pernicious anemia
Polyarteritis nodosa
Polyarthritis
Polyglandular autoimmune
syndrome
Primary biliary cirrhosis
Psoriasis
Reiter’s syndrome
Pyoderma gangrenosum
Reactive arthritis
Rheumatoid arthritis
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Stiff-Person syndrome
Takayasu’s arteritis
Ulcerative colitis
Vogt-Kovanagi-Harada 
disease
Wegener’s granulomatosis


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Appendix 6
Prostate Response Evaluation Criteria
PROSTATE-SPECIFIC ANTIGEN ASSESSMENT
Prostate-specific antigen (PSA) Assessment will be evaluated according to the 
recommendations of the Prostate Cancer Working Group 2 (PCWG2)1 with modification

PSA complete response is defined as a PSA concentration < 0.5 ng/mL for two 
consecutive measurements separated by at least 3 weeks

PSA response will be defined as a PSA concentration < 50% of the PSA reference 
value occurring at any time after treatment is initiated. The PSA reference value will 
be the PSA concentration measured immediately prior to treatment

PSA decrease of ≥ 30% from baseline by Week 12 will also be assessed

PSA progression is defined as follows:
–
In patients where no decrease in PSA from baseline is documented, PSA 
progression is a ≥ 25% increase from the baseline value along with an increase 
in absolute value of 2ng/mL or more after 12 weeks of treatment. It should be 
confirmed by a second value obtained 3 or more weeks later
–
In patients whose PSA nadir is < 100% of the baseline value, PSA progression 
is≥ 25% increase from the nadir and an absolute increase of 2 ng/mL or more 
from the nadir, confirmed by a second value obtained 3 or more weeks later
RADIOGRAPHIC ASSESSMENT

Bone lesions
–
Progression is defined as the appearance of two or more new lesions
–
Progression should be confirmed by a repeat measurement at least 6 weeks 
later demonstrating additional new lesions

Soft tissue lesions
–
Soft tissue lesions should be assessed according to the modified Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria v. 1.1
Patients should be kept on study until no longer experiencing clinical benefit as 
determined by the investigator and an effort should be made not to discontinue therapy 
solely on the basis of an increase in PSA in the absence of other indicators of disease 
progression.
1 Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials 
working group. J Clin Oncol 2008;26:1148−59.


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Appendix 7
Malignant Pleural Mesothelioma Response Evaluation Criteria
RATIONALE
The major problems in applying the RECIST criteria to malignant pleural mesothelioma 
are in the interpretation of the meaning and placement of the "longest uni-dimensional 
diameter" of the target tumor mass to be measured. 
The longest diameter of a tumor mass is frequently that which follows the inner curve of 
the chest wall.  Defining the limits of such a diameter is often problematical. 
When the tumor regresses with treatment, the line may cross an area outside the tumor 
margin because of the curve of the chest wall.  This may produce difficulty with 
reproducibility of measurement.  Furthermore, the longest tumor diameter may be 
between two fixed structures, such as the thoracic vertebrae and the carina, and 
measurement in these areas may not fully reflect tumor response. 
MODIFIED RECIST FOR MALIGNANT PLEURAL MESOTHELIOMA
Modified RECIST criteria have been published with particular reference to malignant 
pleural mesothelioma (Byrne and Nowak, 2004)1:

Response to treatment is evaluated by measuring uni-dimensional tumor thickness 
perpendicular to the chest wall in 2 positions at 3 different levels on CT.  The sum of 
these 6 measurements is defined as the pleural uni-dimensional measure

Transverse cuts at least 1 cm apart and related to anatomical landmarks in the 
thorax were chosen to allow reproducible assessment at later time points

If a measurable tumor was present, transverse cuts in the upper thorax, above the 
level of the main bronchi division were preferred

At reassessment, pleural thickness was measured at the same position and at the 
same level by the same observer. This measurement did not necessarily represent 
the greatest tumor thickness at the level

Nodal, subcutaneous, and other bi-dimensionally measurable lesions were 
measured uni-dimensionally based on the RECIST criteria

Uni-dimensional measurements were included to obtain the total tumor 
measurement

A confirmed response required repeat observation on 2 occasions 4 weeks apart
                                           
1 Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma. Ann Oncol. 2004 Feb;15(2):257-60.


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Appendix 7
Malignant Pleural Mesothelioma Response Evaluation Criteria
The RECIST definition is listed in the table below
Complete response (CR)
Disappearance of all target lesions with no evidence of tumors 
elsewhere
Partial response (PR)
At least a 30%reduction in the total tumor measurement
Progressive disease (PD)
Increase of at least 20% in the total tumor measurement over the 
nadir measurement or the appearance of one or more new lesions
Stable disease (SD)
Those who fulfilled the criteria for neither PR and PD
(cont.)


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of atezolizumab 
may not have an immediate therapeutic effect, and in severe cases, immune-mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the immune-
mediated event.  Patients can be re-challenged with atezolizumab only after approval 
has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab in this study.
TREATMENT INTERRUPTION
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
105 days after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for 105 days to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for 105 days if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures) with Medical Monitor approval.  The investigator and 
the Medical Monitor will determine the acceptable length of treatment interruption.
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.
Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue atezolizumab and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue atezolizumab and contact Medical Monitor. c

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
BALbronchoscopic alveolar lavage.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
HEPATIC EVENTS
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.
Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
LFTliver function tests.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
LFTliver function tests.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


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


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


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


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


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(cont.)
Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must be 
agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged 
with atezolizumab only after approval has been documented by both the investigator (or 
an appropriate delegate) and the Medical Monitor. 
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.


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


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


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


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Management of Adverse Events Associated with Atezolizumab
(cont.)
INFUSION-RELATED REACTIONS
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in 
treating atezolizumab-associated IRRs because of its potential for causing 
agranulocytosis.
Guidelines for medical management of IRRs during Cycle 1 are provided in Table 7.  For
subsequent cycles, IRRs should be managed according to institutional guidelines.
Table 7
Management Guidelines for Infusion-Related Reactions
Event
Management
IRR, Grade 1 

Reduce infusion rate to half the rate being given at the time of 
event onset.

After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate.

If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate.
IRR, Grade 2

Interrupt atezolizumab infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic medication, glucocorticoids, 
epinephrine, bronchodilators, oxygen).

After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset.

For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs.
IRR, Grade 3 or 4

Stop infusion.

Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen).

Permanently discontinue atezolizumab and contact Medical 
Monitor. a
IRRinfusion-related reaction.
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.


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(cont.)
PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of atezolizumab.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests. Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 8.
Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis 
Event
Management
Amylase and/or lipase 
elevation, Grade 2

Continue atezolizumab.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g., 3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


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Table 8
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume 
atezolizumab. b

If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c

For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent.  The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
DERMATOLOGIC EVENTS
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 9.


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Table 9
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue atezolizumab.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue atezolizumab.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Dermatologic 
event, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day 
oral prednisone or equivalent.  The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 10.


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Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Table 10 Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1

Continue atezolizumab.

Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c
Immune-
mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré
syndrome (any 
grade)

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent.  The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to 
10 mg/day oral prednisone or equivalent before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be re-
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-mediated meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.  


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Management of Adverse Events Associated with Atezolizumab
(cont.)
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue atezolizumab and contact Medical Monitor. a

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
RENAL EVENTS
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Table 12 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue atezolizumab.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold atezolizumab for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
Renal event, 
Grade 3 or 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13.
Table 13 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.
Immune-
mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
Table 13 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-
mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Respiratory support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of 10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


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Appendix 8
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab
(cont.)
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).  
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants 4 weeks old)
–
Platelet count 100109/L (100,000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations 
above age-adjusted laboratory-specific norms
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met:

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181109/L (181,000/L)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Patients with suspected HLH or MAS should be treated according to the guidelines in 
Table 14.


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

SAP_001.pdf: 
Official Title: 
An Open-label, Multicohort, Phase II Study of Atezolizumab in 
Advanced Solid Tumors 
NCT Number: 
NCT02458638 
Document Date: 
SAP Version 4: 24-February-2020 


MPDL3280A—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MO29518 – Version 4.0, 12-Feb-20 
 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
AN OPEN-LABEL, MULTICOHORT, PHASE II STUDY OF 
ATEZOLIZUMAB IN ADVANCED SOLID TUMORS 
PROTOCOL NUMBER: 
MO29518 (Version 8, 23-Oct-2019) 
STUDY DRUG: 
Atezolizumab (RO5541267) 
VERSION NUMBER: 
4.0 
IND NUMBER: 
111271 
EUDRACT NUMBER: 
2015-000269-30 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
AUTHORS: 
, Accovion (Version 1) 
, 
Clinipace/Accovion (Version 2) 
, Roche (Version 3) 
, Roche; 
 
, Cytel (Version 4) 
DATE FINAL: 
12 February 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This is a F. Hoffmann-La Roche Ltd document that contains confidential information. Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 


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SIGNATURE PAGE 
Signature:  
 
 
Electronically signed by: 
 
Reason: Approve 
Date: 2020-02-24 11:23:48+01:00 
Biostatistician 
 
F. Hoffmann-La Roche Ltd 
Email: 
 
 
Signature 
 
 
24-Feb-2020 
 
 
Date 
Signature:  
 
 
Electronically signed by: 
 
Reason: Approve 
Date: 2020-02-14 15:07:40+01:00 
 
 
 
 
F. Hoffmann-La Roche Ltd 
Email: 
 
 
 
Signature 
 
 
14-Feb-2020 
 
 
Date 


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STATISTICAL ANALYSIS PLAN HISTORY 
 
SAP Version / Date 
Description 
Version 1 / 12 November 
2015 
Definition of Stage I analyses 
Version 2 / 10 July 2017 
 
Overview of planned cohorts and sub-cohorts per 
protocol amendment 4 (section 2) 
 
Rules added to impute, where possible, NPR endpoint 
for patients with no tumor assessment in the 
appropriate assessment window (section 4.4.1 for NPR 
at 18 weeks and section 4.4.2 for NPR at 24 weeks) 
 
Description of Stage I analyses expanded 
 
Expanded and clarified definition of eligibility and 
evaluability for all efficacy analysis populations (section 
4.1.5) 
 
Analyses for Stage II, and Final analysis added. 
Version 3 / 20 April 2018 
 
Clarified exclusion from this SAP of antibody analysis, 
pharmacokinetic analysis as well as exploratory 
biomarker analysis 
 
Removed modified RECIST analysis 
 
Rescheduled Stage II analysis to be part of combined 
Month 12 analysis 
 
Clarified analysis set definitions 
 
Added waterfall plot 
 
Clarified DOR will only be analyzed if >3 patients with 
CR/PR in the cohort 
 
Simplified summary of study drug exposure (removed 
dose intensity and detailed summaries of delayed 
infusions) 
 
Specified AESIs defined by Roche current standard 
(superseding eCRF tickbox) 
 
Removed most listings (exceptions include deaths, 
SAEs and AESIs) 
Version 4.0 / 12 February 
2020 
 
Added more information about calculation of missed 
and delayed doses 
 
Allowed for minor departures from 12 patients at Stage I 
analysis time 
 
Removed Koyama and Chen adjustment of Stage II 
analysis of NPR (not directly applicable in case of 
departure from intended Stage I sample size) 
 
Updated extended time window for NPR at 18 weeks 
(section 4.4.1): extended window to define imputed 
CR/PR/SD increased up to Day 209 (as for NPR at 24 
weeks) 
 
Analysis of modified RECIST added (BOR only) 
 
PK and ADA analyses added 
 
Biomarker (PD-L1) analysis added. 
 
Clarifications added on the analysis of all cohorts 
combined 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN HISTORY ........................................................... 3 
1. 
BACKGROUND .............................................................................................. 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
Objectives ................................................................................. 8 
2.2 
Determination of Sample Size ................................................... 9 
2.2.1 
Definition of Cohorts and Extensions/Expansions .................. 10 
2.3 
Analysis Timing ...................................................................... 11 
3. 
STUDY CONDUCT ....................................................................................... 12 
4. 
STATISTICAL METHODS ............................................................................ 13 
4.1 
Analysis SETS ....................................................................... 13 
4.1.1 
Intention-to-treat Set .............................................................. 13 
4.1.2 
Safety Set ................................................................................ 14 
4.1.3 
Analysis sets for efficacy analyses .......................................... 14 
4.1.3.1 Eligibility and evaluability ....................................................... 14 
4.1.3.2 Stage I Efficacy Set .............................................................. 14 
4.1.3.3 Stage II (and Subsequent) Efficacy Set ................................ 14 
4.2 
Summaries of Study Conduct ................................................. 14 
4.3 
Summaries of Treatment Group Comparability ....................... 15 
4.4 
Efficacy Analysis ..................................................................... 15 
4.4.1 
Primary Efficacy Endpoint ....................................................... 15 
4.4.2 
Analysis of the Primary Efficacy Endpoint .............................. 16 
4.4.3 
Secondary Efficacy Endpoints ................................................ 16 
4.4.4 
Analysis of the Secondary Efficacy Endpoints ........................ 18 
4.4.4.1 Analysis of NPR, BOR, ORR and CBR ................................ 18 
4.4.4.2 Response and lesion assessments ....................................... 18 
4.4.4.3 Time to event analyses .......................................................... 19 
4.5 
Pharmacokinetic (PK) Analysis ............................................... 19 
4.6 
Immunogenicity Analysis ......................................................... 19 
4.7 
Safety Analyses ...................................................................... 20 
4.7.1 
Exposure to Study Medication ............................................... 20 
4.7.2 
Adverse Events ....................................................................... 20 


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4.7.3 
Laboratory Data ..................................................................... 21 
4.7.4 
Vital Signs and ECG .............................................................. 21 
4.8 
Biomarker Analysis ................................................................. 21 
4.9 
Missing Data .......................................................................... 22 
5. 
REFERENCES ............................................................................................. 22 


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1. 
BACKGROUND 
This study will assess the efficacy and safety of the anti-PDL1 therapeutic antibody 
Atezolizumab for the treatment of various advanced solid tumors. The tumors included in 
this study are listed in Section 2 below. A brief description of their epidemiology and 
prognoses is presented in Table 1 of the Protocol (Section 1.1). 
2. 
STUDY DESIGN 
 
This is an open-label, multicenter, multinational, multi-cohort, phase II study. For each 
patient, the study will consist of a Screening Period (Day –35 to −1), a Treatment Period, 
and a Treatment Discontinuation Visit occurring ≤ 30 days after the last dose of study 
medication. Each cohort will be followed for survival until 2 years after the first dose for 
the final patient in the cohort.   For further illustration please see Figure 1 on study 
schema in the protocol. 
 
The study will include cohorts of patients with the following solid tumors (see Protocol 
version 8): 
 
1) Cervical cancer 
2) Nasopharyngeal carcinoma 
3) Known high microsatellite instability (MSI-H) or mismatch repair (MMR) deficient 
colorectal cancer 
4) Known BRCA 1/2 mutated cancers 
a) BRCA mutated ovarian cancer 
b) BRCA mutated breast cancer and that are not characterized as triple 
negative breast cancer 
5) Soft tissue and visceral sarcoma 
a) Liposarcoma 
b) Leiomyosarcoma 
c) Gastrointestinal stromal tumor (GIST) 
d) Undifferentiated pleomorphic sarcoma and 
e) Known translocation related sarcomas 
f) Radiation induced sarcoma 
g) Osteosarcoma 
h) Chondrosarcoma 
6) Mesothelioma 
a) Pleural mesothelioma 


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b) Peritoneal mesothelioma 
7) Cholangiocarcinoma/cancer of the biliary tract 
8) Thyroid cancer 
a) Anaplastic thyroid cancer 
b) Follicular or papillary thyroid cancer 
c) Medullary thyroid cancer and mixed medullary and follicular or papillary 
thyroid cancer 
9) Gastric adenocarcinoma/adenocarcinoma of the gastro-esophageal junction 
(GEJ) 
10) Other solid tumors – closed to recruitment from Protocol Version 4 onwards 
11) Malignant germ cell tumors 
12) ER+/HER2- metastatic breast cancer with known high mutation load (>100 
mutations) by local test 
13) Thymoma and thymic cancer 
a) Thymoma 
b) Thymic cancer 
14) Gastroenteropancreatic (GEP) and lung neuroendocrine tumors (NETs) 
a) Low and intermediate grades (typical or atypical carcinoid) 
b) Poorly differentiated grade (excluding SCLC) 
15) Known HPV induced squamous cell carcinoma 
a) Head and Neck 
b) Penile cancer 
c) Vaginal cancer/ vulvar cancer 
d) Anal cancer 
16) Known MSI high or MMR deficient tumors (excluding colorectal and gastric 
cancers) 
 
Enrollment in this study will be based on Simon's optimal two-stage design (Simon, 
1989). The primary objective of this study is to evaluate investigator-determined non- 
progression rate (NPR) at 18 weeks in the individual cohorts. 


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2.1 
OBJECTIVES 
 
Efficacy Objectives 
 
The primary efficacy objective for this study is as follows: 
 
To evaluate non-progression rate (NPR) at 18 weeks in patients with advanced solid 
tumors treated with Atezolizumab, defined as the percentage of patients with complete 
response (CR) partial response (PR) or stable disease (SD) as assessed by the 
Investigator1. The secondary efficacy objectives for this study are as follows: 
 
 
To evaluate NPR at 24 weeks, overall response rate (ORR), best overall response 
(BOR), clinical benefit rate (CBR), duration of response (DOR), time to tumor 
progression (TTP) and progression-free survival (PFS), as assessed by the 
Investigator1. 
 
 
To evaluate NPR at 18 and 24 weeks, ORR, BOR, CBR, DOR, TTP and PFS, as 
assessed by the Investigator using modified RECIST2 
 
 
To evaluate overall survival (OS) 
 
Safety Objectives 
 
The safety objectives for this study are as follows: 
 
 
To evaluate the safety and tolerability of Atezolizumab in patients with advanced 
solid tumors 
 
 
To characterize the immunogenic potential of Atezolizumab by measuring anti- 
Atezolizumab antibodies and to explore the potential relationship of the 
immunogenicity response with safety and efficacy 
 
Pharmacokinetic Objectives 
 
The pharmacokinetic (PK) objectives for this study are as follows: 
 
 
 
 
1 That is, using disease progression status as recorded in the clinical database. Investigator 
assessments are carried out according to Response Evaluation Criteria In Solid Tumors, Version 
1.1 (RECIST, v1.1) (except for prostate cancer and malignant pleural mesothelioma) and 
disease-specific criteria for patients with prostate cancer (see Protocol Appendix 6) and malignant 
pleural mesothelioma (see Protocol Appendix 7). 
2 That is, using disease progression status as recorded in the clinical database, for Investigator 
assessments carried out according to modified RECIST criteria as defined in Protocol Appendix 
3. 


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 
To characterize the pharmacokinetics of Atezolizumab 
 
Exploratory Objectives 
 
The exploratory objectives for this study are as follows: 
 
 
To evaluate the relationship between tumor tissue PD-L1 expression and measures 
of efficacy, including NPR at 18 weeks and 24 weeks, ORR, BOR, CBR, DOR, TTP, 
PFS and OS 
 
 
To assess predictive and prognostic exploratory biomarkers(e.g. but not limited to 
protein and genetic markers on DNA and RNA) in archival and/or fresh tumor tissue 
and plasma and their association with disease status and/or response to study 
treatment 
 
 
To evaluate exploratory pharmacodynamic (PD) biomarkers (e.g., genetic markers, 
T, B and NK cell enumeration, T cell subpopulations like CD8+ T, effector/memory T 
cells, regulatory T cells, changes in expression of CD25 or human leukocyte antigen- 
DR [HLA-DR], interferon [IFN]-gamma production,IL-2 and other exploratory 
biomarkers) in tumor tissue, tumor microenvironment and plasma and their 
association with disease status, and/or response to study treatment, tumor 
immunobiology or tumor type 
2.2 
DETERMINATION OF SAMPLE SIZE 
The sample size for this phase II study is based on Simon’s optimal two-stage design 
(Simon, 1989). 
 
In this Phase II study, an NPR of 20% is a level of activity that is not of interest for further 
clinical development, whereas an NPR of 40% is of clinical interest. The type I error will 
be 10% and the study will have 80% power to reject the null hypothesis when the true 
NPR is 40%. 
 
The Simon design in this study requires 12 fully evaluable patients for first stage. If at the 
end of the first stage there are only 0, 1 or 2 patients with non-progressive disease at 
Week 18, the enrollment into this cohort will be terminated (or the cohort may be 
expanded as described below). Otherwise, if more than 2 patients with non-progressive 
disease are observed at the end of Stage I, an additional 13 fully-evaluable patients will 
be enrolled into Stage II. The study drug will be considered of clinical interest in this 
cohort if, at the end of the second stage, there are 8 or more patients with non- 
progressive disease out of 25 total fully-evaluable patients. 
 
It can be assumed that some patients will not be evaluable for NPR. A patient will be 
considered evaluable for NPR if they received study drug, have a baseline tumor 
assessment and at least one tumor assessment post-baseline (per protocol mandated 


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timelines). Thus, more than 25 patients may be needed to be enrolled to obtain 25 fully- 
evaluable patients. 
 
The hypotheses and clinical assumptions will be applied to all cohorts individually. 
 
 
2.2.1 
Definition of Cohorts and Extensions/Expansions 
Statistical analyses will be based on patients with the same individual tumor type in the 
protocol-defined cohorts stated in section 2 above. The cohort for each patient will be 
identified from the data recorded on the “Cohort Assignment” CRF record. 
 
If, during the conduct of the study, a specific subgroup of patients in a cohort is 
identified, the cohort may be modified to include only that specific subgroup, and then 
statistical analysis may be performed based on this subgroup of patients. Subgroups of 
cohorts will be identified by first selecting patients in the appropriate cohort(s), and then 
filtering for patients meeting the required subgroup criteria. 
 
Additionally, a subgroup that applies across multiple tumor types (e.g. a biomarker 
positive subgroup) may be identified to be of interest. 
 
Cohorts of these latter types will be analyzed using the same methods as for the 
protocol-defined cohorts. 
 
Statistical analyses will be performed as well on all patients from all cohorts combined. 
The “All combined” cohort will be analyzed using the same methods as for the protocol- 
defined cohorts, but won’t include the following analyses: demographics, by-patient 
plots, time-to-event analyses, PK, immunogenicity and biomarkers. Some of the 
analyses will be performed only for “All combined” (as specified throughout the SAP). 
 
The enrollment pattern across Stage I and Stage II is shown in Figure 1 below. 


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0
Figure 1 Sample Size for Each Cohort in Stage I/II 
 
 
NP = non-progressors; NPR = non-progression rate. 
Assumptions: H = NPR 20%; H = NPR 40%; power = 80%; alpha = 10%. 
The sample size was estimated using Simon’s optimal two-stage design (Simon 1989). 
*   And no additional clinical benefit in a subgroup. 
 
 
 
2.3 
ANALYSIS TIMING 
Each cohort will be analyzed independently at the following time points: 
 
1. Stage I:  when the first 12 eligible and fully evaluable patients of the cohort have 
passed the week 18 assessment. This analysis will focus on the primary efficacy 
endpoint (NPR) and a targeted subset of Safety analyses (as agreed with the 
Steering Committee as being sufficient for the purpose of making a decision 
whether or not to continue to Stage 2). 
 
2. Month 12: for cohorts that progress to Stage 2, there may be an analysis of the 
majority of outcomes at Month 12 (when all patients of the cohort have been on 
the study for at least 12 months, have prematurely discontinued from the study or 
died). Such analyses are considered informative for potential future trials and 
early publication of individual cohort first results, but are not considered final. 
1


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3. Final analysis: the definitive Final Analysis, on which the CSR will be based, will 
take place following final database lock, which will be when all patients satisfy at 
least one of the following conditions: died, withdrawn consent or lost to follow up, 
or has been followed for survival for a minimum of 24 months after the last 
patient was enrolled, whichever occurs first.  In the Final Analysis, all cohorts will 
be analysed both separately and combined. 
 
 
 
3. 
STUDY CONDUCT 
 
Stopping and continuation rules for Stage I: 
 
Enrolment into the cohort will stop at the end of Stage I if the number of patients with 
non-progressive disease (confirmed or unconfirmed) is 2, 1 or 0 out of 12 patients. 
However, if the overall patient population does not meet requirements at Stage I, but a 
clinical benefit is observed in a specific subgroup (e.g. biomarker positive subgroup) of 
patients, then only this subgroup may be added for further evaluation at Stage I and 
Stage II. 
 
Decisions at the end of Stage I (termination, continuation or continuation in a subgroup) 
will be made by the Sponsor in discussion with the study Steering Committee members. 
 
Rules for Stage II: 
 
A study treatment will be considered to be promising for a given cohort if: 
 
 
there is no unacceptable toxicity , and 
 
 
at 18 weeks, there are 8 or more patients with non-progressive disease out of 25 
fully-evaluable patients. 
 
 
if for logistical reasons there are not exactly 25 fully-evaluable patients in a 
cohort, then a p-value will be calculated allowing for the departure from the 
planned Simon’s design, using the method of Koyama and Chen (2008). By 
analogy with the original design being based on alpha=0.1, a treatment will be 
considered to be promising if p < 0.1.  This p-value can be mapped to a new 
cutoff point in the manner of the original design calculation.  Some values for the 
cutoff as a function of sample size are: 7 or more out of 21 to 24; 8 or more out 
of 25; 9 or more out of 26 to 29; 10 or more out of 30. 
 
 
If the overall patient population does not meet the Stage II criteria, but a clinical benefit is 
observed in a specific subgroup (e.g. biomarker positive subgroup) of patients, then 


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Stage II may be expanded to include additional patients from this specific subgroup in 
order to re-evaluate the Stage II criteria in this patient subgroup. 
 
In all such cases where a “new” cohort is defined based on partial results from the 
planned cohorts, the assumptions for Simon’s design and formal hypothesis testing will 
not hold. Therefore, only the standard summary statistics and confidence intervals will 
be presented.  As an informal guideline, we will consider 8 or more NPR out of 25 
patients as a promising result, but to be interpreted with suitable caution. 
 
 
 
4. 
STATISTICAL METHODS 
 
Categorical data (such as discontinuation reasons or adverse events) will be 
summarized using frequencies and percentages (including a category for missing, if 
appropriate). Continuous endpoints (such as durations or concentrations) will be 
summarized using descriptive statistics (N, mean, standard deviation, median, lower 
quartile, upper quartile, minimum and maximum). Other analysis methods will be 
specified (below) where applicable. 
 
Study Day 1 will be defined as the first day a patient receives study medication. Baseline 
values are determined by the last measurement up to and including date of treatment 
start (Study Day 1). For statistical evaluations (e.g. descriptive summaries) of post- 
baseline data summarised by visit, or by visit and timepoint, only measurements at 
scheduled visits or timepoints are considered. If a measurement is repeated at a 
scheduled visit or time point, then only the latest retest result will be used in calculation 
of the statistical summary.  All data – including from unscheduled measurements – will 
be included in the listings, and used in the calculation of minimum or maximum value 
over the course of the study, and in the potential identification of adverse events. 
 
Any cohort that does not reach the Stage I analysis (i.e. does not reach 12 eligible and 
evaluable patients), will not be presented for statistical analysis per se. (This does not 
preclude that some or all patients within such cohorts may be included in cross-cohort 
analyses.) 
4.1 
ANALYSIS SETS 
4.1.1 
Intention-to-treat Set 
For each cohort, the intention-to-treat (ITT) set will include all patients enrolled in the 
study irrespective of whether they have received study medication or not.  In practice 
during the course of this study, no patient has been enrolled and not received treatment. 
Therefore ITT and Safety sets are the same, and we label this as Safety Set in all 
outputs. 


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4.1.2 
Safety Set 
For each cohort, the Safety Set will include all patients who have received at least one 
dose of study medication. All tables (demographics, efficacy and safety) will include a 
summary by the Safety Set. 
 
4.1.3 
Analysis sets for efficacy analyses 
The Protocol mandates performing the efficacy analysis on “fully evaluable” patients. 
We clarify below how this will be interpreted in detail, and subsequently refer to this 
Efficacy Set as “eligible and evaluable”. 
4.1.3.1 
Eligibility and evaluability 
All patients will be considered eligible for the cohort identified from the data recorded on 
the “Cohort Assignment” CRF unless they have a protocol deviation that compromises 
their efficacy endpoint, as identified in the current version of the Protocol Deviation Plan 
at the time of the analysis. 
 
A patient will be considered evaluable for NPR if they received study drug, have a 
baseline tumor assessment and at least one tumor assessment post-baseline (per 
protocol mandated timelines). Specifically, if a single assessment has been performed, 
this assessment must be performed between days 18 and 66 (inclusive) post Day 1 of 
study treatment. (This latter restriction does not apply in case there are two or more 
assessments.) 
4.1.3.2 
Stage I Efficacy Set 
For each cohort, the Stage I Efficacy analysis set is by intention 12 eligible and 
evaluable patients having reached their Week 18 visit (or to have had their final study 
data collection before Week 18, e.g. due to death or other reason for study withdrawal). 
In some cases, due to late reclassification of protocol deviations, there may in practice 
be a small number fewer or greater than 12 for Stage 1 analysis. 
4.1.3.3 
Stage II (and Subsequent) Efficacy Set 
For each cohort, the Stage II Efficacy analysis set will include all of the eligible and 
evaluable patients in the corresponding safety population, once all patients in the cohort 
have reached Week 18 (or terminated the study). Patients will be considered eligible and 
evaluable for Stage II, independently of eligibility and evaluability assessed at the time of 
Stage I analysis. 
 
The same analysis set will be used for all subsequent efficacy analyses. 
 
4.2 
SUMMARIES OF STUDY CONDUCT 
Enrollment, reasons for treatment discontinuation, reasons for study discontinuation and 
duration of follow up will be summarized for both Safety and Efficacy Sets. For the 
analysis of “All combined”, a summary of enrollment by protocol-defined cohort will be 
provided. 


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Major protocol deviations, as identified in the current version of the Protocol Deviation 
Plan at the time of the analysis, will be listed (and summarized for “All combined” only). 
4.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
This is a single arm study and, consequently, no formal treatment group comparisons 
will be conducted. Demographics (age, sex, ethnicity, and race) and disease history will 
be summarized. Medical history, prior and concomitant therapies data will be 
summarized for “All combined” only. 
4.4 
EFFICACY ANALYSIS 
The majority of efficacy analyses will be performed on both Efficacy and Safety Sets. 
Exceptions are: waterfall plots, PFS, DOR and TTP analyses, which are only presented 
for efficacy analysis sets by convention. 
 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is non progression rate (NPR) at 18 weeks. 
 
Week 18 occurs at Study Day 127. Allowing 15 days either side of the exact Week 18 
study day, assessments that occur between Study Day 112 and Study Day 142 
(inclusive) will be considered as a Week 18 assessment. 
 
Individual patient response at 18 weeks, based on RECIST v1.1, will be categorized as 
“CR”, “CR (imputed)”, “PR”, “PR (imputed)”, “SD”, “SD (imputed)”, “PD”, ”Death in 
absence of PD”, “Discontinuation in absence of PD” or ”Missing” as follows: 
 
1. any patient who recorded PD (as determined by the Investigator) at any post- 
baseline tumor assessment up to Study Day 142 inclusive, will be classified 
as “PD”, 
 
2. any remaining patient who died at or prior to Study Day 142 will be classified 
as “Death in the absence of PD”, 
 
3. any remaining patient will be classified as “CR”, “PR”, or “SD” according to 
their Investigator-reported tumor assessment data that falls within the window 
of Study Day 112 – 142 inclusive (taking the worst case if there are two 
conflicting assessments within the window) 
 
4. for a patient who does not meet any of the above criteria, but who has a 
nearby later assessment (up to Day 209), the patient will be classified as “CR 
(imputed)”, “PR (imputed)” or “SD (imputed)” according to the first tumor 
assessment in the extended window. 
 
5. any remaining patient will be classified as “Discontinuation in absence of PD” 
if they have an End of Study date prior to Study Day 142 or, otherwise, as 
“Missing/Out of window”. 


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Non progression rate (NPR) at 18 weeks is defined as the percentage of patients with 
“CR”, “CR (imputed)”, “PR”, “PR (imputed)”, “SD” or “SD (imputed)” at 18 weeks. The 
denominator is all patients in the analysis (thus in this calculation, Death or 
Discontinuation in the absence of PD, and Missing/Out of window, are, conservatively, 
effectively treated as PD). 
 
 
 
4.4.2 
Analysis of the Primary Efficacy Endpoint 
The number and percentage of progression-free patients (NPR) at 18 weeks (Stage II) 
will be presented along with standard 95% (exact binomial, two-sided) confidence 
intervals for proportions. 
 
 
 
4.4.3 
Secondary Efficacy Endpoints 
Non progression rate (NPR) at 24 weeks is defined as the percentage of patients with 
“CR”, “CR (imputed)”, “PR”, “PR (imputed)”, “SD” or “SD (imputed)” at 24 weeks. 
 
Week 24 occurs at Study Day 169. Allowing 20 days either side of the exact Week 24 
study day, assessments that occur between Study Day 149 and Study Day 189 
(inclusive) will be considered as a Week 24 assessment. 
 
Individual patient response at 24 weeks, based on RECIST v1.1, will be categorized as 
“CR”, “CR (imputed)”, “PR”, “PR (imputed)”, “SD”, “SD (imputed)”, “PD”, ”Death in 
absence of PD”, “Discontinuation in absence of PD” or ”Missing” as follows: 
 
1. any patient who recorded PD at any post-baseline tumor assessment up to 
Study Day 189 inclusive, will be classified as “PD”, 
 
2. any remaining patient who died at or prior to Study Day 189 will be classified 
as “Death in the absence of PD”, 
 
3. any remaining patient will be classified as “CR”, “PR”, or “SD” according to 
their Investigator-reported tumor assessment data that falls within the 
window of Study Day 149 – 189 inclusive (taking the worst case if there are 
two conflicting assessments within the window), 
 
4. for a patient who does not meet any of the above criteria, but who has a 
nearby later assessment (up to Day 209), the patient will be classified as 
“CR (imputed)”, “PR (imputed)” or “SD (imputed)” according to the first tumor 
assessment in the extended window. 


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5. any remaining patient will be classified as “Discontinuation in absence of PD” 
if they have an End of Study date prior to Study Day 189 or, otherwise, as 
“Missing/Out of window”. 
 
 
 
Best overall response (BOR), based on RECIST v1.1, for an individual patient, is 
defined as the best overall response obtained until progressive disease, death or lost to 
follow up, whichever is the first, as follows: 
 
1. CR for a patient with an overall tumour response assessment of CR at two 
consecutive visits at least 28 days apart. If applicable, any tumour 
assessment within the 28 day period must also record CR. 
 
2. PR for a patient with an overall tumour response assessment of PR or CR at 
two consecutive visits at least 28 days apart without being a CR. If 
applicable, any tumour assessment within the 28 day period must also 
record PR or CR. 
 
3. SD, for a patient with an overall tumour response assessment of SD, PR, or 
CR at one or more visits at least 42 days after start of study treatment, but 
are not a confirmed CR or PR. 
 
4. PD, for a patient with an overall tumour response assessment of PD at any 
visit, and does not meet the criteria for a BOR of CR, PR or SD. 
 
5. Missing, for a patient with an assessment of SD, PR or CR in the first 42 
days after start of study treatment and no further tumour assessments 
thereafter. 
 
 
Best overall response will summarize the proportion of patients with each best overall 
response. 
 
Overall response rate (ORR) is defined as the proportion of patients with a BOR of CR 
or PR. 
 
Clinical benefit rate (CBR) is defined as the proportion of patients with a BOR of CR, 
PR or SD. 
 
Duration of response (DOR), based on RECIST v1.1, is defined as the time from the 
first occurrence of a documented objective response (CR or PR) to the time of 
progression or death from any cause, whichever occurs first. For patients who do not die 
or experience disease progression before the end of the study or who are lost to follow- 
up, duration of objective response will be censored at the day of the last tumor 


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assessment.  Note: DOR will not be analysed if there are less than 4 patients available 
for the analysis. 
 
Progression-free survival (PFS), based on RECIST v1.1, is defined as the time from 
the first day of study treatment to the first occurrence of disease progression or death 
from any cause, whichever occurs first. A patient without a PFS event will be censored 
at the time of the last evaluable tumor assessment or, for patients with no tumor 
assessment after the baseline visit, at the time of the first day of study treatment plus 1 
day. 
 
Time to progression (TTP), based on RECIST v1.1, is defined as time from the first 
day of study treatment to the first occurrence of progressive disease or death due to 
disease progression, whichever occurs first. Patients who have not progressed or died 
due to disease progression at the time of study completion or who are lost to follow-up 
will be censored at the date of the last evaluable tumor assessment or, for patients with 
no tumor assessment after the baseline visit, at the time of the first day of study 
treatment plus 1 day. 
 
Overall survival (OS) is defined as the time from the first day of study treatment to 
death from any cause. Patients who are still alive at the time of analysis (clinical cut-off) 
and patients who are lost to follow-up will be censored at the last date they were known 
to be alive. 
 
Modified best overall response (mBOR), based on modified RECIST, for an individual 
patient, is defined as the best overall response obtained until death or lost to follow up, 
whichever is the first. The mBOR categories are obtained in the same manner as for the 
BOR based on RECIST v1.1, as described above. 
 
 
Modified best overall response will summarize the proportion of patients with each 
modified best overall response. 
 
4.4.4 
Analysis of the Secondary Efficacy Endpoints 
 
 
4.4.4.1 
Analysis of NPR, BOR, ORR and CBR 
The secondary endpoints NPR at 24 weeks, BOR, ORR and CBR based on RECIST 
v1.1, as well as mBOR based on modified RECIST, will be analyzed using standard 95% 
(exact binomial, two-sided) confidence intervals for proportions. 
4.4.4.2 
Response and lesion assessments 
A swimmer plot will be provided to illustrate the response assessments over time, and a 
spider plot will be presented to show the change in sum of target tumor diameters (SLD) 
over time. A waterfall plot will show best SLD change from baseline. 


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4.4.4.3 
Time to event analyses 
The time-to-event variables PFS, OS, TTP and DOR will be presented graphically using 
the Kaplan-Meier (KM) approach. The median survival time and its 95% confidence 
interval will be presented. Additionally, the estimated survival rate together with its 
associated 95% confidence interval at 24 weeks, at 6 and 12 months, and at 24 months 
(for OS only) will be presented. 
 
Duration of response will be evaluated only for patients who achieve CR or PR (and only 
analysed if there are more than 3 such patients in a cohort). 
4.5 
PHARMACOKINETIC (PK) ANALYSIS 
The PK analysis will be performed on the safety population. Atezolizumab serum 
concentration data will be summarized descriptively, for each cycle and timepoint at 
which PK is measured. Descriptive statistics will include the numbers of patients below 
the limit of quantification (BLQ), mean, SD, median, minimum and maximum. 
4.6 
IMMUNOGENICITY ANALYSIS 
The immunogenicity analysis will be performed on the safety population. 
 
The anti-atezolizumab antibodies (ADAs) status at baseline will be summarized. 
 
In addition, the incidence of treatment-emergent ADAs will be summarized overall, for all 
patients with an ADA result from at least one post-baseline sample. 
 
The overall ADAs status will be reported in 4 categories: 
 
• 
Negative 
o patient with negative or missing ADA result at baseline and always negative 
post-baseline 
 
• 
Negative (Treatment unaffected) 
o patient with positive ADA at baseline and always negative post-baseline 
o patient with positive ADA at baseline and treatment unaffected, i.e. with all 
post-baseline titer results <0.6 compared compared to baseline titer 
 
• 
Positive (Treatment enhanced) 
o patient with positive ADA and treatment enhanced, defined as at least one 
post-baseline titer result ≥0.6 compared to patient’s baseline titer 
 
• 
Positive (Treatment induced) 
o patient with negative or missing ADA result at baseline and at least one 
positive post-baseline 
 
A patient is considered positive if a titer value > 0 is reported. 


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4.7 
SAFETY ANALYSES 
Safety will be assessed through summaries of AEs, exposure to Atezolizumab, changes 
in laboratory test results as well as changes in vital signs and ECGs. The safety 
variables will be summarized for the safety population. Unless stated otherwise, all 
safety variables will be summarized for each cohort separately. 
 
4.7.1 
Exposure to Study Medication 
Number of infusions will be summarized by descriptive statistics. Time on treatment (last 
dose date minus first dose date, plus 1, expressed in weeks), and total dose received 
will be summarized. 
Missed treatment cycles are not recorded as such in the eCRF (sequential visits are 
labelled with sequential cycle number regardless of length of time between visits). 
Therefore to capture “missed doses” and delayed dose irregularities we categorize 
 
 
Patients with one or more missed cycle as being patients who have >=42 days 
between two consecutively labelled cycles (target cycle time being 21 days) 
 
 
Patients with at least one cycle delayed by 10 days or more (i.e. >=31 days 
between two consecutively labelled cycles).  Patients with one or more missed 
cycle as just defined are also included in this category. 
 
We also present total patient years of exposure to Atezolizumab (per cohort, and across 
the study) calculated as the sum of invididual time on treatment (last day of treatment 
minus first day of treatment plus one day), expressed in years (i.e. days/365.25). 
 
4.7.2 
Adverse Events 
Adverse events (AE) will be coded using MedDRA. 
AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.0. For events of varying severity, the 
most severe grade as documented on the eCRF will be used in the summaries. 
The analysis will focus on treatment-emergent AEs – AEs which start on or after the date 
of first dose of study drug. (For the assignment of ‘treatment-emergent’ in case of 
incomplete dates being recorded on the CRF, see Section 4.8.) 
AEs of Special Interest are defined according to current Roche global guidelines, and are 
identified in the clinical database. (This classification overrides the flag set in the eCRF by 
the Investigator.) 
An overview that summarizes the number of patients with treatment-emergent AEs (and 
the number of events) will be provided including all AEs, related AEs, AEs of Special 
Interest (AESI), Serious AEs (SAEs), related SAEs, SAEs leading to death, related SAEs 
leading to death and AEs leading to treatment discontinuation. The number of patients 
experiencing AEs at each grade (by highest grade) and related AEs at each grade (by 
highest grade) will also be included. 
The number and frequency of patients with treatment-emergent AEs will be presented by 
primary System Organ Class (SOC) and Preferred Term (PT) within SOC, both overall 
and for highest grade within patient, for the following: 
 
All AEs 


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 
Related AEs [“All combined” only] 
 
AESIs (by AESI class and PT rather than by SOC and PT) [“All combined” only] 
 
SAEs [“All combined” only] 
 
Related SAEs [“All combined” only] 
 
SAEs leading to death [“All combined” only] 
 
Related SAEs leading to death [“All combined” only] 
In addition, a summary of non-serious AEs occurring in 5% or more of patients will be 
provided (for regulatory disclosure purposes), for “All combined” only. 
Patient listings will be provided for: 
 
AEs leading to treatment discontinuation or interruption 
 
AESIs 
 
SAEs 
 
All deaths. 
 
 
4.7.3 
Laboratory Data 
Laboratory data will be analysis for “All combined” only. Hematology and chemistry 
laboratory data will be summarized in tables presenting the shift from baseline grade to 
worst NCI CTCAE grade recorded on treatment. Laboratory data recorded at an 
unscheduled visit (if on treatment) will be included in the calculation of worst grade for 
the shift tables. 
 
 
4.7.4 
Vital Signs and ECG 
Vital signs and ECG data will be summarized by visit (for vital signs, by timepoint within 
visit) and presented together with change from baseline, for “All combined” only. 
 
 
 
4.8 
BIOMARKER ANALYSIS 
Status of PD-L1 immune cells (IC) and tumor cells (TC) expression will be summarized 
at baseline, on both efficacy and safety populations. The following categories will be 
used: 
• 
IC 
o IC0: <1% 
o IC1: 1%-<5% 
o IC2: 5%-<10% 
o IC3: ≥10% 
• 
TC 
o TC0: <1% 
o TC1: 1%-<5% 


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In addition, box plots displaying the baseline PD-L1 continuous IC and TC values will be 
provided by NPR status at Week 18 (Yes/No), for the efficacy population. 
 
4.9 
MISSING DATA 
Missing data in the non-progression rate, for the eligible-and-evaluable efficacy 
analyses, will be minimized by extending recruitment to allow for patients who do not 
meet the definitions of eligible and evaluable. Further imputation rules are described in 
section 4.4.1 for NPR at Week 18 and section 4.4.3 for NPR at Week 24. 
 
Time to event endpoints will implement the censoring rules described in Section 4.4.3. 
 
For the flagging of an adverse event or concomitant medication with partial start and/or 
end date as being on treatment: the missing date is not imputed per se but it is 
calculated whether the event or medication could possibly have started or been taken 
while on treatment, in which case it is taken as such. 
 
5. 
REFERENCES 
 
Simon, R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 
10:1-10. 
o TC2: 5%-<50% 
o TC3: ≥50%