Conditions: Cutaneous Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this research is to evaluate whether the administration of atezolizumab before surgical resection of the tumor is feasible and to evaluate the treatment response, safety, and tolerability of atezolizumab.

Detailed description:
Primary Objective:

Determine the feasibility of three doses of atezolizumab prior to surgery in patients with advanced cutaneous squamous cell carcinoma

Secondary Objectives:

* Assess response rates to neoadjuvant atezolizumab

  * Objective response rate following completion of neoadjuvant therapy based on RECIST 1.1 criteria
  * Pathological response rate (major and complete pathological response) in final surgical resection specimen
* Assess change in surgical margins or vital structures preserved following neoadjuvant treatment
* Assess safety and tolerability of neoadjuvant atezolizumab

Arms:
arm 1: Subjects will receive neoadjuvant atezolizumab intravenous (IV) infusion at a fixed dose of 1200 mg on Day 1 (+/- 3 days) of each 21-day cycle for a total of 3 doses prior to surgery, unless there is clinical or radiographic evidence of disease progression.

Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab administered intravenous (IV) infusion at a fixed dose of 1200 mg

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version #15 
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ML42362: NEOADJUVANT ATEZOLIZUMAB IN SURGICALLY 
RESECTABLE ADVANCED CUTANEOUS SQUAMOUS CELL CARCINOMA 
Document History 
Notes 
Version 3       Date: 14 Sep 2020 
Initial Approval from Genentech 
Version 4       Date: 29 Oct 2020 
Revision includes: 
•
Addition of information in regulatory
considerations regarding the study
drug, i.e. reasons why it is IND-
exempt
•
Formatting changes
Version 5      Date: 30 Oct 2020 
Revision includes: 
•
Formatting changes, updating ToC
•
Correcting spelling and grammatical
errors
Version 6     Date: 30 Oct 2020 
Revision includes: 
•
Formatting changes
•
Clarification of the primary objective in 
the statistical plan
Version 7     Date: 04 Nov 2020 
Revision includes: 
•
Modified data safety and monitoring
plan, including adding a stopping rule
•
Updated the statistical plan
Version 8    Date: 12 Nov 2020 
Revision includes: 
•
Updated the statistical plan including
expanding on outcome measures
(primary and secondary)
Version 9     Date: 05 Mar 2021 
Revision includes: 
•
Updated the AE reporting timeline to
Genentech from 15 calendar days to 30
days and clarified site responsibilities
for signal management/ risk
management for per feedback from
Genentech
Version 10   Date: 06 Jul 2021 
Revision includes: 
•
Formatting and topological changes
•
Added Sumaira Aasi as Co-Investigator
•
Updated Section 4.2
o
Clarified sources for Medical
History
•
Updated Section 4.4
o
Clarified vital sign data
collection
•
Updated Section 4.5
o
Clarified Screening Scan
•
Updated Section 5.3
NCT04710498


Protocol Version #15 
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Document History  
Notes  
o Clarified study drug storage and 
dispensation. 
• Updated Section 7.2 
o The number of allotted active 
patients has been increased 
from three to six based on 
contemporary subject safety 
data. 
• Updated Section 7.3.1 
o Clarified AE collection 
• Clarified Procedures in Section 9 
o Clarified pre-infusion vital sign 
collection window, screening 
TSH, and RECIST. 
Version 11 Date: 16 Mar 2022 
Revision includes: 
• Clarify language 
o Section 12.3 language has been 
consolidated with section 7.2 to 
reflect previous amendment to 
six patients. 
• Minor formatting and administrative 
changes 
• Update Section 9 Study Calendar  
o Footnote J: Screening lab 
window extended to 28 days to 
match Inclusion criteria #7 
o Screening window clarified to 
within 28 days prior to start of 
treatment  
• Personnel changes 
o Remove Nikita Bedi as study 
coordinator 
o Add Luis Martinez Ramirez 
study coordinator 
Version 12 Date: 16 MAY 2022 
Revision includes:  
• Clarify language 
o Section 4.5 language to clarify 
collection of tumor response 
evaluations 
o Section 9 Study Calendar 
footnote P & S to clarify 
collection of RECIST 
measurements  


Protocol Version #15 
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Document History  
Notes  
Version 13 Date: 06 DEC 2022 
Revision includes: 
• Minor formatting changes 
• Updated Section 3 
o Clarified section by removing 
limit of 25 patients that can be 
screened for study as this was 
an arbitrary number. 
• Updated Appendix I  
o Added management guidelines 
for  
 Immune-mediated 
Myelitis 
 Immune-mediated facial 
paresis 
o Updated management 
guidelines for 
 Table 1: Pulmonary 
Events 
 Table 4: Endocrine 
Events 
 Table 6: Immune-related 
myocarditis 
 Table 7: Infusion-related 
Reactions and Cytokine-
release Syndrome 
 Table 9: Dermatologic 
Events 
 Table 10: Neurologic 
Disorders 
 Table 12: Renal Events 
 Table 13: Immune-
mediated Myositis 
 Table 14: Suspected 
Hemophagocytic 
Lymphohistiocytosis or 
Macrophage activation 
Syndrome 
o Updated Infusion related 
reactions subsection to 
"Infusion-related Reactions And 
Cytokine-Release Syndrome" 
and added updated information 
o Updated Dermatologic events 
subsection with updated 
information  


Protocol Version #15 
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Document History  
Notes  
o Updated Lymphohistiocytosis 
and macrophage activation 
syndrome subsection with 
updated information  
o Added new references 
Version 14 Date: 29 AUG 2023 
Revisions include: 
• Minor formatting edits 
• Administrative edits 
• Updated Appendix G 
o Added autoimmune myelitis to 
list of autoimmune disease that 
would exclude a patient from 
trial.   
• Updated Appendix I 
o Added missing table header for 
Table 11: Management 
Guidelines for Immune-
Mediated Myelitis 
o Revised management guideline 
table numbering for 
  Table 12: Immune-
Mediated 
Meningoencephalitis 
 Table 13: Renal Events 
 Table 14: Immune-
Mediated Myositis 
o Updated management 
guidelines tables with 
information from IBv19 and 
associated addendum: 
 Tables 1-15 
o Updated references 
Version 15 12AUG2024 
Revision includes: 
• Updated Section 1.2 
o Updated secondary objective to 
clarify that changes in surgery 
will be measured by intensity of 
surgery performed and cost of 
care.   
 
 
 






Protocol Version #15 
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TABLE OF CONTENTS 
PROTOCOL DIRECTOR ..................................................................................................................................................... 5 
CO-INVESTIGATORS ......................................................................................................................................................... 5 
BIOSTATISTICIAN ............................................................................................................................................................. 5 
STUDY COORDINATOR ..................................................................................................................................................... 6 
PROTOCOL SYNOPSIS ............................................................................................................................................... 9 
SCHEMA ...................................................................................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................................. 12 
1. 
OBJECTIVES .................................................................................................................................................... 13 
1.1. 
PRIMARY OBJECTIVE ................................................................................................................................................ 13 
1.2. 
SECONDARY OBJECTIVES ......................................................................................................................................... 13 
1.3. 
EXPLORATORY OBJECTIVES ..................................................................................................................................... 13 
2. 
BACKGROUND ................................................................................................................................................ 14 
2.1 
STUDY DISEASE ......................................................................................................................................................... 14 
2.2 
STUDY AGENT/DEVICE/PROCEDURE ................................................................................................................... 15 
2.3 
RATIONALE ................................................................................................................................................................ 15 
2.4 
STUDY DESIGN........................................................................................................................................................... 17 
2.5 
CORRELATIVE STUDIES BACKGROUND .................................................................................................................. 18 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................................................... 18 
3.1 
INCLUSION CRITERIA ................................................................................................................................................ 18 
3.2 
EXCLUSION CRITERIA ............................................................................................................................................... 18 
3.3 
INFORMED CONSENT PROCESS ............................................................................................................................... 18 
3.4 
STUDY TIMELINE ...................................................................................................................................................... 19 
4. 
TREATMENT PLAN ....................................................................................................................................... 19 
DESCRIPTION OF THE STUDY ..................................................................................................................................................... 19 
4.1 
INFORMED CONSENT FORMS AND SCREENING LOGS .......................................................................................... 19 
4.2 
MEDICAL HISTORY, CONCOMITANT MEDICATION, AND DEMOGRAPHIC DATA ............................................. 20 
4.3 
PHYSICAL EXAMINATIONS ....................................................................................................................................... 20 
4.4 
VITAL SIGNS ............................................................................................................................................................... 20 
4.5 
TUMOR AND RESPONSE EVALUATIONS ................................................................................................................. 20 
4.6 
LABORATORY, BIOMARKER, AND OTHER BIOLOGICAL SAMPLES ...................................................................... 21 
4.7 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .............................................. 23 
4.7.1 PERMITTED THERAPY ............................................................................................................................................... 23 
4.7.2 CAUTIONARY THERAPY FOR ATEZOLIZUMAB-TREATED PATIENTS .................................................................. 24 
4.8 
CRITERIA FOR REMOVAL FROM STUDY ................................................................................................................. 25 
4.8.1 PATIENT DISCONTINUATION FROM STUDY ........................................................................................................... 25 
4.8.2 STUDY DISCONTINUATION ....................................................................................................................................... 25 
4.9 
ALTERNATIVES .......................................................................................................................................................... 26 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ............................................. 26 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE .............................................................................................. 26 
5.2 
AVAILABILITY ............................................................................................................................................................ 27 
5.3 
AGENT ORDERING .................................................................................................................................................... 28 
5.4 
AGENT ACCOUNTABILITY ........................................................................................................................................ 28 
6. 
DOSE MODIFICATIONS ................................................................................................................................ 28 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .......................................................................... 28 
7.1 
POTENTIAL ADVERSE EVENTS................................................................................................................................ 28 
7.2 
SAFETY PARAMETERS AND DEFINITIONS ............................................................................................................. 29 
7.2.1 ADVERSE EVENTS ...................................................................................................................................................... 29 
7.2.2 SERIOUS ADVERSE EVENTS ...................................................................................................................................... 30 
7.2.3 ADVERSE EVENTS OF SPECIAL INTEREST .............................................................................................................. 30 
7.3 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES ............................................. 31 
7.3.1 ADVERSE EVENT REPORTING PERIOD ................................................................................................................... 31 
7.4 
ASSESSMENT OF ADVERSE EVENTS ....................................................................................................................... 32 
7.5 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS .......................................... 33 
7.5.1 ELICITING ADVERSE EVENT INFORMATION .......................................................................................................... 33 


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7.5.2 SPECIFIC INSTRUCTIONS FOR RECORDING ADVERSE EVENTS ............................................................................ 33 
7.6 
ADVERSE EVENT REPORTING ................................................................................................................................. 35 
7.6.1 MEDWATCH 3500A REPORTING GUIDELINES .................................................................................................... 36 
7.6.2 REPORTING TO REGULATORY AUTHORITIES, ETHICS COMMITTEES AND INVESTIGATORS ........................... 37 
7.7 AGGREGATE REPORTS ......................................................................................................................................................... 37 
7.7.1 IND ANNUAL REPORTS ............................................................................................................................................. 37 
7.7.2 OTHER REPORTS ........................................................................................................................................................ 38 
7.8 
STUDY CLOSE-OUT ................................................................................................................................................... 38 
8. 
CORRELATIVE/SPECIAL STUDIES ........................................................................................................... 39 
9. 
STUDY CALENDAR ........................................................................................................................................ 41 
10. MEASUREMENTS .............................................................................................................................................. 46 
10.1  
PRIMARY AND SECONDARY OUTCOME MEASURES .............................................................................................. 46 
10.1.1 RELEVANT SUBSET .................................................................................................................................................. 46 
10.2  
SECONDARY OUTCOME ............................................................................................................................................ 46 
10.2.1 RELEVANT SUBSET .................................................................................................................................................. 47 
11. 
REGULATORY CONSIDERATIONS ...................................................................................................... 47 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ................................................................................................................ 47 
11.2 
DATA AND SAFETY MONITORING PLAN ................................................................................................................ 47 
11.3 
DATA MANAGEMENT PLAN .................................................................................................................................... 48 
11.4 
COMPLIANCE WITH LAWS AND REGULATIONS .................................................................................................... 49 
11.5 
CONFIDENTIALITY .................................................................................................................................................... 49 
12. 
STATISTICAL CONSIDERATIONS ........................................................................................................ 49 
12.1 
STATISTICAL DESIGN................................................................................................................................................ 49 
12.2 
RANDOMIZATION ...................................................................................................................................................... 50 
12.3 
INTERIM ANALYSES ................................................................................................................................................... 50 
12.4 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ...................................................................... 50 
12.5 
PRIMARY ANALYSIS .................................................................................................................................................. 50 
12.6 
SECONDARY ANALYSIS ............................................................................................................................................. 50 
12.7  
SAMPLE SIZE .............................................................................................................................................................. 51 
12.8 
CRITERIA FOR FUTURE STUDIES ............................................................................................................................. 51 
APPENDICES ............................................................................................................................................................. 57 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ........................................................................................................ 57 
I. 
SUBJECT ELIGIBILITY CHECKLIST ........................................................................................................................... 57 
II. 
SUBJECT INFORMATION: ........................................................................................................................................... 57 
III. 
STUDY INFORMATION: .............................................................................................................................................. 57 
IV. 
INCLUSION/EXCLUSION CRITERIA .......................................................................................................................... 57 
V. 
STATEMENT OF ELIGIBILITY .................................................................................................................................... 61 
APPENDIX B: CALCULATION OF CREATININE CLEARANCE USING THE COCKCROFT-GAULT FORMULA ................... 62 
APPENDIX C: SAFETY REPORTING FAX COVER SHEET ..................................................................................................... 63 
APPENDIX D: FDA MEDWATCH 3500 FORM ................................................................................................................... 64 
APPENDIX E: CURRENT NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(NCI CTCAE) ............................................................................................................................................................................. 65 
APPENDIX F: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, VERSION 1.1 (RECIST V1.1) ...................... 66 
APPENDIX G: PREEXISTING AUTOIMMUNE DISEASES AND IMMUNE DEFICIENCIES .................................................... 74 
APPENDIX H: ANAPHYLAXIS PRECAUTIONS ....................................................................................................................... 75 
APPENDIX I: MANAGEMENT OF ATEZOLIZUMAB-SPECIFIC ADVERSE EVENTS ............................................................. 76 
 


Protocol Version #15 
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PROTOCOL SYNOPSIS 
 
TITLE 
Neoadjuvant Atezolizumab in Surgically 
Resectable Advanced Cutaneous Squamous 
Cell Carcinoma 
STUDY PHASE 
N/A Feasibility study 
INDICATION 
Cutaneous Squamous Cell Carcinoma 
INVESTIGATIONAL 
PRODUCT OR PROCEDURE 
Atezolizumab (RO5541267) 
PRIMARY OBJECTIVE 
• Determine the feasibility of three doses of 
atezolizumab prior to surgery in patients with 
advanced cutaneous squamous cell carcinoma 
SECONDARY OBJECTIVES 
• Assess response rates to neoadjuvant 
atezolizumab 
o Objective response rate following 
completion of neoadjuvant therapy 
based on RECIST 1.1 criteria 
o Pathological response rate (major 
and complete pathological 
response) in final surgical resection 
specimen 
• Assess change in surgical plan, as 
measured by intensity of surgery 
performed, cost of care, surgical margins 
or vital structures preserved, following 
neoadjuvant treatment 
• Assess safety and tolerability of 
neoadjuvant atezolizumab 
EXPLORATORY OBJECTIVES 
• Perform correlative studies to assess pre-
treatment biological markers, including 
PD-L1 expression, that are associated with 
response to atezolizumab 
• Evaluate tumors prior to and during 
treatment to identify neoantigen profile 
changes and T-cell receptor repertoire 
changes 
• Evaluate changes in cell-free DNA, 
cytokine profiles associated with immune 
system activation, and lymphocyte 
subpopulations before and during 
treatment 
• Analysis of genes or gene signatures 
associated with tumor immunobiology 
TREATMENT SUMMARY 
Subjects will receive neoadjuvant 
atezolizumab (1200 mg).  Atezolizumab will 
be administered by intravenous (IV) infusion 


Protocol Version #15 
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at a fixed dose of 1200 mg on Day 1 (+/- 3 
days) of each 21-day cycle for a total of 3 
doses prior to surgery, unless there is clinical 
or radiographic evidence of disease 
progression. 
SAMPLE SIZE  
20 evaluable patients 
STATISTICAL 
CONSIDERATIONS 
See stats section 
 
 


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SCHEMA 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AJCC 
American Joint Committee on Cancer 
aPTT 
Activated partial thromboplastin time 
CR 
Complete response 
cSCC 
Cutaneous squamous cell carcinoma 
CT 
Computed tomography 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B core antibody 
HBV 
Hepatitis B virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
Ig 
Immunoglobulin 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
Intravenous 
LPLV 
Last patient, last visit 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
Overall response rate 
OS 
Overall survival 
PK 
Pharmacokinetic 
PDL1 
Programmed death-ligand 1 
RECIST 
Response evaluation criteria in solid tumors 
ULN 
Upper limit of normal 
U.S. 
United States 
 
 


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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
The primary objective is to determine the feasibility of three doses of atezolizumab prior 
to surgery in patients with advanced cutaneous squamous cell carcinoma.  The primary 
outcome measure for each patient is an indicator for successfully completing 3 cycles of 
neoadjuvant atezolizumab, followed by surgical resection of remaining disease.  The 
treatment will be evaluated as non-feasible for patients who have disease progression 
during neoadjuvant treatment, discontinue study medications due to toxicity, or are not 
able to undergo curative surgical resection after 3 cycles of treatment. 
 
This study will gather safety and efficacy data to design a larger, more definitive trial that 
assesses important clinical endpoints including whether surgical margins can be reduced 
without compromising local control, the impact of neoadjuvant treatment on disease 
recurrence rates, and the role of adjuvant radiation and immunotherapy in high-risk 
patients.  This study will also validate the neoadjuvant approach. If the neoadjuvant 
approach is feasible, this study may allow for the addition of an additional cohort that 
evaluates the potential use combination immune checkpoint inhibitors which may have a 
more potent anti-tumor effect. 
 
1.2. 
Secondary Objectives  
 
The secondary objectives of the trial include: 
• Assess response rates to neoadjuvant atezolizumab 
o Objective response rate following completion of neoadjuvant therapy 
based on RECIST 1.1 criteria 
o Pathological response rate (major and complete pathological response) in 
final surgical resection specimen 
• Assess change in surgical plan, as measured by intensity of surgery performed, 
cost of care, surgical margins, or vital structures preserved, following neoadjuvant 
treatment  
• Assess safety and tolerability of neoadjuvant atezolizumab 
 
1.3. 
Exploratory Objectives 
 
The exploratory objectives of this study are: 
 
• Perform correlative studies to assess pre-treatment biological markers, including 
PD-L1 expression, that are associated with response to atezolizumab 
• Evaluate tumors prior to and during treatment to identify neoantigen profile 
changes and T-cell receptor repertoire changes 
• Evaluate changes in cell-free DNA, cytokine profiles associated with immune 
system activation, and lymphocyte subpopulations before and during treatment 
• Analysis of genes or gene signatures associated with tumor immunobiology 
 
 


Protocol Version #15 
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2. 
BACKGROUND 
 
2.1 
Study Disease 
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in 
the US, with over 700,000 cases diagnosed annually, and the incidence is likely to 
continue to rise.  While most cases are successfully treated with ablation or minor 
surgical resection, approximately 2-4% of patients can present with large recurrences, 
deeply invasive local disease, extensive perineural invasion, or regional metastases.  In 
these cases of advanced disease, wide surgical resection, lymph node dissection, and 
reconstructive surgery are often necessary, and usually followed with adjuvant radiation 
therapy.  Despite this aggressive treatment approach, multiple studies of advanced cSCC 
in the U.S. have shown recurrence rates that range from 28-42%, and OS rates that range 
from 22-54%.  Accurate estimates of the mortality burden are elusive since cSCC is not 
captured by national cancer registries, however estimates vary from 2,000 to 15,000 
annual deaths in the U.S. (Karla, Ansouri, ASCO) 
 
In addition, since 80% to 90% of these lesions occur in the head and neck, even smaller 
lesions can leave patients with significant disfigurement and a decreased quality of life.  
Cosmetically sensitive regions such as the nose, eyelids, and ear are very challenging to 
reconstruct when >50% of the structure is removed.  Functionally sensitive regions such 
as the orbital region or lower lip can be significantly distorted causing drooling, impaired 
vision, or corneal exposure. In rare cases, the cancer may require removal of the orbital 
contents leaving a patient with monocular vision.  Multiple studies have shown the 
significant distress, anxiety, and psychological impact of such outcomes. (Moolenburgh, 
Radiotis) 
 
This study will consider patients who have clinically advanced disease with increased 
risk of recurrence, and patients with disease for which surgery would result in significant 
disfigurement or functional impairment (see Inclusion Criteria). 
 
Inhibition Of Pd-1/Pd-L1 Pathway In Cutaneous Squamous Cell Carcinoma 
Cutaneous squamous cell carcinoma most often arises in areas of high sun exposure.  
cSCC has among the highest tumor mutational burden (45.2 mutations/Mb) due to 
cumulative ultraviolet light-induced mutations.  (Walter)  This high mutational burden is 
believed to lead to increased immunogenicity due to the very high expression of 
neoantigens.  (Martincorena) This makes cSCC, similar to other cutaneous malignancies 
such as malignant melanoma and Merkel cell carcinoma, a particularly attractive target 
for immunotherapeutic approaches. 
Studies have shown the impact of targeting the PD-1/PD-L1 pathway in cSCC, and found 
favorable results compared to the relatively low response rates of cytotoxic chemotherapy 
(cisplatin) and anti-EGFR antibodies, with ORR < 30%.  The most significant study was 
for cemiplimab, which received FDA approval for the treatment of locally advanced or 
metastatic cSCC in patients who were not eligible for curative surgery or radiation.  In 
this study, cemiplimab, an IgG4 anti-PD-1 monoclonal antibody, was found to have an 
ORR of 46.7%, with duration of response exceeding 6 months in 61% of patients. 
(Migden) 
 


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Other PD-1/PD-L1 checkpoint inhibitors have shown promising activity in cSCC in small 
cases series, leading to additional larger trials in the locally advanced and 
recurrent/metastatic populations.  Nivolumab (NCT04204837), pemobrolizumab 
(NCT03284424, NCT02883556), and avelumab in combination with cetuximab 
(NCT03944941) are three such inhibitors with further studies underway.  Additional 
studies of cemiplimab (NCT03969004) and pembrolizumab (NCT03833167) are being 
performed in the adjuvant setting following surgery and radiation therapy for advanced 
lesions 
 
2.2 
Study Agent/Device/Procedure 
Background on Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets 
PD L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also 
known as CD80), both of which function as inhibitory receptors expressed on T cells.  
Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to enhance the 
magnitude and quality of tumor-specific T-cell responses, resulting in improved anti 
tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has 
minimal binding to Fc receptors, thus eliminating detectable Fc-effector function and 
associated antibody-mediated clearance of activated effector T cells. 
 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced and adjuvant settings, as 
well as in combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
 
Atezolizumab is approved for the treatment of non-small cell lung cancer, small-cell lung 
cancer and Alveolar Soft Part Sarcoma (ASPS).  The PD-L1 inhibitors including 
atezolizumab have been evaluated in head and neck squamous cell carcinoma and shown 
to have benefit in early stage trials (Colevas, Segal). Its safety, tolerability, efficacy, and 
immunogenicity in adults with advanced solid tumors was evaluated in a phase I/II 
global, multicenter, open-label, first-in-human dose-escalation and expansion study.  In 
two different trials, atezolizumab in combination with NT-I7 (rhIL-7-hyFc) 
(NCT03901573) and in combination with cobimetinib (NCT03108131) is currently being 
investigated for advanced refractory tumors including cSCC. 
 
Details concerning atezolizumab’s clinical development can be found in the investigator 
brochure. 
 
For clinicaltrials.gov compliance 
This study will NOT require an Investigational New Drug application (IND). It is 
considered IND exempt.  
 
2.3 
Rationale 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 


Protocol Version #15 
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result in a significant survival benefit in patients with advanced malignancies (Hodi et al. 
2010; Kantoff et al. 2010; Chen et al. 2012). 
 
There are several benefits of a neoadjuvant approach to cSCC.  Given the critical location 
of these lesions and the impact on patients from disfigurement and functional 
impairment, minimizing tissue resection while not compromising outcomes is an 
important goal of treatment.  Reduction in surgical margins in responders may 
significantly impact a patient’s quality of life and patient reported outcomes. 
 
While the most aggressive cSCCs have been treated with adjuvant chemotherapy, use of 
immune checkpoint inhibitors may have a distinct advantage for being used in the 
neoadjuvant setting.  Inhibition in the presence of a large tumor mass may theoretically 
be a more ideal time to prime the system and potentially induce a stronger and broader 
tumor-specific T-cell response. (O’Donnell)  Given the significant recurrence rates and 
mortality associated with advanced cSCC, future studies could assess if this immune 
response can increase DFS and may ideally select which patients benefit from further 
treatment in the adjuvant setting.  Neoadjuvant window of opportunity trials also provide 
a unique opportunity to study biological correlates and markers of response in surgically 
curable disease. 
 
The experience with neoadjuvant treatment is growing.  A study of neoadjuvant 
nivolumab in untreated, surgically resectable early stage non-small cell lung cancer 
enrolled 22 patients, of which 20 patients were able to complete the 2 cycles of therapy.  
(NCT02259621)  Among these patients, 45% had a major pathological response, and 
none of the patients had any treatment-related delays in surgery.  20 of 21 patients were 
able to undergo complete surgical resection. (Forde) 
 
A pilot study in cSCC was presented at the 44th European Society of Medical Oncology 
in 2019 using 2 doses of neoadjuvant cemiplimab for patients with Stage 3 and 4 cSCC of 
the head and neck. (NCT03565783)  In this study of 20 patients, the treatment was well 
tolerated with no grade 3 or 4 AEs.  55% of patients achieved a pathological complete 
response and 15% of patients achieve a major pathological response (<10% viable 
tumor).  All patients were able to proceed with anticipated curative surgical resection.  
(Gross) 
 
In addition to this trial, other studies have shown a neoadjuvant approach is feasible with 
cutaneous malignancies and can result in decreased surgical defects.  Blank et. al. 
examined neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage 
III melanoma and found that all of the patients in the neoadjuvant treatment arm were 
able to undergo the anticipated surgery.  Of the 9 patients evaluable in the neoadjuvant 
arm, 78% achieved a significant pathological response and majority had a decrease in 
lesion size.  In a trial of vismodegib used in a neoadjuvant fashion prior to treatment of 
high-risk basal cell carcinoma, surgical defect size was reduced by 27% in patients who 
were able to complete 3 months of treatment with all patients able to complete surgical 
resection.  (Ally) 
 


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The risks of this trial, similar to other neoadjuvant trials, include the possibility of disease 
progression resulting in either a more extensive resection that initially anticipated or loss 
of opportunity for curative surgery.  Encouraging data from a preliminary study 
(NCT03565783, Gross) showed that the risk of this is likely low and worth the potential 
opportunity to reduce lesion size.  This risk will be minimized by careful monitoring of 
visible lesions following each cycle, and also includes an additional imaging study after 
the second dose of atezolizumab to check for radiographic evidence of disease 
progression. 
 
The toxicity profile for atezolizumab is expected to be similar to its use for other 
indications. Atezolizumab has been generally well tolerated.  Adverse events with 
potentially immune-related causes consistent with an immunotherapeutic agent, including 
rash, influenza-like illness endocrinopathies, hepatitis or transaminitis, pneumonitis 
colitis, and myasthenia gravis, have been observed (see Atezolizumab Investigator's 
Brochure for detailed safety results).  To date, these events have been manageable with 
treatment or interruption of atezolizumab treatment. 
 
This trial will enroll patients with advanced cutaneous squamous cell carcinoma.  Given 
the significant rates of recurrence and mortality, in addition to the disfigurement and 
functional impairment resulting from aggressive treatment, this population is considered 
appropriate for trials of novel therapeutic candidates.  This feasibility study will be the 
first step towards designing a larger trial that examines surgical margin reduction, disease 
recurrence rates, and optimal adjuvant therapy strategies.  If feasible, this study may also 
test the feasibility of this strategy for use of different combination regimens in the future. 
 
2.4 
Study Design 
An overview of the study is provided in the study flowchart (Section 9). Briefly, upon 
eligibility confirmation and study enrollment, subjects will undergo initial tumor biopsy 
and receive neoadjuvant atezolizumab (1200 mg).  Atezolizumab will be administered by 
intravenous (IV) infusion at a fixed dose of 1200 mg on Day 1 (+/- 3 days) of each 21-
day cycle for a total of 3 doses prior to surgery, unless there is clinical or radiographic 
evidence of disease progression.  If clinically feasible, an additional biopsy will be 
performed after the first dose for biological correlative studies. Patients will be seen prior 
to each cycle to assess response.  A formal assessment including imaging of the head and 
neck will be performed after 2 cycles of treatment.  After the third dose, standard of care 
surgical resection will be performed.  AEs will be assessed up to 30 days after surgical 
resection.  Following surgery, adjuvant therapy will be administered per the standard of 
care, which includes radiation therapy for AJCC Stage 3 and 4 disease. 
 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
• Treatment: protocol designed to evaluate one or more interventions for treating a 
disease, syndrome or condition 
• Single Group  
• Number of intervention arms: 1 
• Open: no masking is used  
• Not randomized 


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• State type of primary outcome or outcome that the protocol is designed to 
evaluate: Feasibility  
 
2.5 
Correlative Studies Background 
Published results suggest that the expression of PD-L1 in tumors correlates with response 
to anti-PD-1 and anti-PD-L1 therapy (Topalian et al. 2012; Herbst et al. 2014; Borghaei 
et al. 2015; Fehrenbacher et al. 2016; Herbst et al. 2016; Rosenberg et al. 2016).  In the 
current study, archival or baseline tumor specimens will be collected from patients and 
tested for PD-L1 expression by a central laboratory during the screening period.  In 
addition to the assessment of PD-L1 status, other exploratory biomarkers, such as 
potential predictive and prognostic biomarkers related to the clinical benefit of 
atezolizumab, tumor immunobiology, mechanisms of resistance, or tumor type, may be 
analyzed. 
 
Archival tumor tissue will be collected at baseline.  Fresh tumor tissue will also be 
collected at baseline and after the first cycle of atezolizumab by biopsy, if deemed 
clinically feasible by the investigator, to enable analysis of tumor tissue biomarkers 
related to resistance, neoantigen expression and changes with treatment, disease 
progression, and clinical benefit of atezolizumab. 
 
Blood samples will be collected at baseline and during the study to evaluate changes in 
surrogate biomarkers.  Changes in biomarkers such as cytokines associated with T-cell 
activation and lymphocyte subpopulations may provide evidence of biologic activity of 
atezolizumab in humans.  Correlations between these biomarkers and safety and efficacy 
endpoints will be explored to identify blood-based biomarkers that might predict which 
patients are more likely to benefit from atezolizumab. 
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Refer to the Participant Eligibility Checklist in Appendix A.  
Patients with advanced surgically-resectable cutaneous squamous cell carcinoma will be 
screened for enrollment in this study to yield 20 evaluable patients 
 
3.1 
Inclusion Criteria 
 
 
Refer to Participant Eligibility Checklist in Appendix A. 
 
3.2 
Exclusion Criteria 
 
 
Refer to Participant Eligibility Checklist in Appendix A. 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 


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study specific procedure. The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in 
the medical record or research file.  
 
 
3.4 
Study Timeline 
Primary Completion: 
The study will reach primary completion 36 months from the time the study opens to 
accrual. 
 
Study Completion: 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  
The end of the study is expected to occur 6 months after the last patient is enrolled.  In 
addition, the Investigator may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 42 months. 
 
 
4. 
TREATMENT PLAN 
Description of the Study 
The schedule of activities to be performed during the study is provided in Section 9.  All 
activities must be performed and documented for each patient.  Patients will be closely 
monitored for safety and tolerability throughout the study.  Patients should be assessed 
for toxicity prior to each dose; dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable. 
 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
(+/- 3 days) of each 21-day cycle), which is the approved dosage for atezolizumab, as 
outlined in the prescribing information.  Anti-tumor activity has been observed across 
doses ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum 
tolerated dose of atezolizumab was not reached and no DLTs were observed at any dose.  
The fixed dose of 1200 mg Q3W (equivalent to an average body weight-based dose of 15 
mg/kg Q3W) was selected on the basis of both nonclinical studies (Deng et al. 2016) and 
available clinical pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab 
Investigator's Brochure for details). 
 
4.1 
Informed Consent Forms and Screening Logs 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 


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screening failure, as applicable. 
 
4.2 
Medical History, Concomitant Medication, and Demographic Data 
Medical history reported via medical records and/or self-reported by the subject, 
including clinically significant diseases, surgeries, cancer history (including prior cancer 
therapies and procedures) will be recorded at baseline.  In addition, all medications (e.g., 
prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to initiation of study 
treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and allergies 
should be recorded. 
 
Demographic data will include age, sex, and self-reported race/ethnicity. 
 
4.3 
Physical Examinations 
A complete physical examination shall be performed at screening and other specified 
visits. Any abnormality identified at baseline should be recorded in the patient’s medical 
records. 
 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated. Changes from baseline abnormalities 
should be recorded in patient notes. New or worsened clinically significant abnormalities 
should be recorded as adverse events in the patient’s medical records. Clinically 
insignificant labs or other events need not be recorded or reported. 
 
4.4 
Vital Signs 
Vital signs will be performed as specified in the study calendar (Section 9). Only 
clinically significant abnormalities (new or worsened) will be recorded as AE’s in the 
patient’s medical records.  
 
4.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline and according to the schedule 
specified in the study calendar (section 9). These are clinical observations and 
judgements used by the investigator and medical team of the patient’s clinical status to 
determine the appropriateness of continuing study intervention. At the investigator’s 
discretion, tumor assessments may be repeated at any time if progressive disease is 
suspected.  All tumor assessments following surgical resection will be per standards of 
care. 
 
All measurable and evaluable lesions should be assessed and documented at screening.  
Tumor assessments performed as standard of care prior to obtaining informed consent 
and within 28 days prior to initiation of study treatment do not have to be repeated at 
screening.  
 


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Overall response at a single timepoint will be assessed by the investigator using RECIST 
v1.1 (see Appendix F) at baseline and Day 38 (± 4 days).   
 
Screening assessments must include CT scans (with IV contrast) or MRI scans of the 
primary site (if present), regional lymphatics, thorax, and depending on the location of 
the tumor, may include other relevant anatomy.  PET/CT or CT of the thorax are 
appropriate preoperative workup; however, cannot substitute for either the CT or MRI of 
the primary site if present, and regional lymphatics. CT of the thorax need not be 
repeated after baseline unless there is clinical indication.  If a CT scan with contrast is 
contraindicated (e.g., in patients with impaired renal clearance), a non-contrast CT scan 
of the chest may be performed and MRI scans of regional lymphatics and, if applicable, 
primary site should be performed.  The same radiographic procedures used to assess 
disease sites at screening should be used for subsequent tumor assessments (e.g., the 
same contrast protocol for CT scans) as listed in section 9. At the investigator's 
discretion, other methods of assessment of measurable disease as per RECIST v1.1 may 
be used. 
 
If a CT scan for primary tumor assessment is performed in a positron emission 
tomography (PET)/CT scanner, all efforts should be made so the CT acquisition is 
consistent with the standards for a full-contrast diagnostic CT scan. 
 
 
 
 
 
4.6 
Laboratory, Biomarker, and other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• See study calendar (Section 9) for details about schedule of laboratory studies 
 
The following samples will be sent to the Investigator or a designee for analysis: 
• Plasma samples for exploratory assessment cell-free DNA at baseline and after 
each cycle of therapy (up to 3 cycles). 
• Serum samples for assessment of cytokine profiles associated with immune 
system activation. 
• Peripheral blood mononuclear cells (PBMC) will be collected and cryopreserved 
after each cycle of therapy (up to 3 cycles) and at the time of surgical resection if 
deemed for possible, for exploratory identification of antigen-specific T cell 
receptors (TCR). 
• Archival or newly collected tumor tissue sample obtained at baseline for 
exploratory research on biomarkers 
o Samples collected via resection, core-needle biopsy, or excisional, 
incisional, punch, or forceps biopsy are preferred.  However, all specimen 
types (e.g., fine-needle aspiration) are acceptable. 
o If archival tumor tissue is unavailable or is determined to be unsuitable for 
exploratory research, a pretreatment tumor biopsy is required. 


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• Tumor tissue sample obtained following the first and subsequent cycles of therapy 
and at the time of surgical resection, if deemed clinically feasible, for exploratory 
research on biomarkers 
o Samples collected via resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are 
preferred. 
 
Exploratory biomarker research may include, but will not be limited to, analysis of genes 
or gene signatures associated with tumor immunobiology, PD-L1, lymphocyte 
subpopulations, T-cell receptor repertoire, peptide-MHC repertoire, or cytokines 
associated with T-cell activation.  Research may involve extraction of DNA, circulating 
tumor DNA, or RNA, analysis of mutations, genomic profiling through use of next-
generation sequencing (NGS) of a comprehensive panel of genes, and analysis of 
proteins. Research will aim to distinguish germline mutations from somatic mutations 
and understanding mechanisms underlying immune cell recognition of tumor cells that 
might predict clinical response to therapy. NGS methods may include whole exome 
sequencing (WES). 
 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research, biological samples will be destroyed when the final 
Clinical Study Report has been completed, with the following exceptions: 
• Blood samples collected for WES will be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with 
the IRB/EC approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
• Plasma and/or serum samples collected for PK or immunogenicity analysis and 
cell-free DNA analysis may be needed for additional characterization and for PK 
or immunogenicity assay development and validation; therefore, these samples 
will be destroyed no later than 5 years after the final Clinical Study Report has 
been completed. 
• Blood, plasma, serum, and tumor tissue samples collected for biomarker research 
will be destroyed no later than 10 years after the final Clinical Study Report has 
been completed. 
• For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival 
tissue blocks will be returned to the site no later than 6 weeks after eligibility 
determination. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the samples 
be destroyed, or local laws require destruction of the samples.  However, if samples have 
been tested prior to withdrawal, results from those tests will remain as part of the overall 
research data. 
 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 11.5. 


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Investigator policy on study data publication.  
 
4.7 
General Concomitant Medication and Supportive Care Guidelines 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to initiation of 
study treatment to the treatment discontinuation visit. All such medications should be 
reported to the investigator and recorded in the patient’s medical records.  
 
4.7.1 Permitted Therapy 
Patients are permitted to use the following therapies during the study: 
• Oral contraceptives 
• Hormone-replacement therapy 
• Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
• Inactivated influenza vaccinations 
• Megestrol acetate administered as an appetite stimulant  
• Mineralocorticoids (e.g., fludrocortisone) 
• Corticosteroids administered for COPD or asthma 
• Low-dose corticosteroids administered for orthostatic hypotension or 
adrenocortical insufficiency 
• Administration of steroids at high dose as indicated by the surgical team or 
anesthesia on the day of surgery or during the post-operative care. 
• Other prescription or OTC medicines not known or thought to interfere with the  
metabolism of or MOA of atezolizumab. Broadly, these typically include 
antihypertensives, lipid lowering agents, antidepressants, thyroid hormone 
replacement, oral hypoglycemic agents and insulin. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent atezolizumab infusions only, at the discretion of the 
investigator. 
 
In general, investigators should manage a patient's care (including preexisting conditions) 
with supportive therapies other than those defined as cautionary or prohibited therapies 
(see Sections 4.2 and 4.3) as clinically indicated, per local standard practice.  Patients 
who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., 
famotidine, cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 


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managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and 
β2-adrenergic agonists; see Appendix I). 
 
4.7.2 Cautionary Therapy for Atezolizumab-Treated Patients 
Corticosteroids and Tumor Necrosis Factor-α Inhibitors 
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab.  Therefore, in situations in which 
systemic corticosteroids or TNF-α inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids and TNF-α inhibitors may be administered at the 
discretion of the investigator. 
 
Systemic corticosteroids are recommended, at the discretion of the investigator, for the 
treatment of specific adverse events when associated with atezolizumab therapy (refer to 
Appendix I for details). Administration of steroids at high dose may be indicated to 
reduce swelling by the surgical team or anesthesia on the day of surgery or during the 
post-operative care. 
 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown.  However, 
herbal therapies not intended for the treatment of cancer (see Section 4.3) may be used 
during the study at the discretion of the investigator. 
 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
• Concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and 
herbal therapy), whether health authority-approved or experimental, is prohibited 
for the duration of the study. Adjuvant treatment with radiation and or systemic 
therapies is permitted per standards of care following the surgical resection. 
• Investigational therapy (other than protocol-mandated study treatment) is 
prohibited within 28 days prior to initiation of study treatment and during study 
treatment. 
• Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab, and for 5 
months after the last dose of atezolizumab. 
• Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL 2) are prohibited within 4 weeks or five drug elimination half-lives (whichever 
is longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab. 
• Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy 
and safety of atezolizumab. 


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4.8 
Criteria for Removal from Study 
Patients must permanently discontinue study treatment (atezolizumab) if they experience 
any of the following: 
• Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be 
unacceptable given the individual patient’s potential response to therapy and 
severity of the event 
• Any medical condition that may jeopardize the patient’s safety if he or she 
continues study treatment 
• Investigator determines it is in the best interest of the patient 
• Use of another non-protocol anti-cancer therapy 
• Pregnancy 
• Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease) 
 
The primary reason for study treatment discontinuation should be documented in the 
patient’s medical records. 
 
4.8.1 Patient Discontinuation from Study 
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: 
• Withdrawal of consent 
• Study termination or site closure 
• Patient non-compliance, defined as failure to comply with protocol requirements 
as determined by the Investigator 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.   
 
The primary reason for withdrawal from the study should be documented in the patient’s 
medical records.  If a patient requests to be withdrawn from the study, this request must 
be documented in the source documents and signed by the investigator.  Patients who 
withdraw from the study will not be replaced. 
 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
 
4.8.2 Study Discontinuation 
The Investigator has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a 


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potential health hazard to patients 
• Patient enrollment is unsatisfactory 
 
4.9 
Alternatives 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study. Patients will be closely monitored for any adverse reactions or 
toxicities, and will be seen after each cycle to minimize risks. In addition, the patients 
will be undergo imaging to assess tumor progression. The alternative to participating in 
this study will the current standard of upfront surgical resection without neoadjuvant 
treatment.  This will be offered to patients and presented as an option instead of enrolling 
in the clinical trial. 
 
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
 
5.1 
 Investigational Agent/Device/Procedure   
The investigational medicinal product (IMP) for this study is atezolizumab. 
 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 
(+/- 3 days) of each 21-day cycle for a total of 3 doses prior to surgery, unless there is 
clinical or radiographic evidence of disease progression. 
 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see Appendix H.  
Atezolizumab infusions will be administered per the instructions outlined in Table 1. 
 


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Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted prior to the 
atezolizumab infusion. 
• 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
• 
Atezolizumab should be infused over 
60 (± 15) minutes. 
• 
If clinically indicated, vital signs should be 
measured every 15 (± 5) minutes during the 
infusion and at 30 (± 10) minutes after the 
infusion. 
• 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
• 
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
• 
Vital signs should be measured within 
60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 (± 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
• 
If clinically indicated, vital signs should be 
measured during the infusion and at 
30 (± 10) minutes after the infusion. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix H. 
 
Any overdose or incorrect administration of atezolizumab should be noted in the patient’s 
medical records and reported according to Section 7.5 (Special Situations Reports).  
Adverse events associated with an overdose or incorrect administration of any of the 
study treatments should be recorded in the patient’s medical records. 
 
Guidelines for discontinuation for patients who experience adverse events are provided in 
Appendix I. 
 
5.2 
Availability 
Genentech will provide atezolizumab.  
 
The atezolizumab 1200 mg drug product will be supplied in a single-use, 20-mL USP/Ph. 
Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, preservative-free clear 
liquid solution intended for IV administration.  The vial is designed to deliver 20 mL 
(1200 mg) of atezolizumab solution but may contain more than the stated volume to 
enable delivery of the entire 20-mL volume.  
 
For information on the formulation and handling of atezolizumab, see the Atezolizumab 
Investigator's Brochure. 
 


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5.3 
Agent Ordering 
The drug will be delivered by Genentech to the Stanford Investigational Drug Services 
(IDS). 
 
Per Stanford standard operating procedures, the Stanford IDS will be responsible for 
storage of atezolizumab and dispensing of the drug after subjects are screened and enrolled 
to the study. 
 
5.4 Agent Accountability 
The Sponsor Investigator of the study will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance 
with 21 Code of Federal Regulations (CFR), Part 312.57 and 312.62 and Genentech 
requirements. 
 
All unused remaining product at the end of the study should be disposed of at the study 
site according to institutional standard operating procedure. If there is no SOP at the site 
for drug destruction, return study drug with the Inventory of Returned Clinical Material 
form as directed by Genentech. 
 
 
6. 
DOSE MODIFICATIONS 
No dose modification for atezolizumab is allowed. 
 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab in completed and ongoing studies.  The anticipated important safety risks 
are outlined below (see Section 7.1).   
 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of atezolizumab will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  Guidelines for 
managing patients who experience anticipated adverse events, including criteria for 
treatment discontinuation, are provided in Appendix I. Refer to Sections 7.2-7.6 for 
details on safety reporting (e.g., adverse events, pregnancies) during the study. 
 
7.1 
Potential Adverse Events 
Atezolizumab has been associated with risks such as the following:  IRRs and immune-
related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 
myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, 
and myositis.  Immune-mediated reactions may involve any organ system and may lead 


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to hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  Refer to 
Appendix 9 of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for 
a detailed description of anticipated safety risks for atezolizumab. 
 
7.2 
Safety Parameters and Definitions 
Safety assessments will consist of monitoring and reporting adverse events and serious 
adverse events per protocol.  This includes all events of death and any study-specific 
issue of concern.  
 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. The DSMC will audit study-related activities to 
determine whether the study has been conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This 
may include review of the following types of documents participating in the study: 
regulatory binders, case report forms, eligibility checklists, and source documents.  In 
addition, the DSMC will regularly review serious adverse events and protocol deviations 
associated with the research to ensure the protection of human subjects.  Results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities 
at the time of continuing review, or in an expedited fashion, as needed. 
 
In addition to the DSMC above, no more than six patients at a time will be permitted to 
be dosed concurrently.  More specifically, we will limit the accrual rate to this such that a 
maximum of 6 patients at any one time will be in the window between immunotherapy 
dosing and 10 days post recovery from definitive surgery.  All patient safety data for this 
study will be reviewed by Drs. Divi and/or Colevas, and documented on the AE log. If 
there are any adverse events (Grade 3 or higher or serious of any grade) attributed to 
checkpoint inhibitor treatment, further enrollment to the study will be put on hold until 
the attribution is understood and the protocol has been modified accordingly (with IRB 
notification and approval) to mitigate the future risks to patients. Our statistical design 
was powered with the least number of patients necessary to achieve our primary 
objective.  If during the course of the study, the number of patients who fail to complete 
the neoadjuvant protocol (due to drug related toxicity or tumor progression) is such that 
the primary objective would be unachievable, the study will be stopped early.  Based on 
our statistical design, if at any point during the study, 4 patients fail to complete the 
neoadjuvant protocol, the study will be stopped early. 
 
7.2.1 Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
cutaneous squamous cell carcinoma that were not present prior to the AE 
reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 


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invasive procedures such as cardiac catheterizations). 
• If applicable, AEs that occur prior to assignment of study treatment associated 
with medication washout, no treatment run-in, or other protocol-mandated 
intervention. 
• Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
 
7.2.2 Serious Adverse Events 
An AE should be classified as an SAE if any of the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
 
7.2.3 Adverse Events of Special Interest 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern 
specific to the product, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor is required. Such an event might require further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial Sponsor to other parties (e.g., Regulatory Authorities) may 
also be warranted. 
 
The following AEs are considered of special interest and must be reported to the 
Genentech Drug Safety expeditiously, irrespective of regulatory seriousness criteria: 
• Cases of potential drug-induced liver injury that include an elevated ALT or 
AST in combination with either an elevated bilirubin or clinical jaundice, as 
defined by Hy's Law and based on the following observations: 
• Treatment-emergent ALT or AST > 3 x ULN in combination with total 
bilirubin > 2 x ULN  
• Treatment-emergent ALT or AST > 3 x ULN in combination with clinical 
jaundice 
• Suspected transmission of an infectious agent by the study treatment 
(STIAMP), 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 


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indicate an infection in a patient exposed to a medicinal product.  This 
term applies only when a contamination of study treatment is suspected. 
 
The Atezolizumab Events of Special Interest Are: 
• Systemic lupus erythematosus 
• Events suggestive of hypersensitivity, infusion-related reactions, cytokine-
release syndrome, macrophage activating syndrome, hemophagocytic 
lymphohistiocytosis  
• Nephritis 
• Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• Vasculitis 
• Autoimmune hemolytic anemia 
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis 
bullous, toxic epidermal necrolysis) 
• Facial Paresis 
• Myelitis 
 
7.3 
Methods and Timing for Assessing and Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s), and 
Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). 
 
7.3.1 Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier.  After this period, investigators should only report SAEs that are attributed to 
prior study treatment. 
 
All adverse events (AEs), regardless of seriousness or relationship to study drug, are to be 
collected only on designated study dates from signing of informed consent through 30 days 
after administration of study drug, and recorded in the study-specific worksheets, with the 
following exceptions: 
 
• AEs that are solely laboratory values; are not related to the study drug; AND are 
clinically non-significant may not be collected.  
• Non serious AEs that are not related to the study drug; are not clinically significant; 
AND are expected in the post-surgery clinical setting may not be collected. 
• SAEs that occur from signing of informed consent to prior to administration of 
study agent may not be collected unless assessed as possibly, probably or definitely-
related to a study procedure. 
 
All patients enrolled in this study receive surgical intervention in the course of their 
standard of care. As a consequence of this surgery, patients may experience certain 


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expected and normal adverse events. The following post-operative adverse events will be 
captured only in the patient’s Electronic Health Record (EHR) source documentation and 
not in the adverse event log. If the adverse event exceeds the grading listed below or occurs 
outside the post-operative time window, the adverse event will be recorded in the Adverse 
Event Logs. 
 
• Surgical wound site and associated, expected secondary signs and symptoms, 
including:  
o CTCAE v5.0 Grade 1 pain associated with surgical wound, including 
headaches – mild pain, little to no limit on adult daily life.  
o CTCAE v5.0 Grade 1 weight loss, anemia, and electrolyte abnormalities.  
 
7.4 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately.  Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to atezolizumab (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply 
the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration 
of atezolizumab, and the AE cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to atezolizumab or with similar treatments; and/or the AE abates or resolves 
upon discontinuation of atezolizumab or dose reduction and, if applicable, reappears 
upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than atezolizumab (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to atezolizumab administration (e.g., 
cancer diagnosed 2 days after first dose of atezolizumab). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Insert (P.I) or current Investigator Brochure (I.B).  
 
Unexpected adverse events are those not listed in the P.I. or current I.B or not identified.  
This includes adverse events for which the specificity or severity is not consistent with 
the description in the P.I. or I.B.  For example, under this definition, hepatic necrosis 
would be unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 


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


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procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study 
 
7.5.2.5 Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.   Table 3 should be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
 
Table 2 
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 (v5.0), 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  
d 
Grade 4 and 5 events must be reported as serious adverse events  
 
7.5.2.6 Pregnancies 
If a female subject becomes pregnant while receiving atezolizumab or within 5 months 
after the last dose of atezolizumab, a report should be completed and expeditiously 
submitted to Genentech, Inc.  Follow-up to obtain the outcome of the pregnancy should 
also occur.   
 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported to Genentech as an SAE.  Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to the atezolizumab 
should be reported to Genentech, Inc. as an SAE. 
 


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7.5.2.7 Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior atezolizumab 
exposure.  If the investigator should become aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a female subject who 
participated in the study, this should be reported as an SAE. 
 
7.5.2.8 Reconciliation (Case Transmission Verification) 
The Investigator agrees to conduct reconciliation for the product.  Genentech and the 
Investigator will agree to the reconciliation periodicity and format, but agree at minimum 
to exchange quarterly line listings of cases received by the other party.  
 
If discrepancies are identified, the Investigator and Genentech will cooperate in resolving 
the discrepancies.  The responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution.  The Investigator shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by the Investigator to Genentech within five 
(5) calendar days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification (CTV) report 
will be sent to Genentech. 
 
7.6 
Adverse Event Reporting 
The Investigator will be responsible for collecting all protocol-defined Adverse Events 
(AEs)/Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Special Situation 
Reports (including pregnancy reports) and Product Complaints (with or without an AE) 
originating from the Study for the Product.  
 
Investigators must report all the above-mentioned single case reports adequately to 
Genentech within the timelines described below.  The completed MedWatch or CIOMS I 
form, or Genentech approved reporting forms should be faxed/emailed immediately upon 
completion to Genentech at the following contacts: 
 
All protocol-defined AEs, SAEs, AESIs, Special Situation Reports (including pregnancy 
reports) and Product Complaints with an AE should be sent to: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
Batch ID/lot ID for biologics associated with AE/SSR/PC/AESI must be included when 
submitting the case reports to Genentech. 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
Transmission of these reports (initial and follow-up) will be either electronically or by 
fax and within the timelines specified below: 


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Type of Report  
Timelines  
Serious Adverse Events  (related and 
not related to the Product) 
 
 
30 calendar days from awareness 
date 
 
Special Situation Reports ( With or 
without AE  and pregnancy) 
Product Complaints (With or without 
AE) 
AESI 
 
It is understood and agreed that the Sponsor will be responsible for the evaluation of AEs, 
SAEs, AESIs, Special Situation reports (including pregnancy reports) and Product 
Complaints (with or without an AE) originating from the study. 
 
Other Special Situation Reports 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special 
Situations Reports should be collected and transmitted to Genentech even in the absence 
of an Adverse Event within thirty (30) calendar days: 
• Data related to product usage during breastfeeding 
• Data related to overdose, abuse, misuse or medication error (including 
potentially exposed or intercepted medication errors) 
• In addition, reasonable attempts should be made to obtain and submit the age 
or age group of the patient, in order to be able to identify potential safety 
signals specific to a particular population 
Product Complaints 
All Product Complaints (with or without an AE) shall be forwarded to Genentech within 
thirty (30) calendar days of the awareness date. 
• A Product Complaint is defined as any written or oral information received 
from a complainant that alleges deficiencies related to identity, quality, safety, 
strength, purity, reliability, durability, effectiveness, or performance of a 
product after it has been released and distributed to the commercial market or 
clinical trial. 
 
7.6.1 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic (Section A) and suspect 
medication information (Section C and D), the report should include the following 
information within the Event Description (Section B.5) of the MedWatch 3500A form: 
o Protocol number and title description  
o Description of event, severity, treatment, and outcome if known 
o Supportive laboratory results and diagnostics (Section B.6) 
o Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
7.6.1.1 Follow-up Information 
Additional information may be added to a previously submitted report by any of the 


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following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with 
the original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B. initial, patient number), protocol description and number, 
if assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
https://www.fda.gov/media/69876/download 
 
7.6.2 Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Genentech, as the Marketing Authorization Holder, will be responsible for the reporting 
of individual case safety reports from the study to the regulatory authority in compliance 
with applicable regulations.  
 
The Investigator, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the Regulatory Authorities 
(FDA) where it has filed a clinical trial approval, in compliance with local regulations.  
 
The Investigator, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the EMA through Eudravigilance 
Clinical Trial Module (EVCTM), where applicable. 
 
The Investigator will be responsible for the expedited reporting of safety reports 
originating from the Study to the Ethics Committees and Institutional Review Boards 
(IRB), where applicable. 
 
Genentech will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
And to the site IRB: 
IRB panel manager 
Fax: (650) 725-8013 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
7.7 Aggregate Reports 
 
7.7.1 Development Safety Update Report 
 
The Parties agree that aggregate reporting obligations for the Study (including Development 


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Safety Update Report [DSURs] and/or Investigational New Drug [IND]) Annual Reports) in 
accordance to the applicable laws and regulations in the concerned countries will reside with the 
investigator, as the Sponsor of the Study. 
 
Upon request, the investigator agrees to share a copy of their own DSUR with Genentech as 
soon as reasonably possible after completion.  
 
Genentech will forward to the investigator an executive summary of the Genentech DSUR upon 
request.  Furthermore, Genentech agrees that the investigator may cross-reference the executive 
summary of the Genentech DSUR, as applicable. 
 
7.7.2 Other Reports 
The Investigator will forward a copy of the Publication to Genentech upon completion of 
the Study. 
 
7.8 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech.  This includes all IND annual reports and the Clinical Study Report (final 
study report).  Additionally, any literature articles that are a result of the study should be 
sent to Genentech.  Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
Atezolizumab IIS Clinical Operations: anti-pdl-1-mpd3280a-gsur@gene.com 
And to Genentech Drug Safety CTV oversight mail box at: ctvistsa@gene.com  
 
 
Queries 
Queries related to the Study will be answered by the Investigator.  However, responses to 
all safety queries from regulatory authorities or for publications will be discussed and 
coordinated between the Parties.  The Parties agree that Genentech shall have the final 
say and control over safety queries relating to the Product.  The Investigator agrees that it 
shall not answer such queries from regulatory authorities and other sources relating to the 
Product independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met.  The Parties will clearly indicate on 
the request the reason for urgency and the date by which a response is required. 
 
Signal Management and Risk Management  
Genentech is responsible for safety signal management (signal detection and/or 
evaluation) for their own Product. However, it is agreed that investigator, as Sponsor of 
the Study, will be primarily responsible for assessment of the benefit-risk balance of the 
Study. 
 
If  investigator - sponsor, issues a safety communication relevant for Genentech (i.e., a 
safety issue that notably impacts the benefit-risk balance of the Study and / or triggers 
any changes to the Study) this will be sent to Roche within five (5) business days of its 


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internal approval. 
 
As needed, Genentech will reasonably assist investigator - sponsor with signal and risk 
management activities related to the Product within the Study. 
 
Genentech will also provide investigator - sponsor with any new relevant information that 
may modify or supplement known data regarding the Product (e.g., relevant Dear 
Investigator Letter). 
 
Compliance with Pharmacovigilance Agreement / Audit 
The Parties shall follow their own procedures for adherence to AE reporting timelines. 
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures. The Parties agree 
to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines. If there is 
any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct ad hoc or institute a 
regular joint meeting to address the issue. In case of concerns related to non-compliance 
of processes, other than exchange timelines, with this Agreement, the Parties will jointly 
discuss and collaborate on clarifying and resolving the issues causing non-compliance. 
Every effort will be made by the non-compliant Party to solve the non-compliance issues 
and inform the other Party of the corrective and preventative actions taken. 
 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an 
audit under the provisions of this Agreement can be requested by either Party. The Parties 
will then discuss and agree in good faith upon the audit scope, agenda and execution of 
the audit. The requesting Party will bear the cost of the audit. 
 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
Blood collection methods:  
Up to 150 ml of blood may be taken for research at baseline, after the first cycle of 
therapy, and at surgery for a maximum total of 300 ml of blood for research purposes 
within the period of a month. The blood will be drawn in Vacutainer tubes. These tubes, 
barcoded labels, and a transport envelope will be provided by the study coordinator(s). 
The blood will be drawn by a phlebotomist or appropriately qualified person. The tubes 
will be labeled with the barcode labels placed in an envelope (which will be included 
with the tubes) and kept at room temperature. A barcode label will also be placed on an 
intake form that has the patient study ID number. The study coordinator will then be 
notified of the blood samples and will arrange for transport to the Biobank section of the 
CTRU.  
 
We will be collecting plasma, serum, and PMBCs from the blood which will be used for 
the following: 
o Plasma samples for exploratory assessment cell-free DNA at baseline, after 
the first cycle of therapy, and at surgery. 


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o Serum samples for assessment of cytokine profiles associated with immune 
system activation. 
o Peripheral blood mononuclear cells (PBMC) will be collected and 
cryopreserved at baseline, after the first cycle of therapy, and at surgery if 
deemed for possible, for exploratory identification of antigen-specific T cell 
receptors (TCR). 
 
Tumor sampling methods: 
When each patient is enrolled on this study, he or she will be assigned an anonymized bar 
code for all samples. The study coordinator will link the barcodes to the patient. The key 
will be kept in REDCap. If archival tissue is unavailable at the time that the patient signs 
consent, or is deemed unsuitable for exploratory research, a pretreatment biopsy is 
required. Tumor tissue sample will also be obtained following the first cycle of therapy 
and at the time of surgical resection, if deemed clinically feasible, for exploratory 
research on biomarkers. The least invasive technique to obtain the sample will be used. 
Samples collected via resection, core-needle biopsy, or excisional, incisional, punch, or 
forceps biopsy are preferred.  However, all specimen types (e.g., fine-needle aspiration) 
are acceptable. If the tissue collected is fresh, the tissue will be placed in saline on ice, 
and Dr. Sunwoo’s laboratory personnel will be notified.  
 
The exploratory biomarker research may include, but will not be limited to analysis of 
genes or gene signatures associated with tumor immunobiology, PD-L1, lymphocyte 
subpopulations, T-cell receptor repertoire, peptide-MHC repertoire, or cytokines 
associated with T-cell activation.  Research may involve extraction of DNA, circulating 
tumor DNA, or RNA, analysis of mutations, genomic profiling through use of next-
generation sequencing (NGS) of a comprehensive panel of genes, and analysis of 
proteins. Research will aim to distinguish germline mutations from somatic mutations 
and understanding mechanisms underlying immune cell recognition of tumor cells that 
might predict clinical response to therapy. NGS methods may include whole exome 
sequencing (WES). De-identified biospecimen may be sent to other (external) 
collaborators. 
 
Please refer to section 4.6 for further information.






 
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Screening a 
Treatment Cycles (21-day cycles) 
Surgery 
Follow-Up 
(or Treatment 
Discontinuation b) 
Cycle 1 
  
Cycle 2 
  
Cycle 3 
Within 28 
days prior to 
start of 
treatment 
Day 1 
(± 3 days) 
Day 14 
(± 7 days) 
Day 21 
(± 3 days) 
Day 38 
(± 4 days) 
Day 42 
(± 3 days) 
2-4 
weeks 
after 
Cycle 3 
10 days ± 5 days 
after surgery 
(or < 30 days after 
last treatment) 
ADA = anti-drug antibody; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; 
NA = not applicable; PK = pharmacokinetic; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WES = whole exome 
sequencing; WGS = whole genome sequencing. 
Notes:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded in the patient’s medical 
records (except in the case of an adverse event).  
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to start of treatment 
may be used; such tests do not need to be repeated for screening.   
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose 
of study treatment.  The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit. 
c Informed consent must be documented before any study-specific screening procedure is performed, and may be obtained more than 28 days 
before initiation of study treatment. 
d If archival tissue is unavailable or is determined to be unsuitable for required testing, a pretreatment tumor biopsy is required.  A pretreatment 
tumor biopsy will also be performed, when clinically feasible, for biomarker assessment.  Refer to Section 4.6 or tissue sample requirements. 
e Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
in the patient’s medical records.  At subsequent visits, record new or worsened clinically significant abnormalities in the patient’s medical 
records.  For the first and subsequent infusions, vital signs should be measured prior to the infusion (taken same day during clinic visit or in 
infusion area) and, if clinically indicated, during or after the infusion. 
f Record abnormalities observed at baseline in the patient’s medical records.  At subsequent visits, record new or worsened clinically 
significant abnormalities in the patient’s medical records. 
g Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  Record new or 
worsened clinically significant abnormalities in the patient’s medical records. 


 
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h ECG recordings will be obtained during screening and as clinically indicated at other timepoints. 
i Hematology includes WBC count, hemoglobin, hematocrit, platelet count, differential count. 
j Screening laboratory test results must be obtained within 28 days prior to initiation of study treatment. 
k If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
l Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, 
albumin, calcium, total bilirubin, alkaline phosphatase, ALT, AST. 
m All women of childbearing potential will have a serum pregnancy test at screening, within 28 days prior to initiation of study treatment. 
n Past TSH lab value may be used for screening if collected within 6 weeks prior to the first administration of atezolizumab. 
o Urinalysis includes pH, specific gravity, glucose, protein, ketones, and blood 
p  Baseline imaging with CT or MRI of primary site (if present) and regional lymphatics; CT Chest or PET scan will be performed only if scans 
were not previously performed within 28 days of screening assessment. The same radiographic modality used to assess disease sites at 
screening should be used for subsequent tumor assessment at baseline and after cycle 2. RECIST measurements are only required at 
baseline, after cycle 2, and ORR can be assessed after cycle 2/surgery. 
q See Section 4.6 for details on exploratory research 
r All measurable and evaluable lesions should be assessed and documented at screening.  Tumor assessments performed as standard of 
care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be repeated at screening.   
s Patients will undergo clinical tumor assessments at baseline and once per cycle. All measurable and evaluable lesions should be re-
assessed at each subsequent tumor evaluation.  RECIST measurements are only required at baseline, after cycle 2, and ORR can be 
assessed after cycle 2/surgery. 
t Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment until the treatment discontinuation visit. 
u After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-
mandated intervention should be reported.  After initiation of study treatment, all adverse events will be reported until 30 days after the last 
dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and 
adverse events of special interest will continue to be reported until 90 days after the last dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first.  After this period, all deaths, regardless of cause, should be reported.  In addition, 
Genentech, Inc. should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior 
exposure to study treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every 
effort should be made to follow all serious adverse events considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported. 


 
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Screening a 
Treatment Cycles (21-day cycles) 
Surgery 
Follow-Up 
(or Treatment 
Discontinuation b) 
Cycle 1 
  
Cycle 2 
  
Cycle 3 
Within 28 
days prior to 
start of 
treatment 
Day 1 
(± 3 days) 
Day 14 
(± 7 days) 
Day 21 
(± 3 days) 
Day 38 
(± 4 days) 
Day 42 
(± 3 days) 
2-4 
weeks 
after 
Cycle 3 
10 days ± 5 days 
after surgery 
(or < 30 days after 
last treatment) 
v The initial dose of atezolizumab will be delivered over 60 (± 15) minutes.  Subsequent infusions will be delivered over 30 (± 10) minutes if the 
previous infusion was tolerated without infusion-associated adverse events, or 60 (± 15) minutes if the patient experienced an infusion-
associated adverse event with the previous infusion. 
w Adjuvant therapy will be delivered as per standard of care for head and neck cutaneous squamous cell carcinoma.  AJCC Stage 3 and 4 
lesions will receive adjuvant radiation therapy beginning 4-8 weeks after the completion of surgery unless the patient is deemed medically 
unfit, or patient declines further treatment. 
 
 


 
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10. MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Primary Outcome Measure 
Title: Percentage of patients that are able to complete 3 cycles of neoadjuvant therapy 
and undergo a curative surgical resection.  
Time Frame: At time of surgery  
Safety Issue: No 
 
10.1  Primary and Secondary Outcome measures 
The primary outcome measure for each patient is an indicator for successfully completing 
3 cycles of neoadjuvant atezolizumab, followed by surgical resection of remaining 
disease.  The treatment will be evaluated as non-feasible for patients who have disease 
progression during neoadjuvant treatment, discontinue study medications due to toxicity, 
or are not able to undergo curative surgical resection after the 3 cycles of treatment.  
Patients who decline surgical intervention after completing the neoadjuvant treatment 
will be considered as having successfully received neoadjuvant treatment. 
 
In this study, feasibility was chosen as the primary endpoint to assess whether patients 
can successfully complete the neoadjuvant treatment without significant disease 
progression precluding curative surgical resection, and with acceptable toxicity.  Since 
the patient population will include tumors that are resectable at presentation (and patients 
will be medically fit to undergo surgery), any postponement of definitive surgical 
resection will need to demonstrate that this does not adversely affect the opportunity for 
curative therapy.  If this postponement of surgery proves to not cause harm and 
administration of neoadjuvant treatment is feasible, this study may add an additional 
cohort to evaluate a combination of immune checkpoint inhibitors in this setting. Future 
studies can be designed that evaluate additional clinical endpoints.  
 
10.1.1 Relevant Subset 
All patients that receive at least 1 dose of Atezolizumab will be considered as “evaluable” 
patients for this feasibility study.  
 
10.2  Secondary Outcome 
The overall response rate and pathological response rate (complete and major 
pathological response) following completion of neoadjuvant therapy will be reported with 
a 95% exact confidence interval. 
 
Objective response rate will be measured based on RECIST v1.1 criteria (Appendix F).  
Overall response rate will be determined based on Appendix F, Table 1. Pathological 
response will be assessed by local pathological review.  Patients with no viable tumor 
seen will be classified as a complete pathological response.  Patients with < 10% of 
viable tumor will be classified as a major pathological response. 
 


 
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The change in surgical margins, vital structures preserved, morbidity, and/or surgical 
approach will be described qualitatively for each patient in the study and summarized. 
 
10.2.1 Relevant Subset 
The objective response rate will be evaluated for all patients that had both sets of imaging 
(pre-treatment and after cycle 2).   All patients that had surgery will be included to assess 
pathological response rate, change in surgical margins, and vital structures preserved.  
 
 
11. 
REGULATORY CONSIDERATIONS 
 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the Stanford IRB and Stanford Cancer Institute Scientific Review 
Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol 
Director will disseminate the protocol amendment information to all participating 
investigators. 
 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate, but in any 
case, the IRB must be updated at least once a year.  The Principal Investigator must also 
keep the IRB informed of any significant AEs. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug 
reactions that are both serious and unexpected.  This generally refers to SAEs that are not 
already identified in the Investigator’s Brochure and that are considered possibly or 
probably related to the molecule or study drug by the investigator.  The study team will 
immediately forward to their IRB any written safety report or update provided by 
Genentech (Investigator’s Brochure, safety amendments and updates, etc.). 
 
Atezolizumab is an FDA approved drug for various indications including non-small cell 
lung cancer, small cell lung cancer, and Alveolar Soft Part Sarcoma (ASPS). etc. Neither 
the investigator, nor the sponsor, Genentech, Inc. intend to report the study data to the 
FDA as a well-controlled study in support of a new indication or any other significant 
change in the labeling for Atezolizumab, nor do we intend, at this time, to utilize the 
study data to support a significant change in the advertising of atezolizumab. The drug is 
currently not approved for CSCC; however we believe this study is IND-exempt, for the 
risks are not expected to be beyond what is seen with the routine SOC use of this agent.  
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. The DSMC will audit study-related activities to 
determine whether the study has been conducted in accordance with the protocol, local 


 
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standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This 
may include review of the following types of documents participating in the study: 
regulatory binders, case report forms, eligibility checklists, and source documents.  In 
addition, the DSMC will regularly review serious adverse events and protocol deviations 
associated with the research to ensure the protection of human subjects.  Results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities 
at the time of continuing review, or in an expedited fashion, as needed. 
 
 
This clinical research study will be monitored both internally by the PI and externally by 
the Stanford University IRB.  In terms of internal review, the PI will continuously 
monitor and tabulate AEs.  Appropriate reporting to the Stanford University IRB will be 
made.  The PI of this study will also continuously monitor the conduct, data, and safety 
of this study to ensure that: 
Interim analyses occur as scheduled, 
Stopping rules for toxicity and/or response are met, 
Risk/benefit ratio is not altered to the detriment of the subjects, 
Appropriate internal monitoring of AEs and outcomes is done, 
Over-accrual does not occur, 
Under-accrual is addressed with appropriate amendments or actions, and 
 Data are being appropriately collected in a reasonably timely manner. 
 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document treatment outcomes for data analysis 
and safety information including AE’s, conmeds collected at the specified timepoints.  
Case report forms will be developed using the REDCap database system and will be 
maintained by the clinical trial coordinators. CRFs will be kept in a locked office, only 
accessible to the research team. The REDCap database for data management will be 
developed prior to enrollment.  The database will be locked 3 months after the last patient 
visit per study calendar for the primary and secondary analyses. 
 
The study coordinator and investigators are responsible for ensuring that the eligibility 
checklist is completed in a legible and timely manner for every patient enrolled in the 
study, and that data are recorded on the appropriate forms and in a timely manner.  Any 
errors on source data should be lined through, but not obliterated, with the correction 
inserted, initialed, and dated by the study coordinator or PI.  All source documents will be 
available for inspection by the FDA and the Stanford University IRB. 
 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of 
the guideline) require that records and documents pertaining to the conduct of clinical 
trials and the distribution of investigational drug, patient records, consent forms, 
laboratory test results, and medication inventory records, must be retained for 2 years 
after the last marketing application approval in an ICH region or after at least 2 years 
have elapsed since formal discontinuation of clinical development of the investigational 


 
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product.  All state and local laws for retention of records also apply. 
 
11.4 
Compliance with Laws and Regulations 
Patients who comply with the requirements of the protocol, are tolerating study treatment, 
and may be receiving benefit will be offered dosing beyond Cycle 1 at the investigator’s 
discretion after a careful assessment and thorough discussion of the potential risks and 
benefits of continued treatment with the patient.  Such patients may have the option to 
receive MPDL3280A treatment as long as they continue to experience clinical benefit in 
the opinion of the investigator until the earlier of unacceptable toxicity, symptomatic 
deterioration attributed to disease progression, or any of the other reasons for treatment 
discontinuation listed in Section 4.8. 
 
11.5 
Confidentiality  
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the ICF (or separate authorization to use and disclose 
personal health information) signed by the patient or unless permitted or required by law. 
 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
 
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other regulatory agencies, national and local health 
authorities, Genentech representatives and collaborators, and the IRB/Ethics Committee 
(EC) for each study site, if appropriate. 
 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Statistical Design 
The primary objective is to determine the feasibility of three doses of atezolizumab prior 
to surgery in patients with advanced cutaneous squamous cell carcinoma. Our baseline 
assumption is that 50% of the population will complete all 3 doses of atezolizumab and 
then proceed to surgery. We can prove that with 20 patients by showing that 85% of the 
patients enrolled will complete the 3 neoadjuvant cycles of PD-L1 and then proceed to 
surgery. We will also be collecting demographic and descriptive data on tumor 
characteristics, and therapies. Please refer to sections 12.4 to 12.7 for the study’s 
statistical plan. 
 
This approach will be considered feasible if 17 or more patients are able to complete 
neoadjuvant treatment and proceed with surgical resection of disease.  If 4 or more 
patients are unable to complete neoadjuvant treatment due to toxicity or tumor 
progression, or have unresectable disease at the time of surgery, this approach will be 
considered unfeasible.  Patients who decline immunotherapy or surgery due to reasons 
not related to toxicity or tumor progression, will not be considered a treatment failure. 


 
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12.2 
Randomization 
Not applicable. 
 
12.3 
Interim analyses 
Accrual will be limited to no more than 6 patients at a given window of immunotherapy 
dosing and 10 days post recovery from surgery.  Toxicity and treatment failures will be 
reviewed prior to each additional patient accrual.  If the number of patients who fail 
neoadjuvant treatment exceeds the maximum number allowable to achieve the primary 
objective, the study will be stopped early (i.e. treatment failure in 4 patients). 
 
12.4 
Descriptive Statistics and Exploratory Data Analysis 
Baseline demographic data, tumor characteristics, staging information, and complete 
treatment data (including surgery and adjuvant therapies), will be recorded and presented 
at the completion of the trial. 
 
12.5 
Primary Analysis  
The evaluation of feasibility will be based on percentage of patients completing 3 cycles 
of neoadjuvant atezolizumab and followed by surgical resection of remaining disease.  
We expect 85% of patients will fall in feasibility category, leaving only 3 patients unable 
to complete 3 cycles and undergo surgery. With such a small subsample, instead of using 
quantitative analysis method, we will develop in-depth, detailed case study aiming to 
assess the potential differences between these cases and the rest of patients in potential 
confounders such as patients’ demographics, comorbidities, tumor stage, and surgical 
morbidity. 
 
The change in surgical plan will be recorded by the primary surgeon based on initial 
assessment of the tumor and the size and location of the tumor at the time of definitive 
surgical resection. 
 
12.6 
Secondary Analysis 
Objective response rate will be assessed per investigator assessment and pathological 
response rate will be assess by local pathology review.  The overall response rate and 
pathological response rate following completion of neoadjuvant therapy will be reported 
with a 95% exact confidence interval. 
The change in surgical margins, vital structures preserved, morbidity, and/or surgical 
approach will be described qualitatively for each patient in the study and summarized.  
For objective response rate, we will look at the response assessment at each cycle for 
visible lesions and record the greatest dimension. For all lesions, we will also be using 
RECIST to assess tumor progression and record tumor size from the CT scan which will 
be done at baseline, and then after cycle 2.  For lesions that are not visible, we will only 
assess response after cycle 2 when an interval set of imaging is performed.   
The pathological response rate will be measured by pathologists at the local institution 


 
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and be recorded as a percentage of viable tumor remaining.  Tumors with 0% viable 
tumor will be considered a complete pathological response, and tumors with >0% and 
≤10% will be classified as a major pathological response.  The change in surgical 
margins will be measured in 3 dimensions by the surgical investigator based on 
anticipated surgical resection at presentation, and again at the time of surgery.  The 
number of vital structures preserved per patient will be recorded and include >50% of the 
nose, lip, ear, or eye. These data will be presented in a table format at the conclusion of 
the study.  
 
12.7  Sample Size 
 
12.7.1 Accrual estimates 
 
 
Based on the number of patients seen at the Stanford Head & Neck Oncology Clinic there 
are about 2 patients seen per month who would qualify for this study. We estimate that 8 
patients annually will be enrolled in the study, and will require 42 months to complete the 
study. 
 
12.7.2 Sample size justification 
The primary objective is to determine the feasibility of three doses of atezolizumab prior 
to surgery in patients with advanced cutaneous squamous cell carcinoma.  The sample 
size of evaluable 20 patients allows at least 80% power to reject the null hypothesis of 
50% if the true fraction is above 80% (or a difference >30%) using binomial enumeration 
of all possible outcomes, with a test at the 5% significance level. We expect the true 
fraction is 85%, which means that we are well powered to detect an effect size that is 
bigger than 30%. 
 
12.7.3 Effect size justification 
The effect size was chosen based on recently published data using immunotherapy for 
mucosal head and neck cancer demonstrating clinical response in approximately 50% of 
patients. 
 
12.8 
Criteria for future studies 
If we meet the endpoint for determining that this approach is feasible, we will move 
towards designing a larger trial that examines surgical margin reduction, disease 
recurrence rates, and optimal adjuvant therapy strategies.  We may also test the feasibility 
of this strategy using different combination regimens in the future to further increase 
response rate and tumor volume reduction.


 
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APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
I. 
Subject Eligibility Checklist 
A Participant Eligibility Checklist must be completed in its entirety for each subject prior 
to registration. The completed, signed, and dated checklist must be retained in the 
patient’s study file and the study’s Regulatory Binder.  
 
The study coordinator, treating physician and an independent reviewer must verify that 
the participant’s eligibility is accurate, complete, and legible in source records. A 
description of the eligibility verification process should be included in the EPIC or other 
Electronic Medical Record progress note.  
 
Protocol Title: 
NEOADJUVANT ATEZOLIZUMAB IN SURGICALLY 
RESECTABLE ADVANCED CUTANEOUS SQUAMOUS 
CELL CARCINOMA 
Protocol Number: 
ENT0082 / IRB-59070 
Principal Investigator: 
Vasu Divi 
 
II. 
Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
III. 
Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
 
IV. 
 Inclusion/Exclusion Criteria 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. Signed Informed Consent Form 
 
 
      
2. Age ≥ 18 years at time of signing Informed Consent Form 
 
 
      
3. Histologically or cytologically confirmed squamous cell 
carcinoma 
 
 
      
4. Measurable disease per RECIST v1.1 
• 
Note that protocol specified imaging is not necessary to 
fulfill this criterion. For example, a patient presenting with a 
visible 4cm primary lesion who has obviously RECIST 
evaluable disease may be considered eligible prior to 
baseline imaging stipulated in the protocol. 
 
 
      
5. Availability of a representative tumor specimen that is suitable 
for determination of PD-L1 immunohistochemical stain 
evaluation. 
 
 
      
6. ECOG Performance Status of 0 or 1 
 
 
      


 
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Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
7. Adequate hematologic and end-organ function appropriate for 
surgery as determined by routine preoperative evaluation. If liver 
function, renal function and hematologic laboratory test results 
are within limits acceptable for elective surgery. Laboratory 
results that will need to be obtained within 28 days prior to 
initiation of study treatment: 
• 
AST, ALT, total bilirubin, and alkaline phosphatase (ALP) ≤ 
2.5 x upper limit of normal (ULN.). 
• 
TSH < 13 
o 
Patients with a history of a high TSH who are receiving 
levothyroxine replacement at the time of eligibility 
evaluation and have no clinical evidence of 
hypothyroidism are eligible. 
 
 
      
8. For patients receiving therapeutic anticoagulation: stable 
anticoagulant regimen 
 
 
      
9. Negative hepatitis B surface antigen (HBsAg) test at screening 
 
 
      
10. For women of childbearing potential:  agreement to remain 
abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods, as defined below: 
Women must remain abstinent or use contraceptive methods with 
a failure rate of < 1% per year during the treatment period and for 
5 months after the final dose of atezolizumab. 
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state (≥ 12 
continuous months of amenorrhea with no identified cause other 
than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of 
childbearing potential may be adapted for alignment with local 
guidelines or requirements. 
Examples of contraceptive methods with a failure rate of < 1% 
per year include bilateral tubal ligation, male sterilization, 
hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in 
relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation 
 
 
      
11. For men: Agreement to remain abstinent (refrain from 
heterosexual intercourse) or use a condom, and agreement to 
refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant 
female partner, men must agree to remain abstinent or use a 
condom during the treatment period and for 5 months after the 
final dose of atezolizumab to avoid exposing the embryo. Men 
must agree to refrain from donating sperm during this same 
period 
 
 
      
 








 
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APPENDIX B: Calculation of Creatinine Clearance Using the Cockcroft-Gault 
Formula 
 
Creatinine Clearance (men) = (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
Creatinine Clearance (women) = 0.85 × (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
 
Source:  Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from 
adjusted serum creatinine (editorial). Nephron 1992;62:249. 
 


 
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APPENDIX C: Safety Reporting Fax Cover Sheet  
 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Patient Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET 
 
 
 


 
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APPENDIX D: FDA MedWatch 3500 Form 
 
This form is included in the study start-up zip file to be sent to sites via email. 
 
 
 


 
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APPENDIX E: Current National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
 
 


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


 
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Bone Lesions: 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, and plain 
films are not considered adequate imaging techniques for measuring bone lesions.  
However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered measurable lesions if 
they meet the definition of measurability described above.  However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previously irradiated area or in an area subjected to other loco-
regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during the study.  Imaging-based 
evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm in 
diameter as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung. 


 
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CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment.  In this guideline, the definition of measurability of lesions on CT scan 
is based on the assumption that CT slice thickness is ≤ 5 mm.  When CT scans have slice 
thickness of > 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and 
during the study should be guided by the tumor type under investigation and the anatomic 
location of the disease.  For patients who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or non-
enhanced) will be performed should also be based on the tumor type and the anatomic 
location of the disease, and should be optimized to allow for comparison with the prior studies 
if possible.  Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward.  Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality, since the same 
lesion may appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, CYTOLOGY, 
HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be utilized 
for objective tumor evaluation . 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline.  
This means that, for instances in which patients have only one or two organ sites involved, a 
maximum of two lesions (one site) and four lesions (two sites), respectively, will be recorded.  
Other lesions (albeit measurable) in those organs will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but in addition should lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance the next largest 
lesion that can be measured reproducibly should be selected. 


 
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Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the 
baseline sum.  The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumor.  Lymph node size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT, this is almost always the axial 
plane; for MRI, the plane of acquisition may be axial, sagittal, or coronal).  The smaller of 
these measures is the short axis.  For example, an abdominal node that is reported as being 
20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.  In 
this example, 20 mm should be recorded as the node measurement.  All other pathological 
nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions.  
Nodes that have a short axis of < 10 mm are considered non-pathological and should not be 
recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-measurable), 
including pathological lymph nodes, should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements are not required.  It is possible to record multiple 
non-target lesions involving the same organ as a single item on the Case Report Form (CRF) 
(e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for lymph 
node lesions) will be calculated for all target lesions at baseline and at each subsequent tumor 
assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to < 10 mm during the study.  Thus, when lymph 
nodes are included as target lesions, the sum of diameters may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of < 10 
mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non−lymph node) recorded at baseline 
should have their actual measurements recorded at each subsequent evaluation, even when 
very small (e.g., 2 mm).  However, sometimes lesions or lymph nodes that are recorded as 
target lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small to 
measure.  When this occurs, it is important that a value be recorded on the CRF, as follows: 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned and "too small to measure" should be ticked.  (Note:  It 


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


 
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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of non-target 
lesions are provided below.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the timepoints 
specified in the schedule of activities. 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of tumor marker 
level 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of substantial 
worsening in non-target lesions in a magnitude that, even in the presence of SD or PR in 
target lesions, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  A modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status.  The designation of overall progression 
solely on the basis of change in non-target lesions in the face of SD or PR in target lesions will 
therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some 
"new" bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the patient’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a "new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, progression should be declared using the date of the initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 


 
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Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients with 
Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target lesions at a 
timepoint, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesions would 
not change the assigned timepoint response.  This would be most likely to happen in the case 
of PD.  For example, if a patient had a baseline sum of 50 mm with three measured lesions 
and during the study only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing lesion.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration."  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions as shown in 
Table 1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 


 
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REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228−47.   
 
 
 
 
 
 


 
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APPENDIX G: Preexisting Autoimmune Diseases and Immune Deficiencies  
 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune deficiencies 
or autoimmune disease listed in the table below are excluded from participating in the study.  
Possible exceptions to this exclusion could be patients with a medical history of such entities 
as atopic disease or childhood arthralgias where the clinical suspicion of autoimmune disease 
is low.  Patients with a history of autoimmune-related hypothyroidism on a stable dose of 
thyroid replacement hormone may be eligible for this study.  In addition, transient autoimmune 
manifestations of an acute infectious disease that resolved upon treatment of the infectious 
agent are not excluded (e.g., acute Lyme arthritis). 
Autoimmune Diseases and Immune Deficiencies 
• Acute disseminated 
encephalomyelitis 
• Addison disease 
• Ankylosing spondylitis 
• Antiphospholipid antibody 
syndrome 
• Aplastic anemia 
• Autoimmune hemolytic 
anemia 
• Autoimmune hepatitis 
• Autoimmune 
hypoparathyroidism 
• Autoimmune hypophysitis 
• Autoimmune myelitis 
• Autoimmune myocarditis 
• Autoimmune oophoritis 
• Autoimmune orchitis 
• Autoimmune 
thrombocytopenic purpura 
• Behçet disease 
• Bullous pemphigoid 
• Chronic fatigue syndrome 
• Chronic inflammatory 
demyelinating 
polyneuropathy 
• Churg-Strauss syndrome 
• Crohn disease  
• Dermatomyositis 
• Diabetes mellitus type 1 
• Dysautonomia 
• Epidermolysis bullosa 
acquisita 
• Gestational pemphigoid 
• Giant cell arteritis 
• Goodpasture syndrome 
• Graves disease 
• Guillain-Barré syndrome 
• Hashimoto disease 
• IgA nephropathy 
• Inflammatory bowel disease 
• Interstitial cystitis 
• Kawasaki disease 
• Lambert-Eaton myasthenia 
syndrome 
• Lupus erythematosus 
• Lyme disease, chronic 
• Meniere syndrome 
• Mooren ulcer 
• Morphea 
• Multiple sclerosis 
• Myasthenia gravis 
 
• Neuromyotonia 
• Opsoclonus myoclonus 
syndrome 
• Optic neuritis 
• Ord thyroiditis 
• Pemphigus 
• Pernicious anemia 
• Polyarteritis nodosa 
• Polyarthritis 
• Polyglandular autoimmune 
syndrome 
• Primary biliary cirrhosis 
• Psoriasis 
• Reiter syndrome 
• Rheumatoid arthritis 
• Sarcoidosis 
• Scleroderma 
• Sjögren syndrome 
• Stiff-Person syndrome 
• Takayasu arteritis 
• Ulcerative colitis 
• Vitiligo 
• Vogt-Koyanagi-Harada 
disease 
• Wegener granulomatosis 
 
 
 


 
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APPENDIX H: Anaphylaxis Precautions 
 
EQUIPMENT NEEDED 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, 
and thermometer 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and endotracheal administration in 
accordance with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
Stop the study treatment infusion. 
Call for additional medical assistance. 
Maintain an adequate airway 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible. 
Administer antihistamines, epinephrine, or other medications as required by participant status 
and as directed by the physician in charge. 
Continue to observe the participant and document observations. 
Draw serum/plasma samples for immunogenicity testing. 
Ask participant to return for washout immunogenicity sample if appropriate. 
 
 


 
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APPENDIX I: Management of Atezolizumab-Specific Adverse Events 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology when clinically 
indicated.   
Although most immune-related adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune-related toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
The following are general recommendations for management of any other adverse events that 
may occur and are not specifically listed in the following subsections. 
• 
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible immune-
related adverse events prior to initiating therapy and throughout treatment and survival 
follow-up. There should be a high level of suspicion that new symptoms are treatment 
related. 
• 
In general, atezolizumab therapy should be continued with close monitoring for Grade 1 
toxicities, with the exception of some neurologic toxicities. 
• 
Consider holding atezolizumab for most Grade 2 toxicities and resume when symptoms 
and/or laboratory values resolve to Grade 1 or better. Corticosteroids (initial dose of 0.5-1 
mg/kg/day of prednisone or equivalent) may be administered. 
• 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a Grade 
3 event. 
• 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day prednisone or equivalent). Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before atezolizumab 
can be resumed. If symptoms do not improve within 48 to 72 hours of high-dose 
corticosteroid use, other immunosuppressants may be offered for some toxicities. 
• 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by hormone-
replacement therapy. 
The investigator should consider the benefit−risk balance for a given patient prior to further 
administration of atezolizumab.   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 the 
investigator (or an appropriate delegate). The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s assessment of the benefits and risks and 
document by the investigator. The Medical Monitor is available to advise as needed.  


 
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Guidelines for managing patients who experience selected adverse events are provided in the 
following sections. Management guidelines are presented by adverse event severity based on 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 
DOSE MODIFICATIONS  
There will be no dose modifications for atezolizumab in this study. 
TREATMENT INTERRUPTION 
There will be no dose modifications for atezolizumab in this study. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will 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. COVID-19 
evaluation should be performed per institutional guidelines where relevant. Management 
guidelines for pulmonary events are provided in Table 1. 


 
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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. 
• For Grade 1 pneumonitis, consider withholding atezolizumab 
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 with or without transbronchial biopsy. 
• 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 the 
Medical Monitor. c 
• For recurrent events or events with no improvement after 48–72 hours of 
corticosteroids, treat as a Grade 3 or 4 event. 
• 
 
Pulmonary event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c 
• Oral or IV broad-spectrum antibiotics should be administered in parallel to 
the immunosuppressive treatment. 
• Bronchoscopy or BAL with or without transbronchial is recommended. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone. 
• 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 the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
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-related event. The decision to rechallenge patients with atezolizumab 
should be based on the investigator’s benefit-risk assessment and document by the investigator. 
The Medical Monitor is available to advise as needed. 
d    In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation.  
 


 
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HEPATIC EVENTS 
 Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; 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 
In patients without HCC 
Hepatic event, 
Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits or to baseline 
values.  
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 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 the 
Medical Monitor. c 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c 
• Consider patient referral to GI specialist for evaluation and liver biopsy to 
establish etiology of hepatic injury.  
• 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. 


 
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 GI=gastrointestinal; HCC = hepatocellular carcinoma; LFT = liver function test; ULN=upper limit of 
normal.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 based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The Medical Monitor is available to advise as 
needed.  
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by 
the investigator. The Medical Monitor is available to advise as needed. 
 
GASTROINTESTINAL EVENTS 
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. 
• If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist   ≥ 5 days, initiate treatment with 
corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. If the 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 the 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 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 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 the 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 the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
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-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by the investigator (or an appropriate delegate).  


 
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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 the Medical Monitor. c 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate 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 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 the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be  based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by 
the investigator. The Medical Monitor is available to advise as needed. 
 
ENDOCRINE EVENTS 
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. 
Table 4 
Management Guidelines for Endocrine Events 


 
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Event 
Management 
Grade 1 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
Grade 2 
hypothyroidism 
• Consider withholding atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
Grade 3 and 4 
hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Refer to an endocrinologist. 
• Admit patient to the hospital for developing myxedema (bradycardia, 
hypothermia, and altered mental status). 
• Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH ≥ 0.1 mU/L and  ≤ 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
• Consider patient referral to endocrinologist. 
TSH < 0.1 mU/L: 
• Follow guidelines for Grade 2 hyperthyroidism. 
• Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
• Consider withholding 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. 
Grade 3 and 4 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
• Refer to an endocrinologist. 
• Resume atezolizumab when symptoms are controlled, and thyroid 
function is improving. 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor for life-threatening immune-mediated hyperthyroidism. c 
 
 
 


 
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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 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 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 the Medical Monitor. c 
Hyperglycemia, Grade 1 
or 2  
• Continue atezolizumab. 
• Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as per 
institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, Grade 3 
or 4 
• Withhold atezolizumab.  
• Initiate treatment with insulin.  
• Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
• Monitor for glucose control. 
• Resume atezolizumab when symptoms resolve and glucose levels 
are stable. 
  


 
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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 corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone 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 the 
Medical Monitor. c 
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), Grade 4  
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate 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. 
• 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 the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be  based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by 
the investigator. The Medical Monitor is available to advise as needed. 
 


 
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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and contact Medical Monitor. c 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.   
• 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  based on the 
investigator’s benefit-risk assessment and in alignment with the protocol requirement for duration 
of treatment and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
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-related event.  The decision to rechallenge patients with atezolizumab 
should be based on the investigator’s benefit-risk assessment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
 


 
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IMMUNE-RELATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
 
IMMUNE-MEDIATED MYOCARDITIS 
  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. Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis. Immune-related myocarditis needs to be distinguished 
from myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a 
recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and appropriate 
treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 6. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain 
and may be associated with immune-mediated myocarditis (see section on myocarditis 
above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any 
patient presenting with chest pain associated with dyspnea or hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury 
related (post myocardial infarction or iatrogenic), and autoimmune disorders, and should be 
managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by performing 
an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
Table 6.  Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a detailed 
cardiac evaluation to determine the etiology and manage accordingly. 
 


 
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Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Events 
Management 
Immune-mediated 
myocarditis, Grades 2-4 
 
Immune-mediated 
pericardial disorders, 
Grades 2−4 
• Permanently discontinue atezolizumab and contact the 
Medical Monitor. a 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or 
VAD or pericardiocentesis as appropriate. 
• Initiate 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 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. 
 
 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome 
(CRS) with Cycle 1 of atezolizumab may receive premedication with antihistamines or 
antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its 
potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of 
cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab 
administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or other 
immune effector cells. Symptoms can be progressive, always include fever at the onset, and 
may include hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 
2019). CRS has been well documented with chimeric antigen receptor T-cell therapies and 
bispecific T-cell engager antibody therapies but has also been reported with immunotherapies 
that target PD-L1 or PD-1 or (Rotz et al. 2017; Adashek and Feldman 2019), including 
atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition 
of the challenges in clinically distinguishing between the two, consolidated guidelines for the 


 
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medical management of IRRs and CRS are provided in Table 7.  For subsequent cycles, IRRs 
should be managed according to institutional guidelines. 
Severe  SARS-COV-2 infection appears to be associated with a (CRS) involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-γ (Merad and Martin 
2020). If a patient develops suspected CRS during the study, a differential diagnosis should 
include COVID-19, which should be confirmed or refuted through assessment of exposure 
history, appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment. If a diagnosis of COVID-19 is confirmed, the disease should be managed as per 
local or institutional guidelines 
 
 
 
 
 


 
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Table 7 
Management Guidelines for Infusion-Related Reactions and Cytokine-
Release Syndrome 
 
Event 
Management 
Grade 1 a 
fever b with or without 
constitutional 
symptoms 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in patients 
with significant symptoms and/or comorbidities, consider managing 
as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines,  antipyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2 a 
fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
hypoxia requiring 
low-flow oxygen d by 
nasal cannula or 
blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate). Administer IV fluids as clinically indicated and 
manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day 
or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. 
• Consider hospitalization until complete resolution of symptoms. If 
no improvement within 24 hours, manage as per Grade 3, that 
is, hospitalize patient (monitoring in the ICU is recommended), 
permanently discontinue atezolizumab, and contact the Medical 
Monitor. 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, 
next dose of atezolizumab may be administered. For subsequent 
infusions, consider administration of oral premedication with 
antihistamines,  antipyretic medications, and/or analgesics and 
monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact the Medical Monitor. 


 
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Event 
Management 
Grade 3 a 
fever b with 
hypotension requiring 
a vasopressor (with 
or without 
vasopressin) 
and/or 
hypoxia requiring 
high-flow oxygen d by 
nasal cannula, face 
mask, non-rebreather 
mask, or venturi 
mask 
• Permanently discontinue atezolizumab the Medical 
Monitor. e 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
• Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended. Administer IV fluids as 
clinically indicated, and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS. 
• Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. 
• Hospitalize patient until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the 
investigator. 
Grade 4 a 
fever b with 
hypotension requiring 
multiple vasopressors 
(excluding 
vasopressin) 
and/or 
hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• Permanently discontinue atezolizumab the Medical 
Monitor. e 
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. Manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS. 
• Administer IV corticosteroids (e.g., methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. For patients who are refractory to 
anti-cytokine therapy, experimental treatmentsf may be considered 
at the discretion of the investigator. 
• Hospitalize patient until complete resolution of symptoms. 


 
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ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway 
pressure; CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; CRS = 
cytokine-release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; eCRF = 
electronic Case Report Form; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; 
IRR = infusion-related reaction; IV=intraveous; MAS = macrophage activation syndrome; NCCN = 
National Cancer Comprehensive Network; NCI = National Cancer Institute. 
Note: These management guidelines have been adapted from the NCCN guidelines for the management of 
CAR T-cell−related toxicities (Version 2.2019). 
a Grading system for these management guidelines is based on ASTCT  Consensus  Grading Scale for 
CRS. NCI CTCAE (version as specified in the protocol) should be used when reporting severity of 
IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities 
associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop 
CRS and who then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer 
required when subsequently determining event severity (grade). In this case, the grade is driven by the 
presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines,  antipyretic medications, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be 
administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at > 6 
L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event. The decision to rechallenge patients with atezolizumab 
should be based on the investigator’s  benefit-risk assessment and documented by the investigator . 
For subsequent infusions, administer oral premedication with antihistamines,  antipyretic medications, 
and/or analgesics, and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and 
extending the infusion time may also be considered after assessing the benefit−risk ratio. 
f  Refer to Riegler et al. (2019) 
 


 
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PANCREATIC EVENTS 
  The differential diagnosis of acute abdominal pain should include pancreatitis.  Appropriate 
workup 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 
Amylase and/or lipase > 1.5−2.0  ×  ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., > 3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0−5.0  ×  ULN: 
• Treat as a Grade 3 event. 
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 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 
the Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c 
  


 
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Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
(cont.) 
 
Event 
Management 
Immune-related pancreatitis, 
Grade 2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with 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 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 
the Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab and 
contact the Medical Monitor. c  
Immune-related pancreatitis, 
Grade 4 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
• Refer patient to GI specialist. 
• Initiate 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 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 the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be  based on the investigator’s benefit-risk 
assessment and in alignment with the protocol requirement for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
 


 
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DERMATOLOGIC EVENTS 
  The majority of cases of rash reported with the use of atezolizumab were mild in severity and 
self limited, with or without pruritus. Although uncommon, cases of severe cutaneous adverse 
reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been 
reported with atezolizumab.  A dermatologist should evaluate persistent and/or severe rash or 
pruritus.  A biopsy should be considered unless contraindicated.  Management guidelines for 
dermatologic events are provided in 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 and, if indicated, biopsy. 
• Initiate treatment with topical corticosteroids. 
• Consider treatment with higher-potency topical corticosteroids if event does 
not improve. 
• If unresponsive to topical corticosteroids, consider oral prednisone 0.5 
mg/kg/day 
Dermatologic event, 
Grade 3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to dermatologist and, if indicated, biopsy. 
• Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, 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 the Medical Monitor. c 
Dermatologic event, 
Grade 4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c 
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis, (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• 
Withhold atezolizumab for suspected Stevens-Johnson syndrome 
or toxic epidermal necrolysis. 
• 
Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
• 
Follow the applicable treatment and management guidelines above. 
• 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
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  based on the investigator’s benefit-risk 
assessment and in alignment with the protocol requirement for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
 


 
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NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  Diagnostic 
workup is essential for an accurate characterization to differentiate between alternative 
etiologies.  Management guidelines for neurologic disorders are provided in Table 10.  
Table 10 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy, Grade 
1 
• Continue atezolizumab. 
• Investigate etiology 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
– 
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 the 
Medical Monitor. c 
• For facial paresis: 
– 
If event resolves fully, resume atezolizumab b 
• If event does not resolve fully while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the Medical Monitor. c 
Immune-related 
neuropathy, Grade 
3 or 4 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue atezolizumab and contact the Medical Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day oral or IV 
prednisone. 
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  based on the investigator’s benefit-risk 
assessment and in alignment with the protocol requirement for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
 
 


 
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Table 1 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not improve. 
• 
Investigate etiology and refer patient to a neurologist. 
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab. 
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
 
IMMUNE-RELATED MENINGOENCEPHALITIS 
Immune-related meningoencephalitis should be suspected in any patient presenting with signs 
or symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, 
neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of 
consciousness.  Encephalopathy from metabolic or electrolyte imbalances needs to be 
distinguished from potential meningoencephalitis resulting from infection (bacterial, viral, or 
fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If 
deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 12. 


 
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Table 12 Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab and contact the Medical 
Monitor. a 
• Refer patient to neurologist. 
• Initiate 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 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. 
 
 
RENAL EVENTS 
  Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including prerenal 
and postrenal causes, and concomitant medications such as non-steroidal anti-inflammatory 
drugs).  Refer the patient to a renal specialist if clinically indicated.  A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 12. 
Table  13 Management Guidelines for Renal Events  
Event 
Management 
Renal event, Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine and urine protein, 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 the 
Medical Monitor. c 


 
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Renal event, Grade 3 
or 4 
• Permanently discontinue atezolizumab and contact the 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  based on the investigator’s benefit-risk 
assessment and in alignment with the protocol requirement for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
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-related event.  The decision to rechallenge patients with atezolizumab 
should be based on the investigator’s benefit-risk assessment and documented by the investigator. 
The Medical Monitor is available to advise as needed. 
 
IMMUNE-MEDIATED MYOSITIS 
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 possible 
myositis should be referred to a rheumatologist or neurologist. Patients with possible myositis 
should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 14. 
Table  14 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. 


 
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Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a and contact 
the 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 the 
Medical Monitor. c 
  


 
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Table  14 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 
the 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 
the Monitor. c 
• For recurrent events, treat as a Grade 4 event. Permanently discontinue 
atezolizumab and contact the Medical Monitor. c 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact the 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  based on the investigator’s benefit-risk 
assessment and in alignment with the protocol requirement for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
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.  The decision to rechallenge patients with 
atezolizumab should be based on the investigator’s benefit-risk assessment and documented by the 
investigator. The Medical Monitor is available to advise as needed. 
 


 
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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).   
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
• 
Fever ≥ 38.5°C 
• 
Splenomegaly 
• 
Peripheral blood cytopenia consisting of at least two of the following: 
o Hemoglobin <  90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
• 
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 (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: 
o Platelet count ≤ 181 × 109/L (181,000/µL) 
o AST ≥ 48 U/L 
o Triglycerides > 1.761 mmol/L (156 mg/dL) 
o Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table  15. 


 
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Table  15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH or 
MAS 
• Permanently discontinue atezolizumab and contact the Medical Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact the Medical 
Monitor and initiate treatment as appropriate according to published 
guidelines (La Rosée 2015; Schram and Berliner 2015; La Rosée et al. 
2019). 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
HLH = hemophagocytic lymphohistiocytosis; IV=intravenous; MAS = macrophage activation 
syndrome. 
Immune-mediated Facial Paresis 
• 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
• 
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies. 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Atezolizumab should be withheld for patients with Grade 1 or 2 immune-mediated facial 
paresis and permanently withdrawn for ≥Grade 3 immune-mediated facial paresis 
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