Clinical trial NCT04477759
Conditions: Head and Neck Neoplasm
Keywords: Radiotherapy Atezolizumab Targeted Radiation Therapy Head and Neck Cancer Cancer Magnetic Resonance Guided Radiation Therapy
Sponsor: Medical College of Wisconsin
Start date: 2021-01-26; Completion date: 2025-04-14
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Locoregional failure remains the principal mode of mortality in head and neck squamous cell carcinoma (HNSCC) treated with conventional chemoradiation therapy. Magnetic resonance-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor response and may improve therapeutic outcomes while limiting toxicities.

This protocol evaluates a novel framework for radiation delivery with concurrent atezolizumab in patients with advanced HNSCC. Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) modifies radiation dose using MRgRT by escalating radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression.

Detailed description:
Locoregional failure remains the principal mode of mortality in head and neck squamous cell carcinoma (HNSCC) treated with conventional chemoradiation therapy. Radiation dose escalation with hypofractionation has shown unparalleled local control in other malignancies, such as non-small cell lung cancer, but has been limited in HNSCC due to toxicity concerns. Magnetic resonance-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor response and may improve therapeutic outcomes while limiting toxicities.

This protocol evaluates a novel framework for radiation delivery using MRgRT with concurrent atezolizumab in patients with advanced HNSCC. Unlike conventional radiotherapy, Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) modifies radiation dose using MRgRT by adapting the radiation plan during the course of treatment, escalating radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression. The hypothesis is that DEHART will safely deliver ablative radiation doses in 15 fractions over 3 weeks while limiting both toxicity and the effect of tumor repopulation by resistant clonogens, thus resulting in an improved therapeutic ratio.

This Phase I clinical trial will encompass the following specific aims: (1) determine the maximum tolerated dose (MTD) of the DEHART regimen delivered using MRgRT with concurrent atezolizumab in a population of patients who are not candidates or unsuitable for definitive chemoradiation therapy; (2) evaluate the toxicity and functional outcomes of the DEHART regimen; and (3) assess the efficacy of DEHART and obtain volumetric and functional imaging correlates of efficacy using MRgRT to serve as hypothesis-generating data for future trials of radiation dose adaptation. A modified Time-to Event Continual Reassessment (TITE-CRM) Phase I Design with three radiation dose levels delivered to regressing disease will be used to determine the MTD: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 15 fractions.

If DEHART is found to be safe and shows a signal of efficacy in this study, a future Phase II trial will be conducted to compare this novel treatment strategy to standard-of care conventionally fractionated chemoradiation in patients with locally advanced HNSCC.

Arms: arm 1: 50 Gy of ionizing radiation therapy will be administered in 15 fractions. arm 2: 50 Gy of ionizing radiation therapy will be administered in 15 fractions. arm 3: 55 Gy of ionizing radiation therapy will be administered in 15 fractions. arm 4: 60 Gy of ionizing radiation therapy will be administered in 15 fractions.
Interventions: intervention 1: 50 Gy Radiation Therapy intervention 2: 55 Gy Radiation Therapy intervention 3: 60 Gy Radiation Therapy intervention 4: Concurrent Atezolizumab intervention 5: Adjuvant Atezolizumab
Intervention descriptions: intervention 1: Ionizing radiation intervention 2: Ionizing radiation intervention 3: Ionizing radiation intervention 4: Atezolizumab (1,680 mg) will be given to all subjects by intravenous injection every 4 weeks following the initiation of radiation treatment up to 1 year from radiation fraction 1. intervention 5: Atezolizumab (1,680 mg) will be given to all subjects by intravenous injection every 28 days following the initiation of radiation treatment up to 1 year.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Date:  July 31, 2023 
Oﬃcial Title of Study:  A Phase I Trial of MR-Guided Dose-Escalated HypofracƟonated AdapƟve 
RadiaƟon Therapy and Immunotherapy in Primary MetastaƟc or Very Locally Advanced PaƟents 
With Head and Neck Cancer 
NCT04477759 
 


Study Short Title: DEHART Study 
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Version Date: 07/31/2023 
 
 
A Phase I Study of MR-Guided Dose-Escalated Hypofractionated 
Adaptive Radiation Therapy and Atezolizumab in Primary Metastatic, 
Locally Advanced and Locally Recurrent  
Patients with Head and Neck Cancer 
Short Title: 
 
 
 
 
 
 
 
 
Musaddiq Awan, MD (Study PI) 
Current Version Number and Date 
v1.0 10/30/2020 
v2.0 07/30/2021 
v3.0 03/14/2022 
v4.0 05/11/2022 
v5.0 07/31/2023 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
DEHART 
Study 


Study Short Title: DEHART Study 
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to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.  


Study Short Title: DEHART Study 
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Title:    A Phase I Study of MR-Guided Dose-Escalated Hypofractionated Adaptive Radiation 
Therapy and Atezolizumab in Primary Metastatic, Locally Advanced and Locally 
Recurrent Patients with Head and Neck Cancer 
MCW Protocol No.: IIT-AWAN-NIH-
DEHART 
IRB Pro No.:  38841 
Clinical trials.gov No.: NCT04477759  
FDA IND No.: Exempt 
Principal Investigator:  
Musaddiq Awan, MD 
Assistant Professor 
Department of Radiation Oncology  
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4365 
Email: mawan@mcw.edu  
Co-investigator:  
Heather Himburg, PhD 
Associate Professor 
Department of Radiation Oncology 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-4676 
Email: hhimburg@mcw.edu  
 
Co-investigator:  
Christopher Schultz, MD 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-4472 
Email:   cschultz@mcw.edu  
Co-investigator:  
Monica Shukla, MD 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-4493 
Email: mshukla@mcw.edu  
 
Co-investigator:  
Selim Firat, MD 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-4453 
Email: sfirat@mcw.edu  
Co-investigator:  
Aditya Shreenivas, MD 
Division of Hematology and Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-4600 
Email: ashreenivas@mcw.edu 
Co-investigator:  
Becky Massey, MD 
Department of Otolaryngology and Head 
and Neck Surgery  
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-8325 
Email: bmassey@mcw.edu  
Co-investigator:  
Michael Stadler, MD 
Department of Otolaryngology and Head and Neck 
Surgery  
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-8548 
Email: mstadler@mcw.edu  


Study Short Title: DEHART Study 
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Co-investigator:  
Eric Paulson, PhD 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-4477 
Email:  epaulsen@mcw.edu  
Co-investigator:  
Stuart Wong, MD 
Department of Medical Oncology  
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-0803 
Email:  swong@mcw.edu  
 
Co-investigator: 
Joseph Zenga, MD 
Department of Otolaryngology and Head 
and Neck Surgery  
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-955-0889 
Email:  jzenga@mcw.edu  
Co-investigator:  
Mohit Agarwal, MD 
Department of Radiology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-805-3122 
Email: magarwal@mcw.edu  
Biostatistician: 
Sergey Tarima, PhD 
Department of Biostatistics 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
414-456-5605 
Email: starima@mcw.edu  
 
Co-investigator: 
Barbara R. Pauloski, PhD, CCC-SLP 
Clinical and Translational Science Institute 
Medical College of Wisconsin 
Milwaukee, WI 53226 
414-229-6719 
Email: bpauloski@mcw.edu   


 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY .............................................................................................................. 8
STUDY SCHEMA ....................................................................................................................... 10
STUDY CALENDAR ................................................................................................................... 11
LIST OF ABBREVIATIONS ....................................................................................................... 14
1 BACKGROUND ....................................................................................................................... 16
1.1 INTRODUCTION .................................................................................................................... 16
1.2 STUDY SIGNIFICANCE AND RATIONALE ................................................................................. 16
1.3 STUDY INNOVATION ............................................................................................................. 19
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS ................................................................. 20
2.1 PRIMARY OBJECTIVES ......................................................................................................... 20
2.2 SECONDARY OBJECTIVES .................................................................................................... 21
2.3 PRIMARY ENDPOINT ............................................................................................................ 21
2.4 SECONDARY ENDPOINT(S) ................................................................................................... 21
3 STUDY DESIGN ...................................................................................................................... 21
3.1 GENERAL DESCRIPTION ....................................................................................................... 21
3.2 STUDY COMPLETION ........................................................................................................... 23
4 SUBJECT PARTICIPATION, DISCONTINUATION, 
AND WITHDRAWAL .................................................................................................................. 23
4.1 SUBJECT STATUS ................................................................................................................ 23
4.2 PRESCREENING AND SCREENING LOG ................................................................................. 24
4.3 CONSENT ............................................................................................................................ 24
4.4 SCREENING PROCEDURES ................................................................................................... 24
4.5 ELIGIBILITY CONFIRMATION .................................................................................................. 25
INCLUSION CRITERIA ................................................................................................................. 25
EXCLUSION CRITERIA ................................................................................................................ 27
4.6 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE ....................... 31
4.7 LOST TO FOLLOW-UP .......................................................................................................... 31
4.8 ACCRUAL SUSPENSION AND CLOSURE ................................................................................. 32
4.9 END OF STUDY DEFINITION .................................................................................................. 32
4.10 STUDY DISCONTINUATION AND CLOSURE ........................................................................... 32
5 TREATMENT PLAN ................................................................................................................ 33
5.1 RADIATION THERAPY ........................................................................................................... 33
5.1.1 Simulation, Localization and Treatment Planning Requirements ........................................... 33
5.1.2 Target Volumes ......................................................................................................................................... 33
5.1.3 Critical Normal Tissues ...................................................................................................................... 33
5.1.4 Radiation Treatment Planning .......................................................................................................... 34
5.1.5 Treatment Verification .............................................................................................................................. 36
5.1.6 Daily Anatomic and Functional Imaging ................................................................................................ 36
5.2 SYSTEMIC THERAPY ............................................................................................................ 36


 
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5.2.1 Drug Administration and Patient Assessment during Systemic Therapy ............................................... 36
5.3 ATEZOLIZUMAB DOSE MANAGEMENT AND MODIFICATIONS .................................................... 37
5.3.1 Pulmonary Events ..................................................................................................................................... 37
5.3.2 Hepatic Events .......................................................................................................................................... 39
5.3.3 Gastrointestinal Events ...................................................................................................................... 40
5.3.4 Endocrine Events ...................................................................................................................................... 42
5.3.5 Ocular Events ............................................................................................................................................ 45
5.3.6 Immune-Mediated Myocarditis ......................................................................................................... 46
5.3.7  INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME ...................... 48
5.3.8 Pancreatic Events ...................................................................................................................................... 52
5.3.9 Dermatologic Events ................................................................................................................................. 55
5.3.10 Neurologic Disorders .............................................................................................................................. 57
5.3.11 Immune-Mediated Meningoencephalitis ............................................................................................... 58
5.3.12 Renal Events ............................................................................................................................................ 59
5.3.13 Immune-Mediated Myositis .................................................................................................................... 60
5.4 DIETARY RESTRICTIONS ...................................................................................................... 64
5.5 MONITORING SUBJECT COMPLIANCE .................................................................................... 64
5.6 ACQUISITION OF TUMOR SPECIMENS.................................................................................... 64
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION  
AND REPORTING REQUIREMENTS ........................................................................................ 65
6.1 DEFINITIONS ....................................................................................................................... 65
6.1.1 Adverse Event ............................................................................................................................................ 65
6.1.2 Serious Adverse Event (SAE) ................................................................................................................... 65
6.1.3 Assessment of Severeity of Adverse Events .............................................................................................. 66
6.1.4 Attribution of an Adverse Event ............................................................................................................... 67
6.1.5 Expectedness of an Adverse Event ........................................................................................................... 68
6.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE         
EVENTS ......................................................................................................................... 68
6.2.1 Collection of Adverse Events .................................................................................................................... 68
6.2.2. Procedures for eliciting, recording, and reporting adverse events ......................................................... 69
6.2.3 Reporting of Adverse Events and Serious Adverse Events ...................................................................... 72
6.2.3.1 Exchange of Single Case Reports with Genentech ............................................................................... 73
6.2.4 Reporting Instructions .............................................................................................................................. 75
6.2.4.1 AGGREGATE REPORTS .................................................................................................. 76
6.2.4.2 OTHER REPORTS .......................................................................................................... 76
6.3 UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ................... 76
6.4 SUBJECT COMPLAINTS ........................................................................................................ 76
6.5 STUDY CLOSE-OUT ............................................................................................................. 77
6.6 QUERIES ............................................................................................................................. 77
6.7 SAFETY CRISIS MANAGEMENT ............................................................................................. 77
6.8 COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT ............................................ 78
7 PHARMACEUTICAL INFORMATION ..................................................................................... 78
7.1 PRODUCT DESCRIPTION ....................................................................................................... 78
7.2 PHYSICAL, CHEMICAL, PHARMACEUTICAL PROPERTIES AND CLINICAL FORMULATION OF 
ATEZOLIZUMAB .............................................................................................................. 79
7.3 PHARMACOLOGY ................................................................................................................ 79
7.4 ASSESSMENT OF SAFETY OF ATEZOLIZUMAB ....................................................................... 79
7.4.1 Safety Plan ............................................................................................................................................. 80
7.4.2 Risks Associated with Atezolizumab .............................................................................................. 80
7.4.3 Safety Parameters and Definitions .................................................................................................. 80


 
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7.4.4 Adverse Events of Special Interest (Immediately Reportable to the investigators ............ 80
7.5 FORMULA ........................................................................................................................... 80
7.6 SUPPLY .............................................................................................................................. 80
7.7 PHYSICAL AND CHEMICAL PROPERTIES ................................................................................ 81
7.8 CLINICAL FORMULATION ....................................................................................................... 81
8 STATISTICAL CONSIDERATIONS ........................................................................................ 82
8.1 STUDY DESIGN.................................................................................................................... 82
8.2 OBJECTIVES AND ANALYSIS PLANS ...................................................................................... 83
8.2.1 Primary Objective and Analysis Plan .................................................................................................. 83
8.2.2  Secondary Objectives ........................................................................................................................ 84
8.3 SAMPLE SIZE JUSTIFICATION ............................................................................................... 84
8.4 STUDY MONITORING, INTERIM ANALYSES, AND EARLY STOPPING RULES .............................. 85
8.5 SYSTEMIC TREATMENT DISCONTINUATION ........................................................................... 86
9 DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................. 87
9.1 DATA AND SAFETY MANAGEMENT OVERVIEW ...................................................................... 87
9.2 STUDY TEAM ....................................................................................................................... 87
9.3 QUALITY ASSURANCE .......................................................................................................... 87
9.4 CLINICAL TRIALS OFFICE ..................................................................................................... 87
9.5 DSMC ................................................................................................................................ 87
10 REGULATORY COMPLIANCE, ETHICS, AND 
STUDY         MANAGEMENT ..................................................................................................... 88
10.1 REGULATORY COMPLIANCE ............................................................................................... 88
10.2 PRE-STUDY DOCUMENTATION ............................................................................................ 88
10.3 INSTITUTIONAL REVIEW BOARD ......................................................................................... 88
10.4 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................... 89
10.5 PROTECTION OF HUMAN SUBJECTS ................................................................................... 90
10.5.1 
Protection from Unnecessary Harm ................................................................................................ 90
10.5.2 
Protection of Privacy ........................................................................................................................ 90
10.5.3
Changes in the Protocol ................................................................................................................... 90
10.6 INVESTIGATOR COMPLIANCE .............................................................................................. 91
11 DATA HANDLING AND RECORD KEEPING....................................................................... 91
11.1 OVERVIEW ........................................................................................................................ 91
11.2 DATA MANAGEMENT RESPONSIBILITIES ............................................................................. 91
11.3 SOURCE DOCUMENTS ....................................................................................................... 92
11.4 CASE REPORT FORMS ....................................................................................................... 93
11.5 STUDY RECORD RETENTION .............................................................................................. 93
APPENDIX 1. PERFORMANCE STATUS CRITERIA ............................................................... 94
APPENDIX 2. LOST TO FOLLOW-UP LETTER ....................................................................... 95
REFERENCES ........................................................................................................................... 96
 


 
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PROTOCOL SUMMARY 
Title 
A Phase I Study of MR-Guided Dose-Escalated Hypofractionated 
Adaptive Radiation Therapy and Atezolizumab in Primary Metastatic, 
Locally Advanced and Locally Recurrent Patients with Head and 
Neck Cancer
IND Sponsor 
Sponsor-Investigator
Principal Investigator  Musaddiq Awan, MD 
Clinical Trial Phase 
I 
Study Population 
Locally Advanced Patients with Head and Neck Cancer 
Primary Objectives 
To determine the maximum-tolerated dose (MTD) of the DEHART 
regimen delivered with adjuvant atezolizumab in patients with  locally 
advanced or de novo metastatic HNSCCs. 
Secondary Objectives 
 
1. To evaluate the efficacy of the DEHART regimen at one year 
as measured by locoregional control and overall survival. 
2. To assess gross tumor shrinkage after six and 11 fractions of 
radiotherapy using the DEHART regimen. 
3. To assess patient quality of life during and after the DEHART 
regimen as measured using multiple patient quality-of-life 
metrics. 
 
Study Design 
We propose a pilot phase I study using a Time-to-Event Continual 
Reassessment (TITE-CRM) design to estimate the MTD. Locally 
advanced (defined as T3-T4NanyM0 or T1-T4 N1-N3M0 or 
locoregionally recurrent after surgery) and de novo metastatic 
HNSCC patients with no prior history of head and neck radiation and 
a life expectancy of at least 12 months will be enrolled.  
 
Baseline symptom evaluation will be obtained using validated 
surveys of head and neck cancer patients: the MD Anderson 
Symptom Inventory for Head and Neck (MDASI-HN) and the MD 
Anderson Dysphagia Inventory for Head and Neck (MDADI-HN). 
Patients will then undergo treatment using DEHART and adjuvant 
atezolizumab and will then be followed for up to one year. 
 


 
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Number of Subjects 
18 
Estimated Time to 
Complete Enrollment: Approximately two years 




 
 
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STUDY CALENDAR 
 
Study Assessment 
Screening1 
Pre-Treatment 
SLP Eval2 
Radiotherapy 
Simulation2
RT 
Fx  
1 
RT 
Fx 
 2 -4 
RT 
Fx 5 
RT 
Fx 
6-9 
RT 
Fx 
10 
RT 
Fx 
11 
RT 
Fx 
12 - 
14 
RT 
Fx 
15 
1 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
2, 3 and 
4 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
Immun
o-
therapy 
Visits 
Post RT 
(q28d + 
7 days) 
3 mo 
Post-
RT 
Follow
-Up3 
(+/- 14 
days) 
6 mo 
Post-
RT 
Follow
-Up  
(+/- 14 
days) 
9 and 
12 mo 
Post-
RT 
Follo
w-up3
(+/- 14 
days) 
Scheduled as per institutional guidelines  
Radiation Oncologist 
Visit 
X 
 
 
X (One visit prior to 
initiaton of fraction 
6) 
X (One visit 
prior to 
initiation of 
fraction 11) 
X (One visit no 
later than 24h after 
fraction 15) 
X 
X 
 
X 
X 
X 
Medical Oncologist 
Visit  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Cisplatin Eligibility 
Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE reporting  
 
Recorded until completion of the 12 month follow-up period 
 
 
 
Concomitant 
Medications 
 
Recorded from signing of the ICF through 30 days after the last dose of study drug 
 
 
 
CBC with Diff 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CMP4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
TSH, T3,T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Amylase/Lipase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Study Assessment 
Screening1 
Pre-Treatment 
SLP Eval2 
Radiotherapy 
Simulation2 
RT 
Fx  
1 
RT 
Fx 
 2 -4 
RT 
Fx 5 
RT 
Fx 
6-9 
RT 
Fx 
10 
RT 
Fx 
11 
RT 
Fx 
12 - 
14 
RT 
Fx 
15 
1 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
2, 3 and 
4 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
Immun
o-
therapy 
Visits 
Post RT 
(q28d + 
7 days) 
3 mo 
Post-
RT 
Follow
-Up3 
(+/- 14 
days) 
6 mo 
Post-
RT 
Follow
-Up  
(+/- 14 
days) 
9 and 
12 mo 
Post-
RT 
Follo
w-up3
(+/- 14 
days) 
Scheduled as per institutional guidelines  
HIV and hepatitis B 
surface antigen 
(HBsAg)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Chest or PET/CT 
to assess for distant 
metastatic disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Simulation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MR simulation 
including 
Anaotmic/Functional 
Acquisitions 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiotherapy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Anatomic/Functional 
MR Acquisitions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
DCE MRI (optional) 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
Radiation Planning 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Atezolizumab 1680 
mg IV 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Research 
Biopsy 
(optional) 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
SLP Evaluation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
VFSS Study 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
FOIS Score 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
DIGEST Grade 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
MDASI-HN Survey 
 
 
X 
 
 
X 
(+/- 
 
X 
(+/- 
 
 
X 
(+/- 
X 
X 
 
X 
X 
X 


 
 
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Study Assessment 
Screening1 
Pre-Treatment 
SLP Eval2 
Radiotherapy 
Simulation2 
RT 
Fx  
1 
RT 
Fx 
 2 -4 
RT 
Fx 5 
RT 
Fx 
6-9 
RT 
Fx 
10 
RT 
Fx 
11 
RT 
Fx 
12 - 
14 
RT 
Fx 
15 
1 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
2, 3 and 
4 wk 
Post-RT 
Follow-
Up3 (+/- 
3 days) 
Immun
o-
therapy 
Visits 
Post RT 
(q28d + 
7 days) 
3 mo 
Post-
RT 
Follow
-Up3 
(+/- 14 
days) 
6 mo 
Post-
RT 
Follow
-Up  
(+/- 14 
days) 
9 and 
12 mo 
Post-
RT 
Follo
w-up3
(+/- 14 
days) 
Scheduled as per institutional guidelines  
48 
hrs) 
48 
hrs) 
48 
hrs) 
MDADI Survey 
 
 
X 
 
 
X 
(+/- 
48h) 
X 
(+/- 
48h) 
X 
(+/- 
48 
hrs)
X 
X 
 
X 
X 
X 
EAT-10 
Questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
PET/CT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Diagnostic Neck 
MRI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1. All screening procedures must occur within 30 days prior to enrollment. 
2. Should be comepletd before starting radiation treatment  
3. If a subject has disease progression/relapse, then they will be followed for treatment-related toxicity up to 1-year, subject 
withdrawal or death as per follow-up requirements. 
4. Including alkaline phosphatase, ALT/AST, total bilirubin, total protein, albumin, calcium, phosphorus, magnesium, creatinine, 
glucose, potassium, sodium, chloride, bicarbonate AND uric acid 
5. For women of childbearing potential. A negative pregnancy test (serum) must be obtained within 30 days prior to the first study 
intervention.  


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Cell (Count) 
CQ 
Chloroquine 
CR 
Complete Response 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
CSF 
Cerebral Spinal Fluid 
CT 
Computerized Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTO 
Clinical Trials Office 
DCE 
Dynamic Contrast Enhancement 
DEHART 
Dose-Escalated Hypofractionated Adaptive Radiotherapy  
DFS 
Disease-Free Survival 
DLT 
Dose-Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HNSCCs 
Head and Neck Squamous Cell Carcinomas  
IP 
Investigational Product 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
MCWCC 
Medical College of Wisconsin Cancer Center 
MRgRT 
MR-guided Radiation Therapy  
MTD 
Maximum-Tolerated Dose 
NCI 
National Cancer Institute 
NSCLCs 
Non-small cell lung cancers  


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ORR
Overall Response Rate 
PD-L1 
Programmed Cell Death Ligand-1  
PR 
Partial Response 
RT 
Radiation Therapy  
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy  
SD 
Stable Disease 
SD 
Standard Deviation 
SRC 
Scientific Review Committee 
TITE-CRM 
Time-to-Event Continual Reassessment 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
UPIRSO   
Unanticipated Problems Involving Risks to Subjects or Others 
 


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1 BACKGROUND 
1.1 Introduction 
Locoregional failure remains the principle mode of mortality in head and neck squamous cell 
carcinomas (HNSCCs) treated with conventional chemoradiation therapy over seven weeks. 
Radiation dose escalation with hypofractionation has shown unparalleled local control in many 
other malignancies, such as non-small cell lung cancer, but has been stymied in HNSCCs due to 
toxicity concerns. MR-guided radiation therapy (MRgRT) allows for adaptive radiation dose 
escalation based on tumor response, which may improve therapeutic outcomes while limiting 
toxicities. 
Our protocol, titled Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART), 
evaluates a novel framework for radiation delivery using MRgRT with atezolizumab in patients 
with advanced HNSCCs. Unlike conventional radiotherapy, DEHART modifies the radiation dose 
using MRgRT by adapting the radiation plan weekly during the course of treatment, escalating 
radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression. 
We hypothesize that DEHART will safely deliver ablative radiation doses in 15 fractions over three 
weeks while limiting both toxicity and the effect of tumor repopulation by resistant clonogens, thus 
resulting in an improved therapeutic ratio. 
We aim to test this hypothesis through a phase I clinical trial with the following specific aims: (1) 
Determine the maximum-tolerated dose (MTD) of the DEHART regimen delivered using MRgRT 
with adjuvant atezolizumab in a population of patients who are not candidates or unsuitable for 
definitive chemoradiation therapy; (2) Evaluate the toxicity and functional outcomes of the 
DEHART regimen including changes in baseline speech, swallow and quality of life; and (3) 
Assess the efficacy of DEHART and obtain volumetric and functional imaging correlates of 
efficacy using MRgRT to serve as hypothesis-generating data for future trials of radiation dose 
adaptation. To determine the MTD of the DEHART regimen, we propose an 18 patient study using 
a modified Time-to-Event Continual Reassessment (TITE-CRM) phase I design with three 
radiation dose levels delivered to regressing disease: 50 Gy in 15 fractions, 55 Gy in 15 fractions 
and 60 Gy in 15 fractions. 
If DEHART is found to be safe and shows a signal of efficacy in this study, we will conduct a future 
phase II trial to compare this novel treatment strategy to standard-of-care conventionally 
fractionated chemoradiation in patients with locally advanced HNSCCs. 
1.2 Study Significance and Rationale 
Hypofractionated Radiation Has Shown Excellent Outcomes for Local Control in Many 
Malignancies: Locoregional failure remains the principle cause of mortality in patients with head 
and neck squamous cell carcinomas (HNSCCs). In many other malignancies, short course, high 
dose per fraction radiation therapy (RT), referred to as hypofractionated RT, has been shown to 
provide excellent local control. For example, using a technique called stereotactic body radiation 
therapy (SBRT), a total dose of 50-54 Gy in 3-5 fractions can be delivered in 1-1.5 weeks for 
early-stage non-small cell lung cancers (NSCLCs), resulting in local control upward of 90%. (1) 
Despite such advances in other malignancies, the use of SBRT in HNSCCs has been limited to 
the re-irradiation setting in which a second course of RT is delivered to a field that received a prior 
full-dose course of RT. This limited use is due to multiple reasons including toxicity concerns of 
using SBRT in the definitive setting, an inability to safely treat microscopic regional nodal disease 
with SBRT, and concerns regarding the efficacy of SBRT at the established HNSCC re-irradiation 


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dose of 40 Gy in 5 fractions. In fact, in the phase II trial establishing this SBRT dose in the re-
irradiation setting, local progression-free survival (PFS) was only 60% with one-year locoregional 
PFS only approaching 37%. (2) Though this modest number accounts for the high mortality rates 
and radioresistance associated with a retreated population, this SBRT regimen is likely insufficient 
for the long-term local control needed in de novo treatment of HNSCCs. 
Another hypofractionated regimen that has been used in NSCLC with local control 
comparable to SBRT (approaching 90%) is 60 Gy in 15 fractions. (3) We find this regimen 
appealing to establish in HNSCCs for three reasons: 1) It may be delivered in only three 
weeks; 2) Using the linear-quadratic model to compare RT dose regimens (11), it is 
equivalent to a 2 Gy per fraction dose (EQD2) of 70 Gy, which is the conventional RT dose 
for gross disease for locally advanced HNSCCs; and 3) It easily allows for integrated 
treatment of areas at risk for microscopic regional disease spread using a safe dose of 40 
Gy in 15 fractions (EQD2 of 42.2 Gy). Further, by delivering this equivalent dose over three 
weeks, there is limited ability for tumor repopulation by relatively radioresistant clonogens, 
resulting in a greater likelihood of tumor control compared to conventional RT based upon first 
principles. 
MR-Guided Adaptive Radiation Therapy May Allow for Safe Hypofractionation in 
HNSCCs: Prior attempts at hypofractionation in HNSCCs have been stymied due to concerns 
regarding acute and late toxicities of radiation as well as the known benefit of radiosensitizing 
cisplatin. In particular, phase I-II trials of SBRT treating small volumes for early stage laryngeal 
cancers have shown moderate to high rates of laryngeal edema and laryngeal necrosis. (4-6) 
Further, laryngeal and/or hypopharyngeal involvement in the reirradiation SBRT experience was 
associated with a 50% rate of Grade 3+ late toxicities. (7) 
In these studies, radiation has typically been given in a non-adaptive fashion, with a single dose 
given to the entire area of gross disease involvement prior to the beginning of therapy without 
modification due to tumor shrinkage. Adaptive RT allows for replanning of radiation based on 
tumor shrinkage. Previously, the ability to perform adaptive RT has been hampered by poor 
quality daily anatomic and functional treatment imaging using cone-beam CT and the lack of a 
framework to rapidly replan patients without a repeat CT simulation. Recently, the development 
of magnetic resonance-guided radiation therapy (MRgRT) has allowed for improved image 
guidance and high-quality acquisition of anatomic and functional imaging daily during RT. (8) In 
anticipation of daily dose adaptation, MRgRT has been developed with rapid plan adaptation in 
mind and a new radiation plan using MRgRT may be obtained in a matter of minutes to hours 
compared to many days for a. typical CT plan. Thus, MRgRT may improve locoregional outcomes 
in patients with HNSCCs by facilitating  safe hypofractionation through anatomic and functional 
imaging response-based radiation dose adaptation. We are uniquely positioned at our institution 
to deliver adaptive RT as we have an MRI-guided linear accelerator, allowing for high-quality 
imaging of gross disease as it visibly regresses during RT. Using our MRI-guided linear 
accelerator, we have observed that during conventionally fractionated RT, rapid regression 
of HNSCCs may be appreciated on MR-guided imaging during the first weeks of 
treatment. Given this, we propose using adapted MR-guided RT (MRgRT) to allow for safe 
delivery of the dose-escalated hypofractionated regimen of 60 Gy in 15 fractions in 
HNSCCs. 
Locoregional Control Remains Critically Important in Locally Advanced and Metastatic 
HNSCCs and in Poor Performance Status Patients. Standard management of the primary 
disease site in patients with primary metastatic HNSCC is not well defined, even though failure to 
control local and regional disease remains the number one cause of morbidity and mortality in 
this population. Additionally, unresectable disease and locally recurrent disease after surgery, is 


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best managed by a clinical trial, per NCCN guidelines. The principle recommendation for primary 
metastatic disease according to NCCN guidelines is to consider locoregional treatment and then 
pursue systemic therapy. 
Despite advances in radiotherapy and chemotherapy delivery, standard-of-care management for 
locally advanced HNSCCs remains concurrent chemoradiation therapy with cisplatin over seven 
weeks of treatment. However, in the case of primary metastatic disease or poor performance 
status patients, this seven-week course significantly delays initiation of systemic therapy. 
Furthermore, it is uncertain whether the side effects associated with chemoradiation, including a 
severe toxicity rate as high as 50%, (9) are justified in these settings of limited life expectancy. 
This has led to variable practice in the management of locoregional disease in these patients: 
some physicians choose to perform upfront concurrent chemoradiation as in the non-metastatic 
setting; some utilize palliative radiotherapy approaches without chemotherapy; (10) while others 
omit upfront radiotherapy altogether in order to proceed immediately to primary systemic 
immunotherapy or chemoimmunotherapy. (11-13)  
 
However, recent data show that despite having primary metastatic disease, very locally advanced 
disease or even poor performance status, HNSCC patients still have a modest life expectancy 
and may be suitable for locoregional treatment and enrollment on a phase I trial. The KEYNOTE-
048 trial reported that the median survival of metastatic patients with PD-L1 immunotherapy 
exceeds one year (13 months). (13) Additionally, Al-Mamgani et al. (14) report the effectiveness 
of hypofractionated radiation using 50 Gy in 16 fractions (median survival 17 months) in patients 
not suitable for curative treatment despite including 9% de novo metastatic patients (the typical 
de novo metastatic rate for HNSCCs) and 16% poor performance status patients. Given the 
variable management of this group of patients and the importance of addressing 
locoregional disease in this population, locally advanced patients, primary metastatic 
patients and poor performance status patients are an excellent patient population to test 
the safety of our novel hypofractionated RT paradigm prior to testing this in a more 
curative population. 
 
Immunotherapy and Radiation Have Shown Synergy in Preclinical Models: The rationale for 
combining radiation with immunotherapy stems from preclinical evidence of a synergistic 
antitumor effect of both treatment modalities on cancer cells. Studies have shown that radiation 
therapy may induce both innate and adaptive anti-tumor immune response.by modulating the 
host¶s immune system, and making tumor cells more susceptible to T-cell-mediated attack. (15) 
In particular, radiation promotes the release of tumor neoantigens from dying tumor cells which 
enhances MHC class I expression and upregulates chemokines, cell-adhesion molecules, and 
other immunomodulatory cell surface molecules, ultimately triggering an antitumor immune 
response and leads to immunogenic cell death. (16) Further, investigators have shown that the 
expression of programmed cell death ligand-1 (PD-L1), a checkpoint activated by tumor cells to 
evade the immune system, is upregulated in response to radiation in preclinical models of multiple 
tumor subtypes. (17, 18) As such there is increased interest in combining PD-1/PD-L1 
immunotherapy to increase the efficacy of both modalities. 
PD/1-PD-L1-targeted Immunotherapy Is Safely Delivered with Radiation Therapy and Has 
Shown Promising Outcomes in Very Advanced and Metastatic HNSCCs and Is Being 
Tested in the Primary Setting. Multiple clinical trials have established the role of primary PD-
1/PD-L1-targeted immunotherapy in locally advanced, recurrent, and metastatic HNSCCs. (11-
13) Checkmate 141 (19) established the role of nivolumab in the second-line setting and 
compared nivolumab with the investigator¶s choice of standard-of-care (SOC) therapy (weekly 
cetuximab, docetaxel, or methotrexate) for platinum-refractory disease demonstrating a 
significant and durable overall survival (OS) advantage for nivolumab 7.7 months versus 5.1 


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months (HR = 0.68, 95%CI: 0.54-0.86). Similarly, the pembrolizumab-based KEYNOTE-012 (20) 
and KEYNOTE-055 trials (21) showed the efficacy of pembrolizumab in cisplatin-refractory and 
cisplatin- and cetuximab-refractory HNSCC. Additionally, pembrolizumab alone and with 
combination chemotherapy (5-FU and cisplatin) has shown improved overall survival in the first-
line setting for treatment of recurrent and metastatic HNSCC in the KEYNOTE-048 (13) study 
when compared to the prior standard of care EXTREME regimen (platinum, 5-FU and cetuximab). 
More recently, one of these PD-1/PD-L1-targeted agents, atezolizumab, has shown efficacy and 
safety in patients with heavily pretreated HNSCCs, potentially suggesting high levels of efficacy 
in the upfront setting. (22). In this study, 21 patients (66%) experienced a treatment-related 
adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 
TRAE (per CTCAE. No grade 5 TRAEs were reported. This TRAE rate of atezolizumab of 66% in 
this study is favorably comparable to the grade 3+ TRAE rate of 55% reported by pembrolizumab 
in KEYNOTE-048. Further, the grade 3+ TRAE rate of 12.5% is much lower than that of 
pembrolizumab on KEYNOTE-048. Objective responses to atezolizumab by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with 
a median duration of response of 7.4 months (range 2.8-45.8 months), which is comparable to 
the any response rate of 17% on KEYNOTE-048 (13). Median progression-free survival with 
atezolizumab was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 
months (range 0.5-51.6+ months) in a heavily pretreated population.  
Given that PD-1/PD-L1-targeted agents have also been safely delivered with definitive 
radiation therapy in patients with non-metastatic HNSCCs (23, 24) and the known efficacy 
of atezolizumab, we propose testing our novel RT regimen with adjuvant atezolizumab in 
this population, providing excellent local therapy without significantly delaying effective 
systemic therapy for these patients. 
1.3 Study Innovation 
DEHART is a novel framework for delivering RT. The DEHART concept is depicted in Figure 1 
utilizing image data from a patient treated using MRgRT. The image on the left demonstrates the 
initial gross disease burden highlighted in pink (including both the base of tongue primary and left 
level 2 lymph node), the area of subclinical microscopic disease spread highlighted in green and 
the area of elective nodal treatment highlighted in blue. The image on the right is a mid-treatment 
image of the same patient, with the residual gross disease highlighted in pink. Classically, the 
pink area would receive the highest dose of radiation, the green area would receive an 
intermediate dose of radiation and the blue area the lowest therapeutic radiation dose to account 
for the relative amount of potential disease in these areas. In conventional fractionation, this would 
typically include a dose of 70 Gy in 35 fractions (EQD2 of 70 Gy) to the pink area, 60-63 Gy in 35 
fractions (EQD2 of 58.55-61.95 Gy) to the green area, and 54-56 Gy in 35 fractions (EQD2 of 
51.93-54.13 Gy) to the green area. Using DEHART, the pink area would receive a dose of up to 
60 Gy in 15 fractions (EQD2 of 70 Gy), the green area would receive a dose of 45 Gy in 15 
fractions (EQD2 of 48.75 Gy) and the blue area would receive a dose of 40 Gy in 15 fractions 
(EQD2 of 42.2 Gy). Though the relative EQD2 of the intermediate and low dose areas is smaller 
than conventional fractionation, the shorter treatment time (less than half the overall treatment 
time) should make the effective dose similar. 


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Figure 1 DEHART Adapts Radiation Based on Tumor Response. Radiation targets volumes for 
a patient treated using DEHART are depicted both pretreatment (left) and mid-treatment 
(right): the pink outlines gross disease which receives the highest dose of radiation, the 
green outlines subclinical spread which receives an intermediate dose of radiation, and 
the blue outlines microscopic nodal disease which receives an even lower dose of 
radiation. In conventional radiotherapy, target volumes and doses are defined pre-
treatment (left) and remain constant. DEHART adapts the pink volume weekly during 
treatment as tumor regresses, (right) allowing for safe radiation dose escalation by 
dynamically reducing the volume receiving the highest radiation dose to the slowest-
responding areas. 
In addition to the difference in dose and fractionation, the second facet of the DEHART regimen 
is changing target volumes. Using the current treatment paradigm, the pink volume would not 
change throughout treatment and would receive the same uniform dose regardless of tumor 
regression during treatment. DEHART would reduce dose to the area that has regressed (no 
longer depicted in pink in the image on the right) to the intermediate radiation dose received 
by the green volume while maintaining the same radiation dose to the residual pink 
volume. This would allow for safe hypofractionation by sparing toxicity to responding tissues. 
2 HYPOTHESIS, OBJECTIVES, AND ENDPOINTS 
We hypothesize that dose-escalated hypofractionated adaptive radiation therapy (DEHART) to 
60 Gy in 15 fractions is safe and tolerable with adjuvant atezolizumab for locoregional disease in 
HNSCC patients. To test this, we propose a phase I radiation dose-escalation trial with adjuvantt 
atezolizumab in a population of HNSCCs not suitable for conventional seven-week 
chemoradiation (including locally advanced and de novo metastatic patients). This allows us to 
establish the safety of this regimen in patients for whom locoregional therapy is critical. If safe 
and demonstrates a signal of efficacy, this phase I trial will serve as a foundation for future trials 
comparing DEHART with atezolizumab to standard-of-care chemoradiation. 
 
2.1 Primary Objectives 
To determine the maximum-tolerated dose (MTD) of the DEHART regimen delivered with adjuvant 
atezolizumab in patients with locally advanced or de novo metastatic HNSCCs. 
 


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2.2 Secondary Objectives
1. To evaluate the efficacy of the DEHART regimen at one year, as measured by locoregional control 
and overall survival. 
2. To assess gross tumor shrinkage after six and eleven fractions of radiotherapy using the DEHART 
regimen. 
3. To assess patient quality of life during and after the DEHART regimen as measured using multiple 
patient quality-of-life metrics. 
 
2.3 Primary Endpoint 
The primary endpoint of the study is to determine the MTD of the DEHART regimen delivered 
with adjuvant atezolizumab, as determined using a modified TITE-CRM Methodology. 
 
2.4 Secondary Endpoint(s) 
 
1. One-year locoregional control of patients receiving DEHART (efficacy objective). 
2. One-year overall survival of patients receiving DEHART (efficacy objective). 
3. Median and mean percent tumor shrinkage at fractions six and 11 of radiotherapy (tumor 
shrinkage objective). 
4. Tumor shrinkage by RECIST criteria at fractions six and 11 of radiotherapy (tumor shrinkage 
objective). 
5. Temporal changes in the CTCAE version 5.0 scores (quality-of-life objective).  
6. Temporal changes in composite MDASI-HN scores, composite MDADI scores, EAT-10 
questionnaire scores, Functional Oral Intake (FOIS) scores and Dynamic Imaging Grade of 
Swallowing Toxicity (DIGEST) grading (quality-of-life objective). 
7. Temporal changes in quantitative MR parameters including DCE in patients undergoing the 
DEHART regimen. 
8. Genomic and transcriptomic changes during treatment with the DEHART regimen. 
3 STUDY DESIGN 
3.1 General Description 
We propose a pilot phase I study using a Time-to-Event Continual Reassessment (TITE-CRM) 
design to estimate the MTD. Locally advanced (defined as T3-T4NanyM0 or T1-T4 N1-N3M0 or 
locoregionally recurrent after surgery) and de novo metastatic HNSCC patients with no prior 
history of head and neck radiation and a life expectancy of at least 12 months will be enrolled. 
Baseline symptom evaluation will be obtained using validated surveys of head and neck cancer 
patients: the MD Anderson Symptom Inventory for Head and Neck (MDASI-HN) (25) and the MD 
Anderson Dysphagia Inventory for Head and Neck (MDADI-HN). (26) Patients will then undergo 
treatment using DEHART and adjuvant atezolizumab and will then be followed for up to one year. 
 
Cumulative radiation dose to the gross disease is the experimental agent in this study, which will 
be the subject of dose escalation. The MTD will be determined as the radiation dose at which 
there is a 30% rate of dose-limiting toxicity (DLT) up to one year after treatment (to allow for the 
development of late toxicities from radiation). 
 
All patients will receive a 15-fraction course of radiation therapy to the primary disease and 
regional nodes, including an elective nodal field using an adaptive image-guided approach. 


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Radiation will be delivered to the elective neck to a total dose of 40 Gy in 15 fractions, to a 1-cm 
anatomically confined margin on initial gross disease to 45 Gy in 15 fractions and to the 
experimental dose in 15 fractions to gross disease (50 Gy, 55 Gy or 60 Gy) with shrinking volumes 
after every five fractions based on tumor response during therapy. All patients will receive adapted 
MR-guided therapy with replanning prior to the delivery of fraction 6 and fraction 11 of 
radiotherapy. 
 
Patients will undergo standard consultation to receive head and neck radiotherapy for HNSCC 
and will be determined to be eligible for the clinical trial. If eligible, patients will receive informed 
consent about the risks and benefits of the trial and if they accept, will sign confirming their 
enrollment. Additional consent will be obtained for research-specific biopsies and dynamic 
contrast MRI acquisitions. If availale, initial diagnostic biopsy specimens (obtained at the time of 
cancer diagnosis prior to enrollment) will be tested for baseline PD-L1 expression/Combined 
Positive Score per standard testing in anatomic pathology. Patients will then undergo standard 
radiotherapy simulation, including CT simulation with and without IV contrast and MRI simulation 
with and without Gadolinium contrast. Patients will complete baseline MDASI-HN and MDADI 
surveys. Patients will also be followed with a speech and language pathologist (SLP) and undergo 
videofluoroscopic swallow studies (VFSS) prior to treatment, three months after treatment and six 
months after treatment, as is standard of care in the treatment of HNSCCs. At baseline and follow-
up SLP evaluations, patients will also complete the EAT-10 questionnaire and the SLP will 
compute both the Functional Oral Intake Scale (FOIS) score and Dynamic Imaging Grade of 
Swallowing Toxicity (DIGEST) grade. On the day of CT and MR simulation, patients who provided 
optional additional consent will undergo a research biopsy for histologic, genomic and RNA 
analysis. 
 
A radiation treatment plan will be developed as per the proposed DEHART regimen: the 
PTV_High (gross disease plus 3-mm setup margin) will receive the experimental dose in 15 
fractions, the PTV_Intermediate (a 1-cm anatomically confined margin on the gross disease plus 
3-mm setup margin) will receive a dose of 45 Gy in 15 fractions and the PTV_Low (elective lymph 
node regions plus 3-mm setup margin) will receive a dose of 40 Gy in 15 fractions. 
 
Patients will then undergo daily MR-guided radiotherapy on a Monday to Friday basis for a total 
of 15 fractions. MR images will be acquired detailing anatomic and functional data on a daily 
basis. On the day of the six and 11th fractions, MR imaging will be acquired for replanning. A new 
gross tumor volume will be segmented on the MR imaging by the treating physician, and a new 
PTV_High volume will be developed. Anatomically confined changes resulting from weight loss 
or tumor shrinkage will be made to the PTV Intermediate and PTV_Low volumes if necessary. An 
adaptive replan will be made to be delivered to begin on the current fraction for the next five 
fractions.  
During each fraction of MR-guided radiotherapy, MR imaging will be obtained for the patients 
including volumetric T1 and/or T2-weighted sequences for tumor visualization, quantitative T1 
maps, quantitative T2 maps and intravoxel incoherent motion diffusion-weighted imaging (IVIM-
DWI) maps. Additionally, patients who provide additional consent will undergo dynamic contrast 
enhancement (DCE) MR imaging on the day of fractions 5, 10 and 15, which would require IV 
placement and contrast injection. As these patients will receive daily MR-guided radiation 
treatment, we do not anticipate any missing MRI acquisitions. 
During treatment, all patients will be evaluated for acute toxicities at least once every five fractions 
with a physician visit. Additionally, patients will complete repeat MDASI-HN and MDADI surveys 
on the day of treatment review. 


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After completion of the DEHART regimen, patients will receive atezolizumab 1680 mg every 
four weeks up to one year after completion of radiotherapy. Patients will be seen in follow-up at 
the following time points after completion of radiotherapy: weekly for the first four weeks, at 
three months, six months, nine months and 12 months. Patients will complete repeat MDASI-
HN and MDADI surveys to assess for quality-of-life outcomes at each follow-up. Repeat 
imaging, including a PET/CT and diagnostic MRI of the head and neck, will be ordered at the 
three-month follow-up. The diagnostic MRI will assess for anatomic response at the primary site 
and lymph nodes and the PET/CT will be to assess for both locoregional response to treatment 
and distant staging. Based on data from PET-NECK, (27) PET obviates the need for salvage 
neck dissection in patients with PET-negative residual lymph node tissue after definitive 
radiation. Further, PET could determine if there is disease progression outside the head and 
neck. 
 
To assess efficacy of the DEHART regimen, evaluation of locoregional control and overall survival 
will be made by the treating radiation oncologist at each follow-up. Patients will be followed for 
disease control until locoregional progression, completion of the 12-month follow-up period, 
patient refusal or death. 
 
In order to understand the acute and long-term toxicities of the DEHART regimen, patients will be 
followed clinically by the treating radiation oncologist, undergo routine MDASI-HN and MDADI 
surveys, and undergo scheduled SLP visits, including VFSS, EAT-10 questionnaires, FOIS 
scoring and DIGEST grading, as detailed in the prior section. For the purposes of this study, acute 
toxicity will be deemed any toxicity that occurs within 90 days of completion of radiation therapy, 
and late toxicity will be deemed any toxicity that occurs more than 90 days after completion of 
radiation therapy. During each weekly treatment review and each post-treatment follow-up, the 
treating physician will record a pain score (scale 1 to 10) and use the Common Terminology 
Criteria for Adverse Events Version 5.0 (CTCAE) to record toxicity scores for dysphagia, oral 
mucositis, dehydration and weight loss. The treating physician will also record tracheostomy tube 
dependence and feeding tube dependence at each visit. 
 
3.2 Study Completion 
The study will reach study completion approximately 24 months from the time the study opens 
to accrual. 
4 SUBJECT PARTICIPATION, DISCONTINUATION, AND 
WITHDRAWAL  
MCW must follow all MCW IRB requirements and policies regarding subject participation, found 
here: 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
4.1 Subject Status 
Subject statuses throughout the trial are defined as follows:   


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Prescreening: preconsent (subject considering trial or study staff considering patient for 
the trial per institutional recruitment methods). 
 
Screening: period after consent, but prior to eligibility confirmation. 
 
Consented: consented, prior to eligibility confirmation. 
 
Eligible: the local investigator confirms all eligibly criteria apply. 
 
On study/enrolled: date eligibility is confirmed. 
 
On arm: date of enrollment. 
 
On treatment: first day treatment was given to the last day treatment was given. 
 
Off treatment: the last day treatment was given. 
 
On follow-up: from last day of treatment to the end of follow-up period. 
 
Off study: follow-up period completed, with no additional data gathered. 
 
Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off study by the local principal investigator. 
 
4.2 Prescreening and Screening Log 
 
The MCW study principal investigator regularly reviews screen failure reasons to understand 
barriers to accrual and consider amending eligibility criteria. Screen failures are defined as 
participants who were considered for the trial to participate in the clinical trial with or without 
consent, but are not subsequently assigned to the study intervention or enrolled in the study. 
MCWCC CTO will follow its SOPs regarding prescreening and screening tracking. 
 
4.3 Consent  
 
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians, and/or other IRB-approved 
recruitment methods. No study conduct, including subject prescreening, can occur until after IRB 
approval. 
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
4.4 Screening Procedures 
 
Refer to study calendar of events. 
 
Visit procedures that were performed as standard of care prior to consent (without the specific 
intent to make the subject eligible for the trial), may count toward screening tests and eligibility if 
they are within the screening window.  
 
 


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4.5 Eligibility Confirmation
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
No waivers of protocol eligibility will be granted. When clinical factors relating to an eligibility item 
are unclear or questionable, the MCW PI can only provide guidance or clarification on eligibility. 
Any eligibility questions should be directed to Musaddiq Awan, MD (mawan@mcw.edu).  
Inclusion Criteria 
1. Patients 18 years or older with AJCC 8th edition T3-T4 N0-N3 M0 or T0-T4 N1-N3 M0 
squamous cell carcinoma of the head and neck  squamous cell carcinoma of the larynx, 
hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary) with 
measurable disease who meet at least one of the following three criteria: 
a) Not candidates for concurrent bolus cisplatin-based chemoradiation 
therapy, as deemed by a medical oncologist. To ensure patients meet this 
criteria, investigators should complete the online tool at comogram.org 
prior to registration to determine if the patient is eligible. Examples of 
contraindications to cisplatin include but are not limited to: 
o Age  70 with moderate to severe comorbidity or vulnerability to 
cisplatin, defined as having one or more of the following conditions 
within four week of registration: 
 
Modified Charlson Comorbidity Index  1. 
 
ACE-27 Index  1. 
 
 score < 0.80. 
 
G-8 score  14. 
 
CARG Toxicity Score  30%. 
 
CIRS-G Score  4. 
o Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as 
having two or more of the following conditions within four weeks prior to 
registration 
Modified Charlson Comorbidity Index  1. 
 
ACE-27 Index  1. 
 
 score < 0.80. 
 
G-8 score  14. 
 
CARG Toxicity Score  30%. 
 
CIRS-G Score  4. 
o Creatinine clearance < 60 cc/min by the Cockroft-Gault formula. 
o Preexisting peripheral neuropathy. 
o Clinical need for a hearing aid or 25+ decibel shift over two contiguous 
frequencies on a pretreatment hearing test. 
b) Refuse concurrent cisplatin-based chemoradiation therapy. 
c) Have recurrent disease after definitive surgical resection or an unresected 
oral cavity cancer (for which primary surgery is considered standard of 
care) 
 
 
CRC Initials: ___________                                                                  Date: _________________ 
Investigator/Enrolling Physician Initials: ___________                         Date: _________________ 


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2. Or any patient 18 years or older with primary metastatic (AJCC 8th edition T1-T4 N0-N3 M1) 
squamous cell carcinoma of the head and neck. 
3. Zubrod performance status 0±3. 
4. Measurable primary and/or nodal tumor in the head and neck region at the time of radiotherapy. 
5. Patients must have the psychological ability and general health that permits completion of the 
study requirements and required follow-up. 
6. Ability to tolerate multiple MRIs. 
7. Adequate hematologic function within 14 days prior to registration defined as follows: Absolute 
neutrophil count (ANC)  1,500 cells/mm3, platelets  100,000 cells/mm3, hemoglobin  9.0 
g/dl,  lymphocyte count 500/mL. (Note: The use of transfusion or other intervention to achieve 
Hgb  9.0 g/dl is acceptable). Adequate hepatic function within 14 days prior to registration 
defined as follows: AST or ALT  2.5 times institutional upper limit of normal, serum bilirubin  
1.5 x institutional upper limit of normal.  
For patients not receiving therapeutic anticoagulation: INR or aPTT  1.5  ULN 
 
For patients receiving therapeutic anticoagulation: stable anticoagulant regimen 
8. Negative HIV test at screening, with the following exception: patients with a positive 
HIV test at screening are eligible provided they are stable on anti-retroviral therapy, 
have a CD4 count  200/ L, and have an undetectable viral load}.
9. Negative hepatitis B surface antigen (HBsAg) test at screening 
10. Inclusion of Covid-19 positive patients will be based on standard institutional protocol.  
11. Female patients must meet one of the following:  
 
Postmenopausal for at least one year before the screening visit, or  
 
Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), or  
 
If subject is of childbearing potential (defined as not satisfying either of the above two 
criteria), agree to practice two acceptable methods of contraception (combination 
methods require use of two of the following: diaphragm with spermicide, cervical cap 
with spermicide, contraceptive sponge, male or female condom, hormonal 
contraceptive) from the time of signing of the informed consent form through 150 
days after the last dose of study agent, AND 
o Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptom-thermal, post ovulation methods] and withdrawal are not acceptable 
contraception methods). 
12. Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to 
one of the following: 
 
Practice effective barrier contraception during the entire study period and through 150 
calendar days after the last dose of study agent, OR 
 
Must also adhere to the guidelines of any study-specific pregnancy prevention 
program, if applicable, OR 
o Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptom-thermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
13. Ability to understand a written informed consent document, and the willingness to sign it. 
  
CRC Initials: ___________                                                                  Date: _________________ 
 Investigator/Enrolling Physician Initials: ___________                         Date: _________________ 


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Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria is ineligible to participate in 
the study. 
1. Prior invasive malignancy within the past three years (except for non-melanomatous skin cancer, 
and early-stage treated prostate cancer); 
2. Life expectancy less than 12 months 
3. Performance status Zubrod >3. 
4. Inability to encompass all gross disease in 19 cm superior to inferior planning target volume to be 
treated on the MR-linac. 
5. MRI-incompatible foreign body. 
6. Claustrophobia precluding ability to tolerate multiple MRIs. 
7. MRI-incompatible pacemaker or ICD placement. 
8. Patients with cochlear implant. 
9. Patients with prior radiation therapy to the head and neck  Note: Prior external beam 
radiotherapy is excluded, but Iodine 131 is allowed. 
10. Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune 
therapy for the study cancer. 
11. Major surgery within 28 days prior to registration. 
12. Body weight  30 kg. 
13. Any of the following severe laboratory abnormalities within 14 days of registration, unless corrected 
prior to it: sodium < 130 mmol/L or > 155 mmol/L; potassium < 3.5 mmol/L or > 6 mmol/L;  glucose 
< 40 mg/dl or > 400 mg/dl; serum calcium (ionized or adjusted for albumin) < 7 mg/dl or > 12.5 
mg/dl; magnesium < 0.9 mg/dl or > 3 mg/dl. 
14. Unstable angina and/or congestive heart failure requiring hospitalization within three months prior to 
step 1 registration. 
15. Transmural myocardial infarction within three months prior to step 1 registration. 
16. Respiratory illness requiring hospitalization at the time of step 1 registration. 
Note: If the respiratory illness is resolved and the patient meets the eligibility status above, then the 
patient can be considered for the trial. 
17. Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy 
or is thought to require oxygen therapy within one year prior to step 1 registration. 
18. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
19. Clinically apparent jaundice and/or known coagulation defects. 
20. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with 
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).The following are 
exceptions to this criterion: Patients with vitiligo or alopecia; patients with hypothyroidism (e.g., 
following Hashimoto syndrome) stable on hormone replacement; any chronic skin condition that 
does not require systemic therapy; Patients without active disease in the last five years may be 
included but only after consultation with the medical oncology study chair; patients with celiac 
disease controlled by diet alone. 
 
CRC Initials: ___________                                                                  Date: _________________  
Investigator/Enrolling Physician Initials: ___________                         Date: _________________ 
 


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21. History of active primary immunodeficiency including, but not limited to Acquired Immune 
Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude 
patients with AIDS from this protocol is necessary because the treatment involved in this 
protocol may be immunosuppressive.  
22. Current or prior use of immunosuppressive medication within 14 days before registration, with the 
exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological 
doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.   
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti TNF-  
agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic 
immunosuppressive medication during study treatment, with the following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant medication or a one-time 
pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a 
contrast allergy) are eligible for the study after Principal Investigator confirmation has been 
obtained. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study. 
23. Receipt of live attenuated vaccination within 30 days prior to registration. 
24. Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or 
limit compliance with study requirements. 
25. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able 
to use medically acceptable forms of contraception during treatment and for five months after the 
last dose of atezolizumab, this exclusion is necessary because the treatment involved in this study 
may be significantly teratogenic. Women who are breastfeeding are also excluded. 
26. Prior allergic reaction or hypersensitivity to atezolizumab or any of study drug excipients. 
27. History of allogenic stem cell or organ transplantation. 
28. Uncontrolled hypertension. 
29. Uncontrolled cardiac arrhythmia. 
30. Uncontrolled serious chronic gastrointestinal condition associated with diarrhea. 
31. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known 
positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) 
are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
32. History of leptomeningeal disease   
 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with 
further growth (e.g., epidural metastasis that is not currently associated with spinal cord 
compression) should be considered for loco-regional therapy if appropriate prior to enrollment. 
33. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurXâ) are allowed. 
34. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or 
corrected serum calcium > ULN) 
 
CRC Initials: ___________                                                                  Date: _________________  
Investigator/Enrolling Physician Initials: ___________                         Date: _________________ 


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35. Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis: 
 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 
 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study. 
 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the 
study provided all of following conditions are met: 
o Rash must cover < 10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus 
ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, 
or high-potency or oral corticosteroids within the previous 12 months 
36. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac 
disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of 
study treatment, unstable arrhythmia, or unstable angina 
37. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study 
treatment, or anticipation of need for a major surgical procedure during the study 
38. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
o Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study 
treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic 
obstructive pulmonary disease exacerbation) are eligible for the study. 
39. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding 
that contraindicates the use of an investigational drug, may affect the interpretation of the results, or 
may render the patient at high risk from treatment complications 
40. Live, attenuated vaccines (e.g., FluMistâ) 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. 
41. Current treatment with anti-viral therapy for HBV 
42. Treatment with investigational therapy within 28 days prior to initiation of study treatment 
43. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-
CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies 
44. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and 
interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation 
of study treatment 
45. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion 
proteins 
46. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation 
47. Known allergy or hypersensitivity to any component of the chemotherapy formulation 
 
 
CRC Initials: ___________                                                                  Date: _________________  
Investigator/Enrolling Physician Initials: ___________                         Date: _________________ 


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48. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 
months after the final dose of study treatment 
49. Women of childbearing potential must have a negative serum pregnancy test result within 14 days 
prior to initiation of study treatment. 
 
I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible.´ 
_______________________________________         
 
_______________ 
                   (CRC Signature)                                                       
        (Date) 
_____________________________________          
 
_______________ 
   (Investigator/Enrolling Physician Signature)                                        (Date)


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4.6 Discontinuation of Study Treatment, Withdrawal, and Compliance 
Discontinuation from the study treatment does not mean discontinuation from the study. Subject 
will be considered in follow-up, study procedures should still be completed as indicated by the 
study protocol, and AEs/SAEs will continue to be reported according to this protocol. 
 
In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
 
Disease progression.  
 
General or specific changes in the subject¶s condition renders the subject unacceptable 
for further treatment in the investigator¶s judgment.  
 
Inter-current illness that prevents further treatment administration.  
 
Subject decides to withdraw from the study.  
 
The subject has significant noncompliance with the protocol (see below).   
 
Unacceptable adverse event(s) and/or dose level reduction beyond requirements as 
detailed in this protocol.  
 
Study stopping rules are met. 
 
Subjects who sign the informed consent form, enroll and receive the study intervention, but 
subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced.  
 
Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow their IRB 
of record¶s SOPs regarding consent withdrawal.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options the 
subject chooses and document the discussion: 
 
 
Full consent withdrawal, with no study follow-up. 
 
Selective consent withdrawal from interventional portion of the study but agrees to continued 
follow-up of associated clinical outcome information.         
Investigator-initiated Withdrawal 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject¶s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject¶s request to 
end participation, a subject¶s noncompliance or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
 
4.7 Lost to Follow-up 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit and/or is unable to be reached for follow-up: 


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The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
o Three telephone calls (at least one day apart) from the study team are unanswered,  
AND  
o A letter (Appendix 2) to the participant¶s last known mailing address goes unanswered, 
AND 
o These contact attempts must be documented in the participant¶s medical record or 
study file.  
 
Update OnCore® (Follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
 
If a subject is considered lost to follow-up, but subsequently contacts the study team, the 
subject should be considered in follow-up again. 
4.8 Accrual Suspension and Closure 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
 
OnCore® tracks accrual throughout the study. 
 
If the study must be suspended, OnCore® is updated to a ³suspended¶ status.´ 
 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.9 End of Study Definition 
A participant is considered to have completed the study if he or she completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the calendar of events or 
has been discontinued. 
 
4.10 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW study PI, DSMC, sponsor, and/or IRB). Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the MCW principal investigator (PI) will promptly inform the MCW 
Institutional Review Board (IRB), and the sponsor and will provide the reason(s) for the termination 
or suspension. Study participants will be contacted, as applicable, and be informed of changes. 
 
 
 


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5 TREATMENT PLAN
 
5.1 Radiation Therapy 
Radiation therapy will be delivered using MR-guided radiation on a 1.5 T high-field MR-linac using 
intensity-modulated radaition therapy. 
 
5.1.1 Simulation, Localization and Treatment Planning Requirements   
 
Patients must be immobilized using a thermoplastic head mask extending to include neck and 
shoulder immobilization. 
Treatment planning CT and MR images will be required for target volume delineation including 
gross tumor volume (GTVs), clinical target volumes (CTVs) and planning target volumes (PTVs). 
CT will be used for dose calculation. All tissues to be irradiated should be included in the CT and 
MR scan. CT and MR slice thickness should be 2 mm or less 
Treatment planning will be performed so the patient may receive treatment on the 1.5 T high-field 
MR-linac. A backup plan will be generated in case of technical issues to be delivered on a 
conventional linear accelerator.
 
5.1.2 Target Volumes  
MRI images will be segmented by the attending radiation oncologist to define the target volumes 
detailed below:  
 
GTVp: The initial GTVp is defined as all known gross disease determined from clinical information, 
endoscopic examination, MRI and PET images. This will be modified at each weekly replan 
(fraction 6 and fraction 11 of radiotherapy) based on clinical information and MRI images on the 
day of the replan. 
GTVn: The GTVn is defined as all suspicious lymph nodes for disease as determined from clinical 
information, CT, MRI and PET images. This will be modified at each weekly replan (fraction 6 and 
fraction 11 of radiotherapy) based on clinical information and MRI images on the day of the replan. 
CTV_High: The high-dose CTV will be the union of the GTVp and GTVn contours.  
CTV_Int: The intermediate-dose CTV will be a 1-cm anatomically confined margin on the initial 
GTVp and GTVn defined on the treatment planning scan. This will not be modified on replanning 
scans except due to anatomic confinement (i.e., due to shrinkage of a level 2 lymph node that 
displaced the sternocleidomastoid muscle without muscle invasion, the CTV_Int on the replanning 
scan should not extend to include muscle) 
CTV_Low: The low-dose CTV will include any involved lymph node levels and elective lymph node 
radiation based upon the guidelines outlined in Biau et al. (Biau Green Journal 2019). The CTV 
low may be truncated inferiorly to ensure that the entire treatment field may be encompassed in a 
19-cm superior-inferior volume. 
Planning Target Volumes: A margin no larger than 3 mm will be added to the CTV_High, CTV_Int 
and CTV _Low to define the PTV_High, PTV_Int and PTV_Low, respectively for daily changes in 
setup motion.  
 
5.1.3 Critical Normal Tissues 
 
Required critical normal tissues to be segmented (recommended labeling in italics) include: 


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Brainstem (Brainstem). 
 
Spinal Cord (SpinalCord). 
 
Brainstem PRV 5 mm (Brainstem_PRV03). 
 
Spinal Cord PRV 5 mm (SpinalCord_PRV05). 
 
Left (OpticNrv_L) and right (OpticNrv_R) optic nerves. 
 
Optic chiasm (OpticChiasm). 
 
Mandible (Bone_Mandible). 
 
Left (Parotid_L) and right (Parotid_R) parotid glands. 
 
Left (Glnd_Submand_L) and right (Glnd_Submand_R) submandibular glands. 
 
Oral cavity (Oral_Cavity). 
 
Lips (Lips). 
 
Supraglottic and glottic larynx (LarynxGSL). 
 
Pharyngeal constrictors (Pharynx). 
 
Trachea (Trachea). 
 
Esophagus on Slices with the PTV (Esophagus_S). 
 
Left (BrachialPlexus_L) and right (BrachialPlexus_R) brachial plexus. 
 
Patient (Patient). 
 
5.1.4 Radiation Treatment Planning 
 
The treatment plan will be based on the analysis of the volumetric dose, including dose volume 
histogram analyses of the PTVs and critical normal tissues. Adaptive IMRT planning is mandatory. 
Patients will undergo radiation re-planning prior to delivery of the sixth and 11th fractions. 
 
5.1.4.1 Dose Fractionation 
 
Once-daily radiation will be given for 15 fractions. The PTV_High will receive the experimental 
dose (Dexperimental) delivered over 15 fractions (3.33 Gy per fraction at the 50 Gy dose level, 3.66 
Gy per fraction at the 55 Gy dose level and 4.0 Gy per fraction at the 60 Gy dose level); the 
PTV_Int will receive a cumulative dose of 45 Gy over 15 fractions (3.0 Gy / fraction); and the 
PTV_Low will receive a cumulative dose of 40 Gy over 15 fractions (2.66 Gy/fraction). Due to the 
adaptive scheme of the protocol, the volume receiving the experimental dose (PTV_High) may 
decrease after fractions 6 and 11 based on response to treatment. In the case of a rapid complete 
response, there may be no PTV_High volume. 
 
5.1.4.2 Dose Specification 
 
The prescribed dose for each PTV volume should cover at least 95% of the volume. Additionally, 
98% of the prescribed dose for each PTV volume should cover at least 98% of the volume. 
As an acceptable deviation, 95% of the prescribed dose for each PTV volume should cover at 
least 95% of the volume. Additionally, 93% of the prescribe dose for each PTV volume should 
cover at least 98% of the volume. 
 
 
 
 
 


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5.1.4.3 Dose Constraints 
 
Required 
Structure 
Dosimetric 
Parameter 
Per Protocol 
Variation Acceptable 
PTV_High 
D95% 
D98%
Dexperimental 
98% of Dexperimental
95% of Dexperimental 
93% of Dexperimental
PTV_Int 
D95% 
D98% 
45 Gy 
44.1 Gy 
42.75 Gy 
41.85 Gy 
PTV_Low 
D95% 
D98% 
40 Gy 
39.2 Gy 
38 Gy 
37.2 
Patient 
D0.03cc 
106% Dexperimental 
110% Dexperimental 
Spinal Cord 
D0.03cc 
30 Gy 
37.5 Gy 
Brainstem 
D0.03cc 
30 Gy 
37.5 Gy 
SpinalCord_PRV05 
D0.03cc 
37.5 Gy 
45 Gy 
Brainstem_PRV03 
D0.03cc 
37.5 Gy 
45 Gy 
OpticNrv_L or OpticNr D0.03cc 
30 Gy 
37.5 Gy 
OpticChiasm 
D0.03cc 
30 Gy 
37.5 Gy 
Mandible 
D0.03cc 
45 Gy 
108% Dexperimental 
Esophagus 
D0.03cc 
45 Gy 
108% Dexperimental 
Trachea 
D0.03cc 
45 Gy 
108% Dexperimental 
BrachialPlexus_L or 
BrachialPlexus_R 
D0.03cc 
40 Gy 
Dexperimental 
 
Recommended 
Structure 
Dosimetric 
Parameter 
Recommended Constraint 
Mandible 
V30 Gy 
V40 Gy 
< 50% 
< 33% 
Parotid_L or Parotid_R 
Dmean 
22 Gy 
Glnd_Submand_L or 
Glnd_Submand_R 
Dmean 
33 Gy 
Pharynx 
Dmean 
37.5 Gy 
LarynxGSL 
Dmean 
37.5 Gy 
Lips 
D0.03cc 
30 Gy 
Oral Cavity 
Dmean 
25 Gy 
Esophagus 
Dmean 
30 Gy 
 
 
 
 
 
 
 


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5.1.5 Treatment Verification 
Daily CBCT or MRI is required for treatment setup.
 
5.1.6 Daily Anatomic and Functional Imaging 
During each fraction of radiation therapy, anatomic and functional imaging maps will be obtained 
during treatment setup and delivery. The following imaging sequences will be acquired: 
 
 
Volumetric T1 and/or T2-weighted imaging for tumor visualization. 
 
Quantitative T1 maps. 
 
Quantitative T2 maps. 
 
Intravoxel Incoherent Motion Diffusion-Weighted Imaging (IVIM-DWI). 
 
Additionally, if a patient provides additional consent, DCE-MRI will be obtained on the day of 
fraction 5, fraction 10 and fraction 15 of radiotherapy. 
 
Functional imaging will be anonymized and stored on research servers with unique identifiers to 
correlate functional images to treatment outcomes for a secondary analysis of tumor-related 
response. 
 
5.2 Systemic Therapy 
 
Following completion of radiotherapy, atezolizumab 1680 mg will be administered every 28 to 35 
days beginning no earlier than 28 days after the first fraction of radiotherapy. There will be a 
minimum gap of 28 days between doses of atezolizumab initiated after completion of radiotherapy. 
Atezolizumab will continue to be administered up to a total of 12 doses. The last dose of 
atezolizumab will be no later than 365 days after the first fraction of radiotherapy and may be 
discontinued at the discretion of the medical oncologist due to toxicity or disease progression. 
   
5.2.1 Drug Administration and Patient Assessment during Systemic Therapy 
After completing radiation, atezolizumab 1680mg will be administered every 28 days for up to a 
total of 12 doses or until 365 days after initiation of radiation treatment. Routine blood work 
including a CBC, CMP and TSH with reflex T4 will be done with each atezolizumab administration. 
A provider and lab visit will be added to all treatment days. 
 
During the first dose of atezolizumab, no premedication will be given prior to infusion. Vital signs 
(heart rate, respiratory rate, blood pressure and temperature) will be measured within 60 minutes 
prior to infusion. Atezolizumab will be infused over 60 (+/- 5) minutes. If clinically indicated, vital 
signs should be measured every 15 (+/-5) minutes during infusion and at 30 (+/-10) minutes after 
the infusion. Patients will be informed about the possibility of delayed postinfusion symptoms and 
instructed to contact their study physician if they develop such symptoms. 
 
During subsequent atezolizumab infusions, atezolizumab should be administered over 30 (+/- 10) 
minutes if previous infusions were tolerated without infusion reaction and 60 minutes (+/- 10) 
minutes if the patient experienced an infusion reaction to atezolizumab previously. Premedication 


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with antihistamines, antipyretics and/or analgesics may be administered for patients who 
previously experienced an infusion-related reaction to atezolizumab. 
 
A history and physical examination should be performed at study screening and prior to the first 
dose of atezolizumab. This history and physical should include pertinent medical history (including 
clinically significant diseases, surgeries, cancer history (including prior cancer therapies and 
procedures)), reproductive status and social history. All medications including prescription drugs, 
over-the-counter medications, vaccines, herbal/homeopathic remedities and nutritional 
supplements used within seven days prior to beginning therapy with atezolizumab will be 
recorded. A complete physical examination should include vital signs, evaluation of the head, 
eyes, ears, nose, and throat, cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary and neurologic symptoms. Any abnormality identified at baseline 
should be recorded on the general medical history and baseline conditions eCRF. 
Prior to each subsequent dose of atezolizumab, an interval medical history should be obtained 
including changes in medications and allergies and symptom-directed physical examinations 
including vital signs should be performed at specified post-baseline visits and as clinically 
indicated. Changes from baseline abnormalities will be recorded. New or worsened clinically 
significant abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
Physical examinations should include the evaluation of the presence and degree of enlarged 
lymph nodes, hepatomegaly, and splenomegaly. 
 
5.3 Atezolizumab Dose Management and Modifications 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, should be used to evaluate for a possible immunogenic etiology. 
 
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications. Discontinuation of atezolizumab may not have an immediate 
therapeutic effect, and in severe cases, immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive 
agents. 
 
The investigator should consider the benefit versis risk balance a given patient may be 
experiencing prior to further administration of atezolizumab. In patients who have met the criteria 
for permanent discontinuation, resumption of atezolizumab may be considered if the patient is 
deriving benefit and has fully recovered from the immune-mediated event. Patients can be 
rechallenged with atezolizumab only after approval has been documented by the study 
investigator. 
 
5.3.1 Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment. 
 


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All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such 
as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension. Management guidelines for 
pulmonary events are provided in Table 1. 
 
Table 1: Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
Event 
Management 
Pulmonary event, 
Grade 1 
 Continue atezolizumab and monitor closely. 
Re-evaluate on serial imaging. 
Consider patient referral to pulmonary specialist. 
 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. 
 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 study investigator. C,d 
 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 study 
investigator. c 
 Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy 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 
one month. 
 
BAL  bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., almost 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by study 
investigator. 


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b If corticosteroids have been initiated, they must be tapered over one month to the equivalent of 
10-mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. Patients can be rechallenged with atezolizumab 
only after approval has been documented by study investigator. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 
5.3.2 Hepatic Events 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in Table 2. Patients with right upper-
quadrant abdominal pain and/or unexplained nausea or vomiting should have liver function tests 
(LFTs) performed immediately and reviewed before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Table 2: Management Guidelines for Hepatic Events 
 
Event 
Management 
Hepatic event, Grade 
1 
 Continue atezolizumab. 
 Monitor LFTs until values resolve to within normal limits 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. c 
 


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Hepatic event, Grade 
3 or 4 
 
Permanently discontinue atezolizumab. c
 Consider patient referral to gastrointestinal 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. 
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 10-mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be on the investigator¶s benefit risk 
assessment and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over one month to 10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event. The decision to re challenge patients with atezolizumab
should be based on the investigator's benefit risk assessment and documented by the investigator. 
 
5.3.3 Gastrointestinal Events 
 
Immune-mediated colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in Table 3. All events of diarrhea or 
colitis should be thoroughly evaluated for other more common etiologies. For events of significant 
duration or magnitude or associated with signs of systemic inflammation or acute-phase reactants 
(e.g., increased C-reactive protein, platelet count, or bandemia): Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, with three to five specimens for standard paraffin 
block to check for inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
 
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 more than 
seven days. 
Monitor closely. 


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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 around  five days, 
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 study investigator. 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 study investigator. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab and contact study 
investigator. 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 
one 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 requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  one month to the equivalent 
of  10-mg/day oral prednisone before atezolizumab can be resumed. 


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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 re challenge patients with atezolizumab
should be based on the investigator's benefit risk assessment and documented by the investigator. 
 
5.3.4 Endocrine Events 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Management guidelines for endocrine events 
are provided in Table 4. 
 
Patients with unexplained symptoms, such as headache, fatigue, myalgias, impotence, 
constipation or mental status changes, should be investigated for the presence of thyroid, pituitary, 
or adrenal endocrinopathies. The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present. 
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, 
and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from primary adrenal 
insufficiency. 
 
Table 4: Management Guidelines for Endocrine Events 
 
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. c 


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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. c 
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. c 


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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. 
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. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), 
Grade 4 
 Permanently discontinue atezolizumab. 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 


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investigator¶s benefit-risk assessment and in alignment with the protocol requirements for the 
duration of treatment and documented 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-mediated event.  The decision to 
re-challenge patients with atezolizumab should be based on the investigator's 
benefit-risk assessment and documented by the investigator. 
5.3.5 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 study investigator. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact 
study investigator. 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 
one 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 on the investigator¶s benefit risk 
assessment and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 


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


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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 
Error! Reference source not found..  Withhold treatment with atezolizumab for Grade 1 
pericarditis and conduct a detailed cardiac evaluation to determine the etiology and manage 
accordingly.  
Table 6 Management Guidelines for Immune-Mediated Cardiac Events  
 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2 4 
 
Immune-mediated 
pericardial disorders, 
 Permanently discontinue atezolizumab.  
 Refer patient to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, 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. 
 


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5.3.7  INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, 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-1 
or PD-L1 (Rotz et al. 2017; Adashek and Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for the 
medical management of IRRs and CRS are provided in Error! Reference source not found.. 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the inflammatory 
cytokines interleukin (IL)-6, IL-10, IL-2, and IFN-  (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include SARS-CoV-2 infection, 
which should be confirmed or refuted through assessment of exposure history, appropriate 
laboratory testing, and clinical or radiologic evaluations per investigator's judgment.  If a 
diagnosis of SARS-CoV-2 infection 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 1a 
Feverb with or without 
constitutional symptoms 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, 
the infusion rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment,c including maintenance of 
IV fluids for hydration. 
 In case of rapid decline or prolonged CRS (> 2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 


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Grade 2a
Feverb with hypotension 
not requiring vasopressors 
and/or 
Hypoxia requiring low-flow 
oxygend 
by nasal cannula or blow-
by 
 Immediately interrupt atezolizumab 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.e 
 Consider hospitalization until complete resolution of 
symptoms. If no improvement within 24 hours, manage as per 
Grade 3, that is, hospitalize patient (monitoring in the ICU is 
recommended), permanently discontinue atezolizumab. 
 If symptoms resolve to Grade 1 or better for 3 consecutive 
days, the next dose of atezolizumab may be administered. For 
subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 
consecutive days, contact the sponsor-investigator. 
 
 
 


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Grade 3a
Feverb with hypotension 
requiring a vasopressor 
(with or without 
vasopressin) 
and/or 
Hypoxia requiring high-
flow oxygend 
by nasal cannula, face 
mask, non-rebreather 
mask, or venturi mask 
 Permanently discontinue atezolizumab.f
 Administer symptomatic treatment.c
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended. Administer IV fluids as 
clinically indicated and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e
 Hospitalize patient until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 4, that is, 
admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed; for patients who are refractory to anti-cytokine 
therapy, experimental treatments may be considered at the 
discretion of the investigator. 
Grade 4a 
Feverb 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.f 
 Administer symptomatic treatment.c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. Manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 6 hours). 
 Consider anti-cytokine therapy.e For patients who are 
refractory to anti-cytokine therapy, experimental treatmentsg 
may be considered at the discretion of the investigator. 
  Hospitalize patient until complete resolution of symptoms. 
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive 
airway pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway 
pressure; CRS= cytokine-release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR 
= infusion-related reaction; MAS= macrophage activation syndrome. 


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Note: The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE (version as specified in the protocol) should be used when reporting 
severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event 
eCRF. Organ toxicities associated with CRS should not influence overall CRS grading. 
b. Fever is defined as temperature  38°C not attributable to any other cause. In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade). In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at > 6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS 
with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data 
are limited, and the role of such treatment in the setting of antibody-associated CRS has 
not been established. 
f.   Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab according to institutional guidelines and the above table.  For subsequent 
infusions, administer oral premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. Premedication with corticosteroids 
and extending the infusion time may also be considered after considering the benefit-risk 
ratio. 
g. Refer to Riegler et al. [61] for information on experimental treatments for CRS. 
 
5.3.8 Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate 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. 
 
 
 
 
 
 
 
 
 
 
 


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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 study 
investigator. c 
 For recurrent events, permanently discontinue 
atezolizumab and contact study investigator. c 
Immune-mediated 
pancreatitis, Grade 2 
or 3 
 Withhold atezolizumab for up to 12 weeks after event 
onset. a 
 Refer patient to GI specialist. 
 Initiate treatment with 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 study 
investigator. c 
 For recurrent events, permanently discontinue 


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atezolizumab and contact study investigator. c 
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue atezolizumab and contact 
study investigator. 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 one month. 
 
GI = gastrointestinal; 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 agreed upon by the investigator 
and the study investigator. 
b If corticosteroids have been initiated, they must be tapered over one 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 re challenge patients with 
atezolizumab should be based on the investigator's benefit risk assessment and documented by 
the investigator.


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5.3.9 Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of 
rash were mild in severity and self-limited, with or without pruritus. 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. 
Table 9: Management Guidelines for Dermatologic Events 
 
Event 
Management 
Dermatologic 
event, Grade 1 
Continue atezolizumab. 
 Consider treatment with topical corticosteroids and/or 
other symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2 
 Continue atezolizumab. 
 Consider patient referral to dermatologist. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical 
corticosteroids if event does not improve. 
 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. 
 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 study investigator. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue atezolizumab and contact 
study investigator. c 
Stevens-Johnso
n 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 
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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 agreed upon the study investigator.b 
If corticosteroids have been initiated, they must be tapered over one 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 re challenge patients with atezolizumab should be based on the 
investigator's benefit risk assessment and documented by the investigator.


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5.3.10 Neurologic Disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic 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-mediated 
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. c 
 For facial paresis: 
± 
If event resolves fully, resume atezolizumab b 
 If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab. c
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 
3 or 4 
 Permanently discontinue atezolizumab. c  
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab. 
 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 agreed upon by the 
investigator and the study investigator. 


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b If corticosteroids have been initiated, they must be tapered over  one 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 re challenge patients with 
atezolizumab should be based on the investigator's benefit risk assessment and documented by 
the investigator. 
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. 
5.3.11 Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 11. 
 
 
 
 
 
 
 


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Table 11: Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab and contact study 
investigator.  
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 
 one month. 
5.3.12 Renal Events 
Immune-mediated nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function. Renal function, including serum creatinine, should 
be monitored throughout study treatment. Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies(including prerenal and postrenal causes, 
and concomitant medications such asnon-steroidal anti-inflammatory drugs). Refer the patient to 
a renal specialist if clinically indicated. A renal biopsy may be required to enable a definitive 
diagnosis and appropriate treatment. Patients with signs and symptoms of nephritis, in the 
absence of an identified alternate etiology, should be treated according to the guidelines in Table 
12. 
Table 12: Management Guidelines for Renal Events
Event 
Management 
Renal event, 
Grade 1 
Continue atezolizumab. 
 Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 1±2 
mg/kg/day oral prednisone. 
 If event resolves to grade 1 or better, resume atezolizumab. b 
 If event does not resolve to grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
study investigator. c 


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Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact study 
investigator. c
Refer patient to renal specialist and consider renal biopsy. 
Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
If event resolves to grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10-mg/day oral prednisone. 
The acceptable length of the extended period of time must be based on the investigator¶s benefit 
risk assessment and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over  one 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 re challenge patients with 
atezolizumab should be based on the investigator's benefit risk assessment and documented by 
the investigator. 
5.3.13 Immune-Mediated Myositis 
Immune-mediated myositis has been associated with the administration of atezolizumab. Myositis 
or inflammatory myopathies are a group of disorders sharing the common feature of inflammatory 
muscle injury; dermatomyositis and polymyositis are among the most common disorders. Initial 
diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging (electromyography/MRI) features, 
and is confirmed with a muscle biopsy. Patients with signs and symptoms of myositis, in the 
absence of an identified alternate etiology, should be treated according to the guidelines in Table 
13. 
 
Table 13: Management Guidelines for Immune-Mediated Myositis 
 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 


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Immune- mediated 
myositis, Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Study investigator. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 
1±2 mg/kg/day IV methylprednisolone and convert to 
1±2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
 If event resolves to grade 1 or better, resume atezolizumab. b 
 If event does not resolve to grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact study investigator. c 
Immune- mediated 
myositis, Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a 
and contact study investigator. 
 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 Study investigator. c 
 For recurrent events, treat as a grade 4 event. 


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Immune- mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab and contact study 
investigator. 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  
one month. 
a Atezolizumab may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of 10-mg/day oral prednisone. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
study investigator.b If corticosteroids have been initiated, they must be tapered over one 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 re challenge patients with 
atezolizumab should be based on the investigator's benefit risk assessment and documented by 
the investigator. 
 
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: 
±     
Hemoglobin <90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
±     
Platelet count < 100  x 109/L (100,000/ L)
±     
ANC < 1.0 x 109/L (1000/ L) 
Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L (150 mg/dL) 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
Low or absent natural killer cell activity 
Ferritin > 500 mg/L (500 ng/mL)


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Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as having 
MAS if the following criteria are met: 
Ferritin > 684 mg/L (684 ng/mL)
At least two of the following: 
±     
Platelet count 181 x 109/L (181,000/ L) 
±
AST 
48 U/L
±     
Triglycerides > 1.761 mmol/L (156 mg/dL) 
±     
Fibrinogen 
 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 14.
Table 14 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
 
Event 
Management
Suspected HLH or 
MAS 
Permanently discontinue atezolizumab and contact Medical Monitor.
Consider patient referral to hematologist. 
Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
Consider initiation of IV corticosteroids and/or an immunosuppressive agent. 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
References 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti programmed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:502 4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:190 6. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465 77. 


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Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release 
syndrome and neurologic toxicity associated with immune effector cells. Biol Blood 
Marrow Transplant 2019;25:625 38. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. 
Up to Date [resouce on the Internet]. 2014 [updated 29 October 2018; cited: 17 May 
2019]. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-
of-hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:355 62. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:481 9. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 
2019;15:323 35. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving PD-1-
directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 
Blood 2015;125:2908 14. 
5.4 Dietary Restrictions 
 
None. 
 
5.5 Monitoring Subject Compliance  
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Comprehensive instructions will be provided to the 
patient in order to ensure compliance with treatment.  
 
5.6 Acquisition of Tumor Specimens 
For patients who provide additional consent, tumor biopsies will be performed prior to any 
treatment on either the day of CT or MR simulation, on the day of the fifth fraction of radiotherapy, 
on the day of the fifteenth fraction of radiotherapy and at the time of locoregional recurrence (if 
applicable). Biopsies will be performed in the clinics under local anesthesia. Tumor from each 
biopsy will be placed in sterile conical tubes filled with prechilled (4°C) CO2 independent media 
(Gibco Cat#: 18045-088) supplemented with 1X antibiotic/antimycotic (Gibco #15240-096). These 
specimens will be immediately transported to Dr. Himburg¶s laboratory for storage and later 
analysis. A portion of each biopsy specimen may be cryopreserved for additional future potential 
in vitro multi-omic correlative studies. These biopsies will allow for the evaluation of genomic and 
transcriptomic changes in the tumor microenvironment resulting from treatment in the DEHART 


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regimen and markers of therapeutic resistance in the recurrent specimens which may provide 
data for novel therapeutic avenues to combine with DEHART. 
6 ADVERSE EVENTS: DEFINITIONS, COLLECTION  AND REPORTING 
REQUIREMENTS 
 
6.1 Definitions 
6.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonisation [ICH], E2A, E6). 
This includes the following: 
 
Adverse events not previously observed in the subject that emerge during the protocol-
specified adverse event reporting period, including signs or symptoms associated with 
head and neck cancer that were not present prior to the adverse event reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations)  
 
If applicable, adverse events 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 adverse event reporting period. 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0, located on the CTEP web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures. 
 
6.1.2 Serious Adverse Event (SAE)  
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
 
Death. Results in death. 
 
Life-threatening. Is life-threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 


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Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person¶s ability to conduct normal life 
functions). 
 
Pregnancy 
 
Congenital anomaly/birth defect: Results in a congenital anomaly/birth defect in a 
neonate/infant born to a mother exposed to the IMP. 
 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
6.1.3 Assessment of Severeity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for assessing 
adverse event severity. The below table should be used for assessing severity for adverse events 
that are not specifically listed in the NCI CTCAE. 
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 


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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. 
6.1.4 Attribution of an Adverse Event 
All AEs and SAEs whether volunteered by the subject, 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. 
An assessment of the relationship between the adverse event and the medical intervention, using 
the following categories:  
Definitely Related: The AE is clearly related to the intervention. There is clear evidence to 
suggest a causal relationship, and other possible contributing factors can be ruled out.  
Probably Related: The AE is likely related to the intervention. There is evidence to suggest a 
causal relationship, and the influence of other factors is unlikely.  
 
Possibly Related: The AE may be related to the intervention. There is some evidence to suggest 
a causal relationship (e.g., the event occurred within a reasonable time after administration of the 
trial intervention). However, the influence of other factors may have contributed to the event (e.g., 
the subject¶s clinical condition, other concomitant events).  
 
Unlikely: The AE is doubtfully related to the intervention. A clinical event, including an abnormal 
laboratory test result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after administration 


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of the trial intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject¶s clinical condition, other concomitant treatments).  
Unrelated: The AE is clearly NOT related to the intervention. The AE is completely independent 
of study intervention, and/or evidence exists that the event is definitely related to another etiology.  
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline:  
Yes: Related (definitely, probably, possibly, unlikely) 
There is a plausible temporal relationship between the onset of the AE and administration of the 
atezolizumab and/or radiotherapy and the AE cannot be readily explained by the subject¶s clinical 
state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of 
response to the study drug or with similar treatments; and/or the AE abates or resolves upon 
discontinuation of the atezolizumab and/or radiation therapy or dose reduction and, if applicable, 
reappears upon rechallenge. 
No: Not Related (unrelated)  
Evidence exists that the AE has an etiology other than the atezolizumab and/or radiation therapy 
(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 two days after first dose of study drug). 
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
6.1.5 Expectedness of an Adverse Event 
Study investigator or treating physician will be responsible for determining whether an AE is 
expected or unexpected as indicated in the protocol, informed consent form and/or drug 
information brochure. Expected adverse events of atezolizumab are those adverse events that 
are listed or characterized in the package insert (PI) or current investigator brochure (IB). 
  
Unexpected adverse events of atezolizumab are those not listed in the PI or current IB or not 
identified that are not attributable to radiotherapy. This includes adverse events for which the 
specificity or severity is not consistent with the description in the PI. or IB. For example, under 
this definition, hepatic necrosis would be unexpected if the PI or IB only referred to elevated 
hepatic enzymes or hepatitis. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is NOT consistent with the risk information previously described for the 
study intervention (atezolizumab and/or radiotherapy). 
6.2 Collection and Reporting Requirements for Adverse Events and Serious Adverse   
      Events 
6.2.1 Collection of Adverse Events 
All (or specify if only certain grade AE needed) adverse events (including SAEs) must be recorded 
in OnCore® and/or an adverse event log. All AEs required to be collected must be graded 


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according to the CTCAE v5. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. Investigator¶s or treating physician¶s 
assessment of AE attributions must also be documented.  
AEs will be collected from the time the subject signs the consent form through completion of the 
entire 12-month follow-up period. After this period, investigators should only report SAEs that are 
attributed to prior study treatment. AEs will be tracked and followed until resolution, subject 
withdraws consent, or is lost to follow-up (including subjects who discontinue early). All adverse 
events collected per the protocol will be followed with appropriate medical management until they 
are resolved, if they are related to the study treatment, or until the investigator deems the event 
to be chronic.  
Please see section 6.2.2 and table 14 to identify the adverse events that need to be reported.  
6.2.2. Procedures for eliciting, recording, and reporting adverse events 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be 
adopted. Examples of non-directive questions include: 
      
³How have you felt since your last clinical visit?´ 
      
³Have you had any new or changed health problems since you were last 
here?´ 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
6.2.2.1  Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, it is 
acceptable to report the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
6.2.2.2  Deaths 
All deaths that occur during the protocol-specified AE reporting period (see section I), 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 ³Unexplained Death.´  
6.2.2.3  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 
reassessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 


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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., ³more frequent headaches´). 
6.2.2.4  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 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  
6.2.2.5  Pregnancy  
If a female subject becomes pregnant while receiving the study drug or five months after the last 
dose of study drug, 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 as an SAE. Similarly, any congenital anomaly/birth defect in a child born to a female 
subject exposed to the study drug should be reported as an SAE.  
6.2.2.6  AEs of Special Interest (AESIs)  
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. 
Adverse events of special interest for this study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy¶s law: 
 
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 
 
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an 
infectious agent. A transmission of an infectious agent may be suspected from clinical 


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symptoms or laboratory findings that indicate an infection in a patient exposed to a 
medicinal product. This term applies only when a contamination of the study drug is 
suspected  
The Events of Special Interest specific to atezolizumab are: 
 
Systemic lupus erythematosus. 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release 
syndrome, macrophage activating syndrome and 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). 
 
Myelitis 
 
Facial paresis 
6.2.2.7  Other Special Situations Reports  
The following other Special Situations Reports should be collected even in the absence of an 
adverse event and transmitted to Genentech: 
 
 
Data related to the product usage during breastfeeding. 
 
Data related to overdose, abuse, misuse or medication error (including potentially exposed 
or intercepted medication errors). 
 
In addition, reasonable attempts should be made to obtain and submit the age or age 
group of the patient, in order to be able to identify potential safety signals specific to a 
particular population. 
6.2.2.8 Product complaints  
A product complaint is defined as any written or oral information received from a complainant that 
alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial.    
6.2.2.9 Post-Study Adverse Events  
For studies involving extended follow-up period, the investigator after the end of the adverse event 
reporting period should report all deaths, (regardless of cause), and any serious adverse event 
including development of cancer or a congenital anomaly in a subsequently conceived offspring 
of a female subject who participated in the study that is believed to be related to prior exposure 
to study drug. 
Case transmission verification will be performed by both parties during this period to ensure 
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6.2.3 Reporting of Adverse Events and Serious Adverse Events 
Sponsor-investigator will be responsible for collecting all protocol-defined adverse events 
(AEs)/serious adverse events (SAEs), pregnancy reports, other special situation reports, AESIs 
and product complaints with an AE where the patient has been exposed to the investigational 
product 
Please refer to table 15 below to identify adverse events that meet reporting requirements.  
 
All serious adverse events (SAEs) must also be documented in OnCore®. 
 
Table 15 
 
1. Guidance on adverse event reporting to the IRB is available online at MCW IRB Policies and 
Procedures.  
2. For expedited DSMC reporting, study coordinator/research nurse must notify the DSMC via 
email including the subject ID, date of event, grade, relatedness, expectedness, and a short 
narrative. DSMC will review data entered into OnCore®.  
3. For routine reporting, the events will be reported to IRB as part of the annual continuing 
progress report and the DSMC will review data entered into OnCore® at the time of scheduled 
monitoring. 
4. Fatal or life-threatening SAEs meeting the criteria indicated in the above table will be reported 
to FDA no later than seven calendar days after study staff¶s initial awareness of the event. If 
the SAE is not fatal or life-threatening and meets the above criteria, the timeline for submitting 
an IND safety report to FDA is no later than 15 calendar days after study staff¶s initial 
awareness of the event. See section 6.2.3 for detailed reporting instructions.
 
 
Attribution 
SAE 
AE 
Grade 1, 2 & 3 
Grade 4 and 5 
Grade 3 
Grade 4  
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 
Unrelated 
Unlikely 
IRB1 and 
DSMC2- 
Routine 
Review3
 
 
 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
DSMC2- 
Routine 
Review3 
DSMC2- 
Within 5 
calendar 
days 
DSMC2- 
Within 5 
calendar 
days 
Possible 
Probable
Definite 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 
 
 
 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 


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6.2.3.1 Exchange of Single Case Reports with Genentech 
All protocol-defined adverse events (AEs)/serious adverse events (SAEs), pregnancy reports, 
other special situation reports, AESIs and product complaints with an AE where the patient has 
been exposed to the product must be reported to Genentech. The Council for International 
Organizations of Medical Sciences (CIOMS) forms should be sent to the Genentech contact 
specified below. Transmission of these reports (initial and follow-up) will be either electronically 
via email or by fax and within the timelines specified below: 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
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: 
Serious Adverse Drug Reactions (SADRs) 
30 calendar days of the awareness date 
Other SAEs 
30 calendar days of the awareness date. 
Special Situation Reports (Pregnancy) 
Special Situation Reports (Other) 
30 calendar days of the awareness date. 
30 calendar days of the awareness date. 
Product Complaints 
30 calendar days of the awareness date. 
AESIs 
30 calendar days of the awareness date. 
 
Serious Adverse Drug Reactions (SADRs) 
Serious AE reports that are related to the product or where the causality is assessed as unknown 
or not provided shall be transmitted to Genentech within 30 calendar days of the awareness date.  


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Other SAEs 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within 30 
calendar days of the awareness date. 
 
Special Situation Reports 
o Pregnancy reports 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as 
defined herein, any reports of pregnancy, where the fetus may have been exposed to 
the product, shall be transmitted to Genentech within 30 calendar days of the 
awareness date. Pregnancies will be followed up until the outcome of the pregnancy 
is known, whenever possible, based upon due diligence taken to obtain the follow-up 
information. 
 
o Other special situation reports, as defined above, shall be transmitted to Genentech 
within 30 calendar days of the awareness date. 
 
 
Product Complaints 
All product complaints (with or without an AE) shall be forwarded to Genentech within 30 calendar 
days of the awareness date.  
 
AESIs  
AESIs requiring expedited reporting (related or possibly related to Genentech product or where 
the causality is assessed as unknown or not provided) shall be forwarded to Genentech within 30 
calendar days  
6.2.3.2. Case Transmission Verification of Single-Case Reports 
The sponsor agrees to conduct the case transmission verification to ensure that all single-case 
reports have been adequately received by Genentech via sponsor-investigator emailing 
Genentech a quarterly line-listing documenting single case reports sent by sponsor-investigator 
to Genentech in the preceding time period.  
The periodic line-listing will be exchanged within seven calendar days of the end of the agreed 
time period. Confirmation of receipt should be received within the time period mutually agreed 
upon.                 
If discrepancies are identified, the sponsor and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a case-by-
case basis until satisfactory resolution. The sponsor shall receive reconciliation guidance 
documents within the µActivation Package.¶ 
Following case transmission verification, single-case reports which have not been received by 
Genentech shall be forwarded by sponsor-investigator to Genentech within five calendar days 
from request by Genentech. 


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At the end of the study, a final cumulative case transmission verification report will be sent to 
Genentech. 
6.2.4 Reporting Instructions  
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
Sponsor 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. 
 
Sponsor 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. 
 
Sponsor 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. 
 
Sponsor investigator will be responsible for the distribution of safety information to its own 
investigators, where relevant, in accordance with local regulations. 
 
Food and Drug Administration  
An IND safety report will be submitted for any adverse event that meets all three 
definitions: possibly related to the study drug, unexpected, and serious. If the adverse 
event does not meet one of the above definitions, it should not be submitted as an 
expedited IND safety report.  
7 Calendar Day Telephone or Fax Report 
  
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the Investigator to be possibly related to the use of 
atezolizumab. An unexpected adverse event is one that is not already described in the 
atezolizumab Investigator Brochure. Such reports are to be telephoned or faxed to the 
FDA and Genentech within 7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably 
or possibly related to the use of atezolizumab. An unexpected adverse event is one that 
is not already described in the atezolizumab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the 
IND concerning similar events should be analyzed and the significance of the new report 
in light of the previous, similar reports commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of 
the event. The FDA prefers these reports on a MedWatch 3500 form, but alternative 
formats are acceptable (e.g., summary letter). 


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Any relevant additional information that pertains to a previously submitted IND safety 
report will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon 
as the information is available (21 CFR 312.32(d)(2)).  
Suggested Reporting Form: 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm  
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed 
to Genentech Drug Safety: 
  
Fax: (650) 225-4682 or (650) 225-4630 
Email: usds_aereporting-d@gene.com 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
  
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
6.2.4.1 Aggregate Reports 
All IND annual reports submitted to the FDA by the sponsor-investigator should be copied to 
Genentech 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box: ctvist_drugsafety@gene.com  
6.2.4.2 Other Reports 
Sponsor-investigator will forward a copy of the final study report to Genentech upon completion 
of the study. 
 
6.3 Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website.  
6.4 Subject Complaints 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can call the 
Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. 
This information is provided to the subject in their consent.  


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A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who identify 
a potential product complaint situation should immediately contact the drug manufacturer and 
report the event. Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a drug manufacturer representative. 
Product complaints in and of themselves are not reportable events. If a product complaint results 
in an SAE, an SAE form should be completed. 
6.5 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: ctvist_drugsafety@gene.com 
6.6 Queries 
Queries related to the study will be answered by sponsor-investigator. However, responses to all 
safety  queries  from  regulatory  authorities  or  for publications will be discussed and coordinated 
between the parties. The parties agree that Genentech shall have the final say and control over 
safety queries relating to the product. Sponsor-investigator agrees that it shall not answer such 
queries from regulatory authorities and other sources relating to the product independently but 
shall redirect such queries to Genentech.  
Both parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required.  
6.7 Safety Crisis Management  
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), 
on the conduct of the study, may lead to labeling changes or regulatory actions that limit or restrict 
the way in which the product is used, or where there is media involvement, the party where the 
crisis originates will contact the other Party as soon as possible.  
The parties agree that Genentech shall have the final say and control over safety crisis 
management issues relating to the product. Sponsor-investigator agrees that it shall not answer 
such queries from media and other sources relating to the product but shall redirect such queries 
to Genentech. 
 


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6.8 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 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.
7 PHARMACEUTICAL INFORMATION 
Atezolizumab 
 
7.1 Product description  
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which 
function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell 
responses, resulting in improved anti-tumor activity (PMID: 26970723). Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution at position 298 
on the heavy chain, which results in a non-glycosylated antibody that has minimal binding to Fc 
receptors and, consequently, eliminates detectable Fc effector function. By eliminating Fc-effector 
function and antibody-dependent cell-mediated cytotoxicity, antibody-mediated clearance of 
activated effector T cells is also eliminated. Atezolizumab shows anti-tumor activity in both 
nonclinical models and patients with cancer and is being investigated as a potential therapy in a 
wide variety of malignancies. Atezolizumab is being studied as a single agent in the advanced 
cancer and adjuvant therapy settings, as well as in combination with chemotherapy, targeted 
therapy, and cancer immunotherapy. Atezolizumab is approved in approximately 90 countries for 
one or more of the following indications: non small cell lung cancer (NSCLC), extensive-stage 
small-cell lung cancer, hepatocellular carcinoma and alveolar soft part sarcoma. 
 
Atezolizumab targets programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (ICs) 
or tumor cells (TCs) and prevents interaction with the programmed death-1 (PD-1) receptor and 
B7.1 (CD80), both of which function as inhibitory receptors expressed on T cells and other 
immune cells. Interference of the PD-L1:PD-1 and PD-L1:B7.1 interactions may enhance the 


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magnitude and quality of the tumor-specific T cell response through increased T cell priming, 
expansion, and/or effector function. 
7.2 Physical, Chemical, Pharmaceutical Properties and Clinical Formulation of 
Atezolizumab 
For intravenous administration, atezolizumab is provided in 20-mL (Formulation 1200mg every 3 
week), and 15-mL (Formulation 840 mg every 2week) glass vials. All Formulations are in a 
solution containing histidine acetate, sucrose, and polysorbate 20. 
 
7.3 Pharmacology 
 
Pharmacokinetics and pharmacodynamics data of Atezolizumab have been analyzed from the 
following atezolizumab monotherapy studies: PCD4989g (22), J028944 (28), IMvigor210 (29), 
IMvigor211 (30), BIRCH (31), POPLAR (32), FIR 29775807 (33), and OAK (34).  
An analysis of 906 patients (35) from two phase I and one phase II metastatic urothelial cancer 
studies (PCD4989g (22), J028944 (28),  IMvigor210 (29)) were the first to report the clinical 
pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited 
linear PK over a dose range of 1±20 mg/kg, including the labelled 1,200 mg dose. The clearance, 
volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) 
analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. The 
PopPK analysis suggested that steady state was obtained after 6 to 9 weeks (2 to 3 cycles) of 
repeated dosing. The systemic accumulation in the area under the concentration-time curve 
(AUC), maximum concentration (Cmax), and trough concentration (Cmin) were 1.91, 1.46, and 
2.75-fold, respectively, following q3w intravenous (IV) administration of 1200 mg atezolizumab.  
Based on an analysis of exposure-safety and exposure-efficacy data, the following factors had no 
clinically relevant effect: age (21-89 years), body weight, sex, positive ADA status, albumin levels, 
tumor burden, region or ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 
expression, or Eastern Cooperative Oncology Group (ECOG) status. The effect of moderate or 
severe hepatic impairment on the pharmacokinetics of atezolizumab is unknown. 
7.4 Assessment of Safety of Atezolizumab 
Safety findings of single agent atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of atezolizumab and 
the underlying disease. Overall, treatment with atezolizumab is well tolerated with a manageable 
adverse event profile. Currently, no MTD, no DLTs, and no clear dose-related trends in the 
incidence of adverse events (AEs) have been determined. Among 3178 patients treated with 
single-agent atezolizumab for whom pooled safety data are available the most commonly reported 
AEs (around 10%) included fatigue, decreased appetite, nausea, cough, dyspnea, constipation, 
pyrexia, diarrhea, anemia, back pain, vomiting, asthenia, arthralgia, pruritus, rash, headache, 
urinary tract infection, and peripheral edema. 
 
Immune-mediated AEs are consistent with the role of the PD-L1/PD-1 pathway in regulating 
peripheral tolerance. Given the mechanism of action of atezolizumab, events associated with 
inflammation and/or immune-mediated AEs are closely monitored during the atezolizumab clinical 
program. Immune-mediated AEs associated with atezolizumab include pneumonitis, hepatitis, 
colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, 
hypophysitis, 
Guillain-Barré 
syndrome, 
myasthenic 
syndrome/myasthenia 
gravis, 


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meningoencephalitis, myocarditis, nephritis, and myositis. Guidance regarding the management 
of immune-mediated AEs is provided in Section 5.2. 
7.4.1 Safety Plan  
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. 
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 and radiation 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 interruption or discontinuation, are provided in 
Section 5.2. 
7.4.2 Risks Associated with Atezolizumab  
Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, meningoencephalitis, myocarditis, nephritis, myositis and severe cutaneous 
adverse reactions. Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Refer to Section 5.2 
of the protocol for a detailed description of anticipated safety risks for atezolizumab. 
 
7.4.3 Safety Parameters and Definitions  
 
Safety assessments will consist of monitoring and recording adverse events, including serious 
adverse events and adverse events of special interest, performing protocol-specified safety 
laboratory assessments, measuring protocol-specified vital signs, and conducting other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
7.4.4 Adverse Events of Special Interest (Immediately Reportable to the investigators 
For patients receiving active treatment with atezolizumab, adverse events of special interest are 
required to be reported. Please refer to section 6.2.2.6 for adverse events of special interest for 
this study. 
7.5 Formula 
Atezolizumab is a fully humanized IgG1 isotype antibody against the programmed cell death-
ligand 1 (PD-L1). Atezolizumab is a commercially available drug and will be supplied at no cost 
by Genentech, Inc. 
7.6 Supply 
Atezolizumab is a commercially available drug and will be supplied at no cost by the manufacturer 
Genentech, Inc. 


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7.7 Physical and Chemical Properties 
       Late Phase I/II, Phase III, and Commercial Material 
Generic name 
Atezolizumab 
 
 
 
 
Chemical name 
Humanized monoclonal antibody 
 
 
based on a human IgG1 
 
 
framework containing heavy chain  
 
VH
sequences. 
 
Chemical structure 
The recombinant antibody 
consists 
 
of two heavy chains and two light 
 
 
chains with inter and intra chain 
 
 
disulfide bonds that are typical of
 
IgG1 antibodies. 
 
Molecular weight 
150 KD 
 
Description 
Colorless to slightly yellow 
solution 
 
Atezolizumab lacks the N-linked oligosaccharides typically observed on other CHO-derived 
monoclonal antibodies because it incorporates an amino acid substitution (asparagine to alanine) 
at position 298 in the CH2 domain of each heavy chain, resulting in a non-glycosylated antibody. 
This non-glycosylated antibody has minimal binding to Fc  receptors and, consequently, prevents 
Fc-effector function and depletion of cells expressing PD-L1 at expected concentrations in 
humans. 
7.8 Clinical formulation 
 
The manufacture of atezolizumab drug substance consists of cell culture, harvest, and 
purification. Please find the dose formulations and vial configurations in the table below. Results 
from a study by Morrissey et Al support the interchangeable use of 840 mg q2w, 1200 mg q3w, 
and 1680 mg q4w dosing regimens for atezolizumab, as they are anticipated to demonstrate 
comparable efficacy and safety profiles while offering patients greater flexibility and convenience 
in their treatment. (36) 
 
 
Phase III/ Commercial Drug 
Product (F03) 
Phase III/ Commercial 
Drug Product (F05) 
Administration 
Intravenous 
Intravenous 
Appearance 
Colorless-to-slightly-yellow 
preservative-free 
clear liquid solution 
Colorless-to-slightly-yellow 
preservative-free clear 
liquid solution 
Concentration of 
Ateozlizumab 
60 mg/mL 
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Nominal 
Atezolizumab 
Amount per Vial 
1200 mg 
840 mg 
Other Excipients 
Histidine acetate 
buffered at pH 5.8 
containing sucrose 
and polysorbate 20 
Histidine acetate 
buffered at pH 5.8 
containing sucrose 
and polysorbate 20 
Primary Packaging 
20 mL glass vial 
15 mL glass vial 
Extractable Volume 
20.0 mL 
14.0 mL 
Atezolizumab drug products must be refrigerated at 2°C-8°C (36°F-46°F) upon receipt until use. 
Atezolizumab and the diluent vials should not be used beyond the expiration date provided by the 
manufacturer. No preservative is used in the atezolizumab Drug Product or the diluent; therefore, 
the vial is intended for single use only. Discard any unused portion of drug remaining in a vial. 
Vial contents should not be frozen or shaken and should be protected from light by keeping the 
vial in the outer carton. 
For intravenous administration, atezolizumab in Formulation F03 or F05 will be administered in 
IV infusion bags containing 0.9% sodium chloride (NaCl) and infusion lines equipped with 0.2 or 
0.22 
m in-line filters. The IV bag may be constructed of polyvinyl chloride, polyolefin or 
polyethylene, the IV infusion line may be constructed of polyvinyl chloride, polyethylene, or 
polybutadiene and the 0.2 or 0.22 m in-line filter may be constructed of polyethersulfone or 
polysulfone. The use of administration supplies composed of materials other than those listed 
should be avoided if possible. Atezolizumab can be diluted to concentrations between 3.2 mg/mL 
and 16.8 mg/mL in IV bags containing 0.9% NaCl. Atezolizumab must be prepared/diluted under 
appropriate aseptic conditions as it does not contain antimicrobial preservatives. The prepared 
solution for infusion should be used immediately to limit microbial growth in case of potential 
accidental contamination. If not used immediately, in-use storage time and conditions prior to use 
are the responsibility of the user. For flat or fixed dosing (e.g., 840 mg, 1200 mg, or 1680 mg) in 
IV infusion bags, the dose solution may be stored at 2°C-8°C (36°F-46°F) for 24 hours or at 
ambient temperature  25°C (77°F) for 8 hours.
8 STATISTICAL CONSIDERATIONS 
8.1 Study Design 
This is a Phase I dose-escalation trial of radiation dose using a novel radiation treatment regimen 
called DEHART. The primary objective of the study is to determine the maximum tolerated dose 
(MTD) of the DEHART regimen using the Time-to-Event Continual Reassessment Methodology 
(TITE-CRM). The MTD will be determined as the radiation dose at which there is a 30% rate of 
dose-limiting toxicity (DLT) up to 12 months after completion of radiation treatment (to allow for 
the development of late toxicities from radiation treatment). There will be three cumulative 
radiation dose levels to gross disease: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 
15 fractions. The total sample size for this study is 18 patients to be recruited over 12 months. 
TITE-CRM is an adaptive Phase I trial design methodology which allows for MTD-finding by 
weighting the follow-up contribution of previously enrolled patients to the selection of the dose 
level for each newly enrolled patient. If a patient dies of disease progression without evidence of 
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TITE-CRM allows for dose modification even if patients have not completed the entire follow-up 
period. At the enrollment of each new patient (beyond three initial patients enrolled after the 
protocol amendment removing the concurrent atezolizumab dose who start with the lowest dose 
of 50 Gy), all available follow-up for all patients already on study enrolled after the protocol 
amendment removing the concurrent dose of atezolizumab, will be used to determine the dose 
level for the newly enrolled patient based on the TITE-CRM methodology. For example, if three 
patients are enrolled every two months, by month seven, the first patient who did not receive 
concurrent atezolizumab (who enrolled in month 1) provides up to 6 months of follow-up whereas 
the ninth patient who did not receive concurrent atezolizumab (who enrolled in month 6) provides 
only about 1 month of follow-up. All available follow-up data from the first nine patients who did 
not receive concurrent atezolizumab will be used by the TITE-CRM model to make a decision on 
the dose for the tenth patient. Unlike a standard 3+3 design, the TITE-CRM model may maintain 
the current dose level, increase the dose level or decrease the dose level based on all available 
follow-up data at the time of enrollment of the tenth patient.  
To implement the TITE-CRM model, we will be using the titecrm function from the R package 
dfcrm. An unconstrained TITE-CRM model potentially allows for rapid early dose escalation from 
50 Gy to 60 Gy. To prevent this overly aggressive dose escalation we will require at least 3 
sequential patients to be enrolled at 55 Gy before increasing to 60 Gy. 
 
8.2 Objectives and Analysis Plans 
8.2.1 Primary Objective and Analysis Plan 
 
The primary objective of the study is to determine the maximum tolerated dose (MTD) of the 
DEHART regimen delivered with adjuvant atezolizumab in patients with locally advanced or de 
novo metastatic HNSCCs. 
 
The MTD will be determined as the radiation dose at which there is a 30% rate of dose-limiting 
toxicity (DLT) up to 12 months after completion of radiation treatment (to allow for the development 
of late toxicities from radiation treatment) using the TITE-CRM design. 
 
A DLT will be defined for the purposes of this protocol as an inability to complete radiation 
treatment within 30 days of the start of radiotherapy not deemed to be related to disease 
progression or unrelated death, unacceptable toxicity within one year of treatment (Grade 4+ 
toxicity) probably or definitely related to radiation treatment as deemed by the treating physician, 
or a death within one year of treatment deemed probably or definitely related to treatment. 
Expected Grade 3 acute toxicities typical of head and neck radiation, acute dermatitis, acute 
mucositis, feeding tube placement, electrolyte abnormalities, pain requiring narcotic medication 
and dehydration requiring IV hydration, resolving within 90 days of treatment will NOT be 
considered DLTs. Grade 4+ late toxicities that may be considered a DLT of reirradiation include 
but are not limited to: 
 
 
Chondronecrosis of the laryngeal cartilages 
 
Laryngeal edema requiring tracheostomy 
 
Carotid blowout syndrome or other life-threatening vascular bleed 
 
Aspiration pneumonia requiring ICU admission not related to tumor progression 
 
Chronic non-healing wound or soft tissue necrosis requiring flap reconstruction  
 
Brainstem necrosis 
 
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Grade 1-3 immune-related toxicity from atezolizumab will not be considered a DLT. Additionally, 
death deemed unrelated to radiation or atezolizumab (such as death due to malignancy or other 
comorbidity) will not be considered a DLT. 
All patients who initiate radiation therapy will be evaluable for the primary endpoint as long as 
they initiate radiation therapy. 
8.2.2  Secondary Objectives 
1. To evaluate the efficacy of the DEHART regimen at 1-year as measured by locoregional 
control and overall survival 
a. To estimate 1-year locoregional recurrence, patients will be followed for 
locoregional recurrence during the 12-month follow-up period with death as a 
competing risk using the methodology of Fine and Gray. Cumulative incidence 
curve will be plotted to describe overtime dynamics of locoregional recurrence. 
 
b. To estimate 1-year overall survival, the Kaplan-Meier methodology will be 
used. 
2. To assess gross tumor shrinkage after 6 and 11 fractions of radiotherapy using DEHART 
a. Median and mean percent volume of gross tumor shrinkage after 6 and 11 
fractions of radiotherapy using the DEHART regimen 
 
b. Response rate by RECIST criteria at fractions 6 and 11 of radiotherapy 
 
c. The gross tumor volume as contoured on the pre-treatment, fraction 6 and 
fraction 11 scans for each individual patient will be plotted using longitudinal 
plots. 
3. To assess patient quality of life during and after the DEHART regimen as measured using 
multiple patient quality-of-life metrics 
a. Quality of life changes will be determined by measuring the following quality of 
life/toxicity scores at the endpoints specified in the study calendar: CTCAE 
version 5.0 scores, composite MDASI-HN scores, composite MDADI scores, 
EAT-10 questionnaire scores, Functional Oral Intake (FOIS) scores and 
Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) grading. 
 
b. To determine changes in quality of life and toxicity scores, longitudinal plots of 
these scores will be used to determine whether these return to baseline or 
improve after treatment. 
 
8.3 Sample Size Justification 
 
The projected sample size will be 18, and we estimate an accrual rate of 3 patients every 2 
months for a total estimated accrual time of 12 months. Patients will be recruited for the study 
based on whether they are not candidates for full course definitive chemoradiation either due to 
inability to tolerate cisplatin, locoregionally recurrent disease after surgery, or de novo 
metastatic disease. Based on our tumor board presentations, we typically have 6 patients who 
meet these criteria every month, so the proposed study of 18 patients can be easily 
accomplished within 12 months of opening if we are able to enroll 25% of eligible patients on 
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To verify the feasibility of detecting the MTD with this modified TITE-CRM methodology using a 
sample size of 18, Monte-Carlo simulation studies (1000 resamples each) with various a priori 
estimates of toxicity at the 3 doses levels were performed. For these simulation studies the 
following assumptions were made: (1) a constant hazard of observing a DLT through all available 
follow-up; (2) a median survival of 17 months (based on a similar patient population reported in 
Al-Mamgani et al. (14)) (constant hazards as well); (3) a study accrual rate of 3 patients every 2 
months during first 12 months and (4) toxicity as a function of dose is modeled using a 1-
parameter logistic regression. The results of these simulation studies are detailed in the table 
below. 
Assumed 1-year toxicity rates at 50, 55, 
and 60 Gy 
Probability that MTD is declared at 50, 55 
and 60 Gy 
5%, 15%, 30% 
4.3%, 32.9%, 62.8%
15%, 30%, 45% 
31.7%, 47.1%, 21.2% 
30%, 45%, 60% 
78.1%, 18.4%, 3.5% 
10%, 30%, 50% 
23.7%, 54.8%, 21.5% 
10%, 20%, 30% 
10.5%, 37.6, 51.9%
The probability of correctly identifying the MTD depends on the assumed toxicity at each dose 
level. However, using a wide variety of assumed toxicities at each dose level and a sample size 
of 18, results in a good probability of detecting the MTD (~50% or more at each assumed toxicity 
level). Further, the chance of incorrectly selecting a dose level higher than the true MTD is 
reasonable (~20% or less at each assumed toxicity level). 
Due to the amendment removing the concurrent atezolizumab dose and restarting the TITE-CRM, 
it may be possible that we will only have sufficient funding and drug support to enroll 13 additional 
patients (though we intend to obtain funding and drug support for a complete set of 18 patients 
after the removal of the concurrent atezolizumab dose). To ensure that we will still conduct a 
meaningful study with as few as 13 patients, we ran similar Monte-Carlo simulation studies (1000 
resamples each) for a study of only 13 patients. The results of these simulation studies are 
detailed in the table below and demonstrate that we only minimally increase the chance of 
declaring an MTD higher than the actual MTD with as few as 13 patients: 
Assumed 1-year toxicity rates at 50, 55 and 60 
Gy 
Probability MTD is declared at 50, 55 and 60 
Gy 
5%, 15%, 30% 
8.3%, 30.1%, 61.3% 
15%, 30%, 45% 
35.3%, 40.4%, 24.7% 
30%, 45%, 60% 
75%, 20.5%,3.9% 
10%, 30%, 50% 
29.4%, 45.3%, 25.2% 
10%, 20%, 30% 
16.8%, 33.8%, 49.8% 
8.4 Study Monitoring, Interim Analyses, and Early Stopping Rules 
This is a Phase I clinical trial. Patients will receive continued follow-up during and after treatment 
up to 12 months after completion of the DEHART regimen. All side effects will be reported and 
any adverse events will be reported to the IRB as per national and local clinical trial requirements. 
The project is monitored at all times by the Principal Investigator and/or co-investigators. A 
physician is present at all exams. The Institutional IRB reviews each project yearly. If at any time 
during the study, the probability that the MTD is below 50 Gy is greater than 95%, accrual will be 


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suspended temporarily. Accrual will only resume, if, after further follow-up, this probability is less 
than 95%. 
Adverse Event Reporting: Any adverse event such as unanticipated or severe toxicity from 
radiation would be reported to the IRB under the guidelines as required by our Institution. Any 
DLT will be reported to the MCW DSMC within 5 calendar days of the study staff¶s knowledge of 
such an event. 
8.5 Systemic Treatment Discontinuation  
Patients must permanently discontinue 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 determination that treatment discontinuation is in the best interest of the 
patient 
 
Use of another non-protocol anti-cancer therapy 
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented on the appropriate 
eCRF. Patients who discontinue study treatment prematurely will not be replaced. Patients will 
return to the clinic for a treatment/surveillance discontinuation visit 30 days after the final dose of 
study treatment or final visit or telephone contact.  
 
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 patient discontinuation from the study may include, but are not limited to, the following: 
 
 
Patient withdrawal of consent 
 
Study termination  
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the study. The 
primary reason for discontinuation from the study should be documented on the appropriate 
eCRF. 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. 
 
Study Discontinuation by PI  


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The PI has the right to terminate this study at any time. Reasons for terminating the study may 
include, but are not limited to, the following: 
The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to patients. Patient enrollment is unsatisfactory. 
9 DATA AND SAFETY MONITORING PLAN (DSMP) 
9.1 Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal 
investigator of the study with safety and progress reports submitted to the DSMC.  
The DSMP for this study will involve the following entities: 
9.2 Study Team 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist, and the study biostatistician. While subjects are on study, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to review 
study status. This review will include but not be limited to reportable SAEs and UPIRSOs and an 
update of the ongoing study summary that describes study progress in terms of the study schema. 
The appropriateness of further subject enrollment and the specific intervention for a next subject 
enrollment is addressed. All meetings including attendance are documented.  
9.3 Quality Assurance  
The MCWCC Clinical Trials Office provides ongoing quality assurance audits. This protocol was 
classified as high risk and will be reviewed internally by the MCW Cancer Center Clinical Trials 
Office Quality Assurance Staff according to the MCWCC Data and Safety Monitoring Plan and 
current version SOP, 6.5.2 Internal Quality Assurance Reviews. 
 
9.4 Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
9.5 DSMC 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at MCW 
includes a plan for safety and data monitoring. 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  


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This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
 
Review the clinical trial for data integrity and safety  
 
Review all DSM reports 
 
Submit a summary of any recommendations related to study conduct  
 
Terminate the study if deemed unsafe for patients  
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained 
in the study research file and updated as membership changes. The committee will review reports 
from the study PI twice annually (or more frequently if needed) and provide recommendations on 
trial continuation, suspension, or termination as necessary.  
Any available DSMC letters will be submitted to the IRB of record as required. 
10 REGULATORY COMPLIANCE, ETHICS, AND STUDY    
     MANAGEMENT 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
10.1 Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and 45 CFR 46 
Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and Neonates), C 
(Prisoners), and D (Children), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
10.2 Pre-study Documentation  
Prior to implementing this protocol at MCWCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the MCW 
IRB.  
10.3 Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the MCW Institutional Review Board. Prior to obtaining MCW approval, the protocol must be 


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approved by the Medical College of Wisconsin Cancer Center Scientific Review Committee. The 
initial protocol and all protocol amendments must be approved by the IRB prior to implementation.  
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual¶s agreeing to participate in 
the study and continues throughout the individual¶s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise. In accordance with 46 CR 46.111, the subject will sign and date the informed consent 
document prior to any procedures being done specifically for the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (i.e., ³Although not required, the 
subject¶s spouse was present during the consenting process and signed as the witness.´ Or 
³Although not required, hospital staff was present for consenting process and signed as a 
witness.´) 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Patients that require reconsenting will be defined in the IRB approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. The MCWCC CTO will follow the 
MCW/FH IRB¶s policy for subjects who demonstrate limited English proficiency or limited literacy.  
After the subject¶s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject¶s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject¶s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
10.4 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, [and the sponsor(s) and their agents] (include bracketed portion if 
applicable). This confidentiality includes the clinical information relating to participating subjects, 
as well as any genetic or biological testing. 


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The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator. 
The conditions for maintaining confidentiality of the subjects¶ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects.  
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the information 
and keep it confidential, but it is possible that an unauthorized person might see it. Depending on 
the kind of information being collected, it might be used in a way that could embarrass the subject 
or affect his/her ability to get insurance. 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject¶s data/PHI are stored in the locked Clinical Research office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the Case Report Forms contain the study identifiers, subject initials, date of birth and date of 
service.  
The principal investigator will allow access to all source data and documents for the purposes of 
monitoring, audits, IRB review, and regulatory inspections.  
The study monitor/s or other authorized representatives of the principal investigator may inspect 
all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this study. 
The clinical study site will permit access to such records. 
10.5 Protection of Human Subjects 
10.5.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject¶s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately 
and clearly communicates the nature of the research to be done and its associated risks and 
benefits. 
10.5.2  Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be asked to sign informed consent documents. The original signed document will become part of 
the patient¶s medical records, and each patient will receive a copy of the signed document.  
10.5.3 Changes in the Protocol 


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Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five working days after implementation.  
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review, and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
10.6 Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
Onsite Audits 
Auditing is essential to ensure that research conducted at the Medical College of Wisconsin 
(MCW) Cancer Center is of the highest quality and meets MCW and regulatory agency standards.  
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data 
capture records and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
11 DATA HANDLING AND RECORD KEEPING 
11.1 Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data is 
protected from physical damage as well as from tampering, loss, or theft. This project¶s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians, and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
11.2 Data Management Responsibilities 
Principal Investigator 


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The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication, and investigational 
product(s), measurements, exams, evaluations, and adverse events; c) corrections are applied 
to clinical research data according to principles of good research practice (i.e., single-line delete, 
date and initial). He or she will ensure that there is correlation between the case report forms and 
the source documents.  
Research Coordinator  
A research coordinator creates, collects, and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject¶s outcomes, adverse events, and compliance to study procedures. 
Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
11.3 Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test 
reports, etc.) are maintained in the patient¶s clinical file.  
All source documents will be written following ALCOA standards:  
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of events. 
If a clinical observation cannot be entered when made, chronology 
should be recorded. Acceptable amount of delay should be defined 
and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 


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11.4 Case Report Forms  
The principal investigator and/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 outcomes. All study data will be entered into 
OnCore® via standardized CRFs, in accordance with the study calendar, using single data entry 
with a secure access account. The Clinical Research Coordinator will complete the CRFs as soon 
as possible upon completion of the study visit; the investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient¶s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
11.5 Study Record Retention 
The principal investigator is required to maintain adequate records. 
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
 


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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
predisease performance without 
restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 


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APPENDIX 2. LOST TO FOLLOW-UP LETTER 
Date: ___________________________________ 
 
 
Dear ___________________________________, 
 
 
The research study team has been unable to contact you regarding the clinical trial (A Phase I 
Study of MR-Guided Dose-Escalated Hypofractionated Adaptive Radiation Therapy and 
Immunotherapy in Primary Metastatic or Very Locally Advanced Patients with Head and Neck 
Cancer) you participated in. 
 
We would like to discuss how you are doing and if we may continue contacting you. 
 
 
 
Please contact us at 
_____________________________________________________________ 
 
 
Sincerely, 
 
 
___________________________________ 
 


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Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation 
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19. 
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. 
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L1 expression. Oral Oncol. 2018;81:45-51. 
20. 
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical 
activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of 
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Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, 
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nivolumab (Nivo) concomitant with cetuximab-radiotherapy for intermediate (IR) and high-risk 
(HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG 
3504. Journal of Clinical Oncology. 2018;36(15_suppl):6010-. 
24. 
Yu Y, Lee NY. JAVELIN Head and Neck 100: a Phase III trial of avelumab and 
chemoradiation for locally advanced head and neck cancer. Future Oncol. 2019;15(7):687-94. 
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Rosenthal DI, Mendoza TR, Chambers MS, Asper JA, Gning I, Kies MS, et al. 
Measuring head and neck cancer symptom burden: the development and validation of the M. D. 
Anderson symptom inventory, head and neck module. Head Neck. 2007;29(10):923-31. 
26. 
Chen AY, Frankowski R, Bishop-Leone J, Hebert T, Leyk S, Lewin J, et al. The 
development and validation of a dysphagia-specific quality-of-life questionnaire for patients with 
head and neck cancer: the M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck 
Surg. 2001;127(7):870-6. 
27. 
Mehanna H, Wong WL, McConkey CC, Rahman JK, Robinson M, Hartley AG, et al. 
PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J 
Med. 2016;374(15):1444-54. 
28. 
Mizugaki H, Yamamoto N, Murakami H, Kenmotsu H, Fujiwara Y, Ishida Y, et al. Phase I 
dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin 
monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors. Invest 
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29. 
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. 
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and 
metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 
2017;389(10064):67-76. 
30. 
Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. 
Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or 
metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised 
controlled trial. Lancet. 2018;391(10122):748-57. 


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31. 
Peters S, Gettinger S, Johnson ML, Jänne PA, Garassino MC, Christoph D, et al. Phase 
II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed 
Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol. 
2017;35(24):2781-9. 
32. 
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. 
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer 
(POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 
2016;387(10030):1837-46. 
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Spigel DR, Chaft JE, Gettinger S, Chao BH, Dirix L, Schmid P, et al. FIR: Efficacy, 
Safety, and Biomarker Analysis of a Phase II Open-Label Study of Atezolizumab in PD-L1-
Selected Patients With NSCLC. J Thorac Oncol. 2018;13(11):1733-42. 
34. 
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. 
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer 
(OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 
2017;389(10066):255-65. 
35. 
Stroh M, Winter H, Marchand M, Claret L, Eppler S, Ruppel J, et al. Clinical 
Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma. 
Clin Pharmacol Ther. 2017;102(2):305-12. 
36. 
Morrissey KM, Marchand M, Patel H, Zhang R, Wu B, Phyllis Chan H, et al. Alternative 
dosing regimens for atezolizumab: an example of model-informed drug development in the 
postmarketing setting. Cancer Chemother Pharmacol. 2019;84(6):1257-67. 

ICF_001.pdf: 
Consent Date:  Approval Period 9/12/2023-6/11/2024; Stamped eﬀecƟve 9/12/2023 
Oﬃcial Title of Study:  A Phase I Trial of MR-Guided Dose-Escalated HypofracƟonated AdapƟve 
RadiaƟon Therapy and Immunotherapy in Primary MetastaƟc or Very Locally Advanced PaƟents 
With Head and Neck Cancer 
NCT04477759 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 1 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
9/12/2023 
 
MCW IRB
 
 
Medical College of Wisconsin  
INTRODUCTION TO THE INFORMED CONSENT 
 
 
IIT-AWAN-NIH-DEHART: A Phase I Study of MR-Guided Dose-Escalated Hypofractionated 
Adaptive Radiation Therapy and Immunotherapy in Primary Metastatic or Very Locally 
Advanced Patients with Head and Neck Cancer 
 
Musaddiq Awan, MD 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
414-805-6700 
 
 
 
 
Definitions 
Magnetic Resonance-guided Radiation Therapy (MRgRT) – a new way of administering 
radiation therapy by using MRI scans to determine how your cancer is changing throughout 
your treatment. It is considered investigational in this study because it has not been 
approved by the FDA for treatment of your type of cancer. 
Hypofractionated – radiation therapy that is given in a smaller number of fractions (visits) 
but with a higher dose of radiation compared to standard radiation therapy. 
Atezolizumab – an immunotherapy drug administered with radiation therapy. Atezolizumab 
is considered investigational in this study because it has not been approved by the FDA for 
treatment of your type of cancer. 
Dynamic Contract Enhancement (DCE) MRI – imaging that allows your study doctor to 
see greater detail about your tumor, including the blood vessels going into and out of your 
tumor. Researchers believe that blood vessels surrounding a tumor help feed a tumor to 
allow it to survive and grow. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 2 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
9/12/2023 
 
MCW IRB
 
Purpose 
This project is being done to test an 
experimental treatment for your HNSCC. This 
study will use a new way of administering 
radiation therapy for HNSCC called Magnetic 
Resonance-guided Radiation Therapy 
(MRgRT). 
Length 
You will be in this research project for about 
14 months, from the time of Screening 
through Follow-up visits. 
 
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
Radiation Therapy risks: 
 
Dry mouth 
 
Loss of taste buds 
 
Thick saliva 
 
A skin burn that looks like a sunburn 
 
Fatigue 
 
Pain requiring numbing or pain 
medicine 
 
Unable to eat requiring a feeding tube 
 
IV fluids for dehydration 
 
Scar tissue in neck 
 
Difficulty opening your mouth 
 
Swallowing difficulty with big bites and 
dry food 
 
HSV1/HSV2 reactivation (oral 
soreness, blisters, rash) 
Atezolizumab risks: 
 
Fatigue 
 
Joint pain (arthralgia) 
 
Lack of energy (asthenia) 
 
Decreased appetite 
 
Diarrhea 
 
Shortness of breath (dyspnea)  
 
Urinary tract infection 
 
Cough 
 
Itching of the skin 
 
Nausea 
 
Fever 
 
Rash 
 
Vomiting 
 
Muscle and bone pain  
 
HSV1/HSV2 reactivation (oral 
soreness, blisters, rash) 
Procedures 
All subjects in this study will receive the same 
treatment: MRgRT combined with 
Atezolizumab immunotherapy. You will 
receive radiation therapy over 15 visits, given 
5 days a week for 3 weeks. 
 
List of visits: 
 
Screening Visit(s) 
- Total Number: approx. 1-3 
- Total Time: approx. 6-10 hours 
 
Pre-Treatment Visits 
- Total Number: approx. 1-2 
- Total Time: approx. 4-8 hours 
 
Treatment Visits 
- Total Number: 15 
- Total Time: approx. 4-6 hours each 
 
Follow-up Visits 
- Total Number: approx. 20-25 
- Total Time: approx. 2-4 hours each 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- Blood collection for routine 
laboratory tests and pregnancy test 
- Atezolizumab administration, via IV 
infusion 
 
Non-invasive Procedures 
- Radiation therapy 
- Physical exam and vital signs 
- Performance assessment 
- Tumor assessments by PET/CT and 
MRI 
- Questionnaires 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 3 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
9/12/2023 
 
MCW IRB
 
My Other Options 
You do not have to join this project. Your other 
options may include: 
1. Joining a different project 
2. Routine care for this condition  
3. Getting no treatment for this condition 
 
Benefits 
We don’t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
 
If you have more questions about this project at any time, you can call Musaddiq Awan, MD 
at 414-805-6700. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 4 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
9/12/2023 
 
MCW IRB
CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have head and neck 
squamous cell carcinoma (HNSCC). 
 
A total of about 18 people are expected to participate in this research the Medical College of 
Wisconsin/Froedtert Hospital. 
 
The Director of the project is Musaddiq Awan, MD in the Department of Radiation Oncology. A 
research team works with Dr. Awan. You can ask who these people are.  
 
This project is funded by a grant from the National Institutes of Health (NIH). 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
do not agree to join, or if you leave, you will not be penalized or lose any benefits that you had 
before starting the research project. Even if you join this project, you do not have to stay in it. 
You may stop at any time. Take as much time as you need to make your choice.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
The purpose of this study is to test an experimental treatment for your HNSCC. This study will 
use a new way of administering radiation therapy for HNSCC called Magnetic Resonance-
guided Radiation Therapy (MRgRT), MRgRT uses weekly MRI scans to track how your cancer 
changes over the course of treatment. This makes it possible to increase the dose of radiation 
given to specific areas that need it while reducing the dose of radiation given to specific areas 
where the tumor is getting smaller. Subjects in this study will also receive the immunotherapy 
drug Atezolizumab after radiation therapy. Researchers hope that this treatment plan will result 
in better outcomes and fewer adverse effects compared to standard radiation therapy. This 
treatment is investigational, meaning it has not been approved by the FDA for the treatment of 
your cancer. 
 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us develop better 
treatments for head and neck cancer. 
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
STUDY TREATMENTS 
 
All subjects in this study will receive the same treatment: MRgRT combined with Atezolizumab 
immunotherapy. 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
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The radiation therapy will be hypofractionated. This means it will be given in a smaller number 
of fractions (visits) but with a higher dose of radiation compared to standard radiation therapy. If 
you participate in this study, you will receive radiation therapy over 15 visits. This will be given 5 
days a week for 3 weeks. You will receive a total radiation dose of 50 Gy, 55 Gy, or 60 Gy over 
the course of treatment, depending on the recommended dosing at the time of your enrollment. 
 
Atezolizumab will be given as an IV infusion over 1 hour for the first dose. You will be monitored 
during the infusion. A reaction to the infusion is uncommon. However, you should let the 
infusion staff know if you experience chills, itching, shortness of breath, swelling of your 
face/lips, or feel like you may pass out. If any of these symptoms occur, you may be given 
medications, and the infusion may be stopped or slowed until side effects resolve. If you do not 
experience side effects with your first infusion, subsequent infusions of Atezolizumab may be 
given over 30 minutes.  
 
The first dose of Atezolizumab will be administered after your radiation therapy. You will receive 
Atezolizumab every 4-5 weeks. You will be able to receive up to 12 doses of Atezolizumab over 
the course of 1 year. 
 
STUDY VISITS 
 
The study is divided into 4 periods: Screening, Pre-Treatment, Radiation Therapy Treatment, 
and Follow-up. 
 
Screening 
After you sign the informed consent form, you will have visits with both a radiation oncologist 
and a medical oncologist. Both doctors will assess your disease, ask you some questions about 
your health and medications you are taking, and run some tests to determine if you are eligible. 
If some of the tests were completed recently, they may not have to be repeated for the study. 
The Screening period will last up to 30 days. 
 
Pre-Treatment 
You will have a few preparatory visits that are standard for patients who receive head and neck 
radiation therapy. Your radiation oncologist will acquire practice MRI images that will help plan 
where your radiation treatment is delivered. These Pre-Treatment period also include a visit with 
a speech and language pathologist.  
 
Radiation Therapy Treatment 
Your radiation therapy and Atezolizumab treatment will be administered as described above. 
Your study doctors will monitor your health during these visits. If you experience any adverse 
reactions to either of the treatments, your treatment plan may be modified or you may be given 
additional premedications. At the beginning of each week, your radiation therapy plan may be 
adjusted to account for how your cancer is responding to your treatment. 
 
Follow-Up 
The Follow-up period will begin after your radiation therapy is completed and will last up to 1 
year. You will continue to come to the clinic for Atezolizumab immunotherapy during this period 
of the study. Your study doctors will monitor how your cancer continues to respond to treatment. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 6 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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Follow-up visits take place weekly for the first month after you complete radiation therapy. Then 
visits will be at 3, 6, 9, and 12 months after the end of your radiation therapy. 
 
STUDY ASSESSMENTS 
 
Screening 
You will need to have all or some of the following exams, tests, or procedures to find out if you 
can be in the study. They may be done even if you do not join the study. If some of the tests 
were completed recently, they may not have to be repeated. 
 
Informed consent: Prior to any study-related procedures being performed, you will be 
required to voluntarily sign and date this consent form. 
 
Medical history: You will be asked about if you experienced any changes in your health 
status. 
 
Medications: You will be asked about any changes in your current medications, including 
over-the-counter medications, vitamins, and herbal supplements. 
 
Physical examination: You will receive a complete physical examination, including 
weight and height. 
 
Vital signs: Your blood pressure, temperature, and heart rate will be checked. 
 
Blood tests: Blood samples will be collected for: 
o Blood cell counts, blood chemistry, clotting ability, and organ function 
o Pregnancy, if you are a female patient capable of having children  
o For HIV and Hepatitis B infections 
As part of the screening procedures, your blood will be tested for diseases that 
can be passed on to other people by transfusion, including AIDS (the disease 
caused by the HIV virus) and Hepatitis B. If certain tests are positive, we will 
inform you and inform certain government health agencies as required by law. 
Results of your blood test will be released only to authorized persons as 
governed by Wisconsin law. A list of persons to be notified and reasons that will 
cause release of your blood test is available upon request. Results of the blood 
test will be released to the study team. 
 
Performance status: An assessment of your overall health and ability to perform daily 
tasks 
 
Tumor assessment by CT or PET/CT scan 
 
Pre-Treatment 
The following assessments or activities will be performed during the Pre-Treatment visits. 
 
Medical history: You will be asked about if you experienced any changes in your health 
status. 
 
Medications: You will be asked about any changes in your current medications, including 
over-the-counter medications, vitamins, and herbal supplements. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 7 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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 
Radiation planning: Your radiation oncologist will run simulation MRI images in order to 
plan your treatment. 
 
Speech and language pathologist visit: A speech and language pathologist will perform a 
number of baseline evaluations about your speech and your ability to swallow food. 
 
Questionnaires: You will be asked to complete baseline questionnaires about your 
overall health and wellbeing. These are MDASI-HN, MDADI, and EAT-10. 
 
Radiation Therapy Treatment 
The following assessments or activities will be performed during the Radiation Therapy 
Treatment visits. 
 
Medical history: You will be asked about if you experienced any changes in your health 
status. 
 
Medications: You will be asked about any changes in your current medications, including 
over-the-counter medications, vitamins, and herbal supplements. 
 
Physical examination: You will receive a complete physical examination, including 
weight and height. 
 
Vital signs: Your blood pressure, temperature, and heart rate will be checked. 
 
Radiation therapy: You will receive 15 radiation therapy fractions, given 5 days a week 
for 3 weeks. 
 
Questionnaires: You will be asked to complete questionnaires about your overall health 
and wellbeing. These are MDASI-HN, MDADI, and EAT-10. 
 
Follow-up 
The following assessments or activities will be performed during the Follow-up period. Not all 
assessments will be performed at every Follow-up visit. 
 
Medical history: You will be asked about if you experienced any changes in your health 
status. 
 
Medications: You will be asked about any changes in your current medications, including 
over-the-counter medications, vitamins, and herbal supplements. 
 
Physical examination: You will receive a complete physical examination, including 
weight and height. 
 
Vital signs: Your blood pressure, temperature, and heart rate will be checked. 
 
Atezolizumab treatment: You will receive Atezolizumab immunotherapy every 4-5 weeks 
for up to 1 year from the beginning of your radiation therapy.  
 
Vital signs: Your blood pressure, temperature, and heart rate will be checked. 
 
Blood tests: On days you receive Atezolizumab, blood samples will be collected for: 
o Blood cell counts, blood chemistry, and organ function 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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 
Speech and language pathologist visit: At the visits 3 and 6 months after radiation 
therapy, a speech and language pathologist will perform a number of evaluations about 
your speech and your ability to swallow food. 
 
Questionnaires: You will be asked to complete questionnaires about your overall health 
and wellbeing. These are MDASI-HN, MDADI, and EAT-10. 
 
Imaging assessments: You will have a PET/CT and MRI of the head and neck at the visit 
at 3 months after radiation therapy. 
 
CONSENT FOR ADDITIONAL OPTIONAL PROCEDURES 
 
If you agree, we would like to obtain your consent to perform additional procedures. You do not 
need to provide consent to these additional procedures to participate in the study. 
 
We would like to perform Dynamic Contract Enhancement MRI (DCE) MRI imaging on the day 
of fractions 5, 10, and 15 of radiation therapy. DCE MRI imaging allows your study doctor to see 
greater detail about your tumor, including the blood vessels going into and out of your tumor. 
Researchers believe that blood vessels surrounding a tumor help feed a tumor to allow it to 
survive and grow. This DCE MRI imaging would requirement IV placement and injection of 
gadolinium contrast. 
 
MRI (Magnetic Resonance Imaging) is a way for us to see inside your body. MRI uses a 
powerful magnet, radio waves and a computer to produce detailed pictures of organs, bones 
and other internal body structures. For the MRI, you will lie on a table inside a scanner tube for 
about 30 minutes, while the scanner moves the reading unit over the areas of your body to be 
scanned.  
 
A liquid containing a gadolinium contrast “dye” will be injected into your vein.  This increases the 
ability of the MRI scan to show certain tissues in the brain or elsewhere in the body. 
 
We would also like to collect tumor tissue samples by research only biopsies. These would 
occur on the day of your simulation imaging to plan your radiation therapy treatment and on the 
days of Radiation Therapy Treatment fractions 5 and 15. 
 
In this project, we will do genetic testing on your tumor tissue biospecimens. This will be 
collected at the visits listed in the “CONSENT FOR ADDITIONAL OPTIONAL PROCEDURES” 
heading above. Genetic testing will be done because sponsor would like to understand the 
response of biomarkers to study drug treatment and to understand how the study drugs and 
underlying disease works.  
 
This genetic testing is for research only. The purpose is not to discover information that could be 
used to change your medical care, make or change your diagnosis, or advise you on your risk of 
diseases.  
 
The biospecimens collected for this part of the project will be coded, which means they will be 
labeled with numbers and/or letters instead of information that could identify you. Only the 
research team will be able to link the code to you. The sample will also be labeled with date of 
collection, which could potentially be used to identify you. The research team will make every 
effort to protect the information and keep it confidential, but it is possible that an unauthorized 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 9 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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person might see it. Depending on the kind of information being collected, it might be used in a 
way that could embarrass you.  
 
It is against federal law (Genetic Information Nondiscrimination Act, or GINA) for health 
insurance companies to deny health insurance, or large employers to deny jobs, based on your 
genetic information. But the same law does not protect your ability to get disability, life, or long-
term care insurance.  
 
You will not be given your genetic test results. 
 
Please indicate below if you are willing to undergo DCE MRI imaging and additional 
tumor biopsies as described above. If you are not willing to agree to this, you are still 
able to participate in the study. 
 
_______ (Initials)  YES, I willingly agree to undergo DCE MRI imaging and additional 
tumor biopsies as described above. 
 
_______ (Initials)  NO, I do NOT agree to undergo DCE MRI imaging and additional tumor 
biopsies as described above. 
 
B2. HOW LONG WILL I BE IN THE PROJECT? 
From the Screening to Follow-up visits, you will be in this research project for about 14 months.   
 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time, including during the MRI scans. If you 
leave, your regular medical care will not change. If you are thinking about leaving, please tell the 
research doctor.  
 
The research doctor can tell you about the effects of stopping, and you and the research doctor 
can talk about what follow-up care would help you the most. 
 
You might be asked to come back for one more visit to check your health. 
 
The research doctor may take you out of this project at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the project rules. 
 
The whole project is stopped. 
 
If this happens, the research doctor will tell you. 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
You should not breastfeed a baby while you are receiving Atezolizumab treatment. 
 
You should discuss with your study doctor before you receive any vaccines, including a COVID-
19 vaccine. Some types of vaccines are not allowed during the study. Your doctor can tell you 
which these are. 
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 10 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that you may get an 
intervention that does not help your condition or may make it worse.  There also may be 
problems (side effects) we do not know about yet, from the intervention itself, or how it 
combines with other drugs you are taking. If we learn about new important side effects, we will 
tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health. In an emergency, call 911. 
 
C2. RISKS OF THE INTERVENTION 
The research intervention itself may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.   
 
RADIATION RISKS 
 
Risks and side effects related to the radiation include those which are: 
 
Likely (20% or greater of the time): 
 
Dry mouth 
 
Loss of taste buds 
 
Thick saliva 
 
A skin burn that looks like a sunburn 
 
Fatigue 
 
Pain requiring numbing or pain medicine 
 
Less Likely (occurs 10-20% of the time): 
 
Unable to eat requiring a feeding tube 
 
IV fluids for dehydration 
 
Scar tissue in neck 
 
Difficulty opening your mouth 
 
Swallowing difficulty with big bites and dry food 
 
HSV1/HSV2 reactivation (oral soreness, blisters, rash) 
 
Rare but serious (2-10% of the time): 
 
Bleeding or Carotid blowout – leaky blood vessel in your neck that can bleed.  A carotid 
blowout can be fatal. 
 
Infection 
 
Non-healing wound 
 
Mandible necrosis – the jaw bone gets weak or fractures 
 
Teeth damage/loss 
 
Permanent feeding tube 
 
Permanent breathing tube 
 
Death 
 
Radiation induced cancer 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 11 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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In addition to radiation therapy you may receive additional radiation from diagnostic procedures 
to evaluate your condition. The principal risk associated with a radiation dose is the possibility of 
developing a radiation-induced cancer later in life. However, the additional risk of radiation-
induced cancer from these diagnostic procedures is low compared to the risks from the radiation 
therapy. 
 
ATEZOLIZUMAB RISKS 
 
Atezolizumab is designed to increase the number of immune system cells in your body that can 
fight cancer. These cells may cause inflammation within the tumor, as well as in normal tissue. 
Therefore, by taking Atezolizumab, you may develop a condition where there is inflammation 
against a part of your own body (an autoimmune condition).  
 
SIDE EFFECTS KNOWN TO BE ASSOCIATED WITH ATEZOLIZUMAB 
The side effects associated with Atezolizumab are listed below. There may be side effects that 
are not known at this time. 
 
Side Effects Known to Be Associated with Atezolizumab 
Very common 
(occurs in more 
than 10% of 
patients) 
 Fatigue 
 Joint pain (arthralgia) 
 Lack of energy (asthenia) 
 Decreased appetite 
 Diarrhea 
 Shortness of breath (dyspnea)  
 Urinary tract infection 
 Cough 
 Back pain 
 Itching of the skin (pruritis) 
 Nausea 
 Fever 
 Rash 
 Vomiting 
 Muscle and bone pain (myalgia, 
musculoskeletal pain and bone 
pain) 
 Headache 
 HSV1/HSV2 reactivation (oral 
soreness, blisters, rash) 
Common 
(occurs in 
1%10% of 
patients) 
 Chills 
 Difficulty swallowing (dysphagia)  
 Increase in liver enzymes, which 
may indicate inflammation of the 
liver 
 Allergic reaction or intolerance to 
medication (hypersensitivity)  
 Decreased level of potassium in 
blood (hypokalemia)  
 Decreased level of sodium in 
blood (hyponatremia)  
 Low blood pressure 
(hypotension) 
 Underactive thyroid gland 
(hypothyroidism)  
 Inflammation of the intestines 
(colitis) 
 Decreased oxygen supply in 
body resulting in shortness of 
breath (hypoxia) 
 Influenza-like symptoms  
 Infusion-related reaction  
 Inflammation of the lungs 
(pneumonitis)  
 Low platelet count in the blood, 
which may make you more likely 
to bruise or bleed 
(thrombocytopenia) 
 Inflammation of the liver 
(hepatitis)  


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 12 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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 Inflammation of the throat and 
nasal cavities (nasopharyngitis) 
 Dry skin 
 Increased blood sugar level 
(hyperglycemia) 
 Pain at the back of the throat 
(oropharyngeal pain) 
 Stomach area pain (abdominal 
pain)  
 Increased blood level of 
creatinine, a substance normally 
eliminated by the kidneys into 
the urine 
 Immune mediated pericardial 
disorders may occur. Pericarditis 
(inflammation of the lining of the 
heart) may be associated with 
pericardial effusion (fluid in the 
lining of the heart), which may 
progress to cardiac tamponade. 
Cardiac tamponade puts 
pressure on the heart and keeps 
it from filling properly. Symptoms 
include low blood pressure, 
shortness of breath, and 
lightheadedness. If your blood 
pressure drops too low, cardiac 
tamponade can be fatal. 
Less common 
but important 
(occurs in less 
than 1% of 
patients) 
 Decreased production of 
hormones by the adrenal glands 
(adrenal insufficiency) 
 Diabetes 
 Overactive thyroid gland 
(hyperthyroidism) 
 Inflammation of the brain and 
membrane surrounding the brain 
and spinal cord 
(meningoencephalitis) 
 Inflammation of the pituitary 
gland (hypophysitis) 
 Inflammation of the heart muscle 
(myocarditis) or membrane 
surrounding the heart 
(pericarditis) 
 Inflammation of the kidneys 
(nephritis) 
 Severe skin or mucosal 
reactions (severe cutaneous 
adverse reactions including 
Stevens-Johnson syndrome and 
Toxic epidermal necrolysis) 
 Facial paresis, inability to move 
the muscles of the face 
 Myelitis. Inflammation of the 
spinal cord 
 Nerve damage that may cause 
muscle weakness and/or 
paralysis (Guillain-Barré 
syndrome)  
 Nerve damage resulting in 
muscle weakness (myasthenic 
syndrome/myasthenia gravis) 
 Inflammation of the pancreas 
(pancreatitis), including increase 
in pancreatic enzymes (such as 
amylase and lipase) 
 Severe high levels of sugar and 
acids in the blood or urine 
(diabetic ketoacidosis) 
 Inflammation or damage of the 
muscles (myositis) 
 Severe immune reactions 
affecting white blood cell 
activation causing an overactive 
immune response including 
cytokine release syndrome, 
hemophagocytic 
lymphohistiocytosis (HLH) and 
macrophage activation 
syndrome (MAS) 
 Hemophagocytic 
lymphohistiocytosis, a rare but 
potentially fatal condition in 
which certain white blood cells 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 13 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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Among the side effects known to be associated with Atezolizumab, Roche and your study 
doctors would like you to pay more attention to the following:  
 
Inflammation of the intestines (colitis); symptoms may include diarrhea, blood in stool, and 
pain in stomach area 
 
Inflammation of the thyroid glands (hypothyroidism, hyperthyroidism); symptoms may 
include headaches, fatigue, weight loss, weight gain, change in mood, hair loss, and 
constipation 
 
Inflammation of the adrenal glands (adrenal insufficiency); symptoms may include 
dizziness, irritability, fainting, low blood pressure, skin darkening, and craving of salty foods 
 
Inflammation of the pituitary gland (hypophysitis); symptoms may include fatigue and 
headaches that will not go away, increased thirst, increased urination, and changes in 
vision 
Side effects that may occur at the same time include hypothyroidism and adrenal 
insufficiency (see above for details).  
 
Inflammation of the liver (hepatitis); symptoms may include yellowing of skin, pain in 
stomach area, nausea, vomiting, itching, fatigue, bleeding or bruising under the skin, and 
dark urine 
 
Inflammation of the brain and membrane surrounding the brain and spinal cord 
(meningoencephalitis); symptoms may include neck stiffness, headache, fever, chills, 
vomiting, seizure, irritability, and eye sensitivity to light 
 
Nerve damage resulting in muscle weakness (myasthenic syndrome/myasthenia gravis); 
symptoms may include weakness in the arm and leg muscles, double vision, and difficulties 
with speech and chewing 
 
Nerve damage that may cause muscle weakness and/or paralysis (Guillain-Barré 
syndrome); symptoms may include tingling in fingers and toes, fatigue, and difficulty 
walking 
 
Inflammation of the lungs (pneumonitis); symptoms may include new or worsening cough, 
shortness of breath, and chest pain 
 
Inflammation of the heart muscle (myocarditis); symptoms may include shortness of breath, 
decreased exercise tolerance, fatigue, chest pain, swelling of the ankles or legs, irregular 
heartbeat, and fainting 
 
Reactions associated with infusion (events occurring during or within 1 day of infusion); 
symptoms may include fever, chills, shortness of breath, and sudden reddening of the face, 
neck, or chest 
(histiocytes and lymphocytes) 
build up in and damage organs, 
including the bone marrow, liver, 
and spleen, and destroy other 
blood cells 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 14 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
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 
Inflammation of the pancreas (pancreatitis); symptoms may include abdominal pain, 
nausea, vomiting, and fever 
 
Condition of high levels of sugar in the blood (diabetes mellitus); symptoms may include 
increased thirst, increased hunger, frequent urination, irritability, and fatigue 
 
Inflammation of the kidneys (nephritis); symptoms may include changes in urine output and 
color, pain in pelvis, and swelling of the body and may lead to failure of the kidneys 
 
Inflammation or damage of the muscles (myositis, myopathies including rhabdomyolysis); 
symptoms may include muscle pain and weakness, urine with a dark brown or reddish 
color, nausea, and vomiting 
 
Severe skin or mucosal reactions (severe cutaneous adverse reactions); symptoms may 
include itching, skin blistering, peeling or sores, and/or ulcers in mouth or in lining of nose, 
throat, or genital area 
 
Allergic Reactions 
Allergic reactions may occur with Atezolizumab and typically occur while it is being given into 
your vein or shortly after it has been given. Symptoms could include nausea, vomiting, skin 
reactions (hives or rash), difficulty breathing, or low blood pressure. These reactions could be 
mild or severe and might lead to death or permanent disability. If you experience any of these 
symptoms, your study doctor will interrupt, or even stop, the delivery of Atezolizumab into your 
vein. Your study doctor may also give you some drugs to treat these symptoms.  
 
SIDE EFFECTS POTENTIALLY ASSOCIATED WITH ATEZOLIZUMAB  
The following are side effects that may be associated with Atezolizumab: 
 
Development of special antibodies to Atezolizumab (proteins made in the body that respond 
to a substance that is foreign to the body) by your immune system 
If you develop these special antibodies, it may affect your body’s ability to respond to 
Atezolizumab in the future. Blood samples will be drawn to monitor for the development 
of these antibodies during study treatment and at your treatment discontinuation visit. 
 
Potential to cause harm to a developing fetus 
 
Inflammation of the eye (uveitis); symptoms may include eye pain and redness, vision 
problems, and blurry vision 
 
Inflammation of the blood vessels that can lead to damage of different organs (vasculitis); 
symptoms may include fever, fatigue, weight loss, weakness, general aches and pains, 
rash, headache, lightheadedness, shortness of breath, and numbness 
 
Breakdown of red blood cells (autoimmune hemolytic anemia); symptoms may include 
fatigue, fever, lightheadedness, paleness of the skin, yellowing of the skin and/or eyes, 
weakness, and inability to do physical activity 
 
IMMUNE REACTION  
In rare situations, an immune reaction can occur with administration of Atezolizumab. This 
reaction can cause side effects related to severe inflammation and/or severe infection. Several 


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Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
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organs in your body (for example liver, kidney, lungs, and bone marrow) may become involved, 
causing a serious condition, which could lead to hospitalization, life-threatening circumstances, 
or even death. Symptoms may include very low blood pressure that does not respond to 
standard treatment, very high fever, cough, severe shortness of breath requiring oxygen therapy 
and/or intubation, severe dizziness, confusion, weakness, decreased urination with failure of the 
kidneys, abnormal liver function, very low blood cell counts, and/or bleeding within the organs. 
 
If you experience any of these symptoms, you should notify your doctor immediately, as you 
may need immediate treatment and hospitalization. Your study doctor may give you drugs to 
treat these symptoms. 
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT 
Other procedures that are part of the research also involve some risks: 
 
Blood collection 
Blood collection may cause some discomfort, bleeding or bruising at the puncture site. A small 
blood crust or swelling may occur at this site. In rare cases, fainting or local infection may occur. 
If you feel discomfort during blood collection, please report this to the study doctor or staff at the 
time. 
 
PET/CT 
The risks with a PET/CT scan include: 
 
Exposure to radiation. The amount of radiation from one PET/CT scan will depend on 
the area of the body being scanned but is generally about equal to 10 years of 
background radiation (the amount that you would be exposed to from sunlight and other 
sources in your everyday life).  
 
Possible allergic reaction to the contrast dye used to help doctors see the different 
organs and your cancer better. These scans may involve dyes being injected into one of 
your veins. There is a risk of allergic reaction to the dye. This reaction may be mild (such 
as a skin rash or hives) to severe (such as breathing difficulties and shock). There is a 
risk that the injection of dyes may cause: 
o Pain 
o Swelling 
o Bruising 
o Irritation, or redness at the injection site 
o Feeling faint 
o Infection (rare)  
 
Your study doctor may take steps to prevent these risks from happening. He or she may 
recommend medications that may help with these side effects. You may be asked to sign a 
separate consent form for these procedures. 
 
Magnetic Resonance Imaging 
MRI scans use a very powerful magnet to stimulate atoms in a person’s body. Those atoms will 
be detected by the scanner to produce an image of the scanned body. Any ferromagnetic metal 
implant may be displaced or overheat, if you have any such implant you should not have the 
MRI scans. In addition, you need to lie still in the small half-enclosed space of the machine for a 
long period of time (30 to 40 minutes) during the MRI, which may make you uncomfortable. 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
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There is no exposure to x-rays or radioactivity during an MRI (Magnetic Resonance Imaging) 
scan, and the risk of injury is very low.  However, MRI is not safe for everyone.  Serious injury or 
death can result if you go into the scanner with certain metal objects in or attached to your body.  
For example, it is not safe to have an MRI scan if you have a cardiac pacemaker, defibrillator, 
certain metal or implants in your body or have metal in or near your eye.  
 
The MRI scanner makes loud banging sounds that can cause hearing damage, but with 
earplugs properly worn, there is no known risk of permanent hearing damage.  Rarely, your 
hearing may be less sensitive for several days after an MRI scan, but if this happens your 
hearing should return to normal within a few days. Some individuals may feel hot or dizzy during 
the MRI scan. This varies from person to person. You may feel some discomfort because you 
are lying still for a long time, or because of the padding used to keep your head from moving.  
Some people feel anxious being in closed or narrow spaces. The scanner operator will be in 
constant contact with you, and if you choose, you can be taken out of the scanner quickly. 
Please alert staff to any concerns during the procedure. 
 
Side effects, such as mild headache, nausea, or burning at the injection site can occur from the 
gadolinium contrast “dye”. Some people are allergic to gadolinium, experiencing hives and itchy 
eyes, or very rarely, a bee-sting type of severe allergic reaction (anaphylactic shock). Use of 
gadolinium may be linked to a rare but sometimes fatal condition (nephrogenic systemic fibrosis 
or NSF) in people with severe chronic kidney disease or acute kidney problems. Therefore, 
before you are given this dye for MRI, your risk factors for kidney disease will be reviewed and a 
blood test will be done to check for kidney disease. 
 
In addition, there may be some unknown or unanticipated risks or discomforts in addition to 
those specified above because some of the procedures are relatively new and are attempts to 
advance medical knowledge. Every known precaution will be taken to ensure your personal 
safety and to minimize discomfort. 
 
Biopsies 
Risks associated with biopsies include pain, redness, swelling, bleeding, bruising, draining at 
the needle site, abnormal wound healing, fever, infection, and allergic reaction to the medication 
used to perform the biopsy procedure. 
 
Questionnaires 
The answers that you give are confidential, but there is always a risk that your answers will be 
read by people who should not read your personal information. You may also feel 
uncomfortable answering some of the questions. 
 
Privacy and Confidentiality 
Another risk may be loss of confidentiality. Every effort will be made to keep your research 
records confidential but we cannot guarantee it. Depending on the kind of information being 
collected, if your research information were accidentally seen, it might be used in a way that 
could embarrass you or affect your ability to get insurance. If you have questions, you can talk 
to the project director about whether this could apply to you. 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health. The study team can use this Certificate to legally refuse to disclose 
information that may identify you in any federal, state, or local civil, criminal, administrative, 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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legislative, or other proceedings, for example, if there is a court subpoena. The study team will 
use the Certificate to resist any demands for information that would identify you. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United 
States federal or state government agency sponsoring the project and that will be used for 
auditing or program evaluation of agency funded projects or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, medical care provider, or other person obtains your written consent to 
receive research information, then the researchers will not use the Certificate to withhold that 
information. 
 
C4. REPRODUCTIVE RISKS 
Risks to subjects who could become pregnant 
We do not know if the study drug causes harm to a baby, so we do not want anyone who might 
be pregnant to enter the project. 
 
You should not become pregnant or nurse a baby while in this project. You must tell the 
research doctor right away if you think you are pregnant. You will be asked to have a pregnancy 
test to be sure you are not pregnant at the start of the project.  
 
You may not donate eggs during your participation in the project or for 5 months after stopping 
the study drugs. 
 
Risks to a subject’s partner(s) 
If you and your partner(s) are able to become pregnant, one or both of you must use some form 
of effective birth control, because it is unknown if the study drug could affect a baby. You must 
tell the research doctor right away if you think your partner is pregnant. 
 
You may not donate sperm during your participation in the project or for 5 months after stopping 
the study drug. 
 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use two forms of highly effective birth control while 
you are in this project.   
 
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy/tubal ligation or vasectomy) 
 
Limiting sexual activity to a partner who has undergone surgical sterilization  
 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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 
Use of diaphragm with condoms (“double barrier”) 
 
You should continue using birth control for 5 months after stopping the study drug. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us develop better 
treatments for head and neck cancer. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
Most of the medical care that you will receive in this project is considered routine care for your 
condition and would be recommended whether or not you join the project.  Costs for routine 
care will be billed to you or your insurance carrier.  For routine clinical care, you will be 
responsible for paying any copayment, coinsurance, or deductible that is required by your 
insurance carrier.  
 
Activities / costs that are part of the project will not be billed to you or your insurance company. 
These are: 
 
Atezolizumab supply 
 
Blood tests for 
o Thyroid function (TSH) 
o Clotting (PT/INR)  
o HIV and Hepatitis B testing 
 
Costs associated with the videofluoroscopic swallow studies, part of the speech and 
language pathologist visits 
 
Collection, processing, and analysis of research specimens (tissue) 
 
Contrast agent associated with DCE MRI scans 
 
Some insurers will not pay for drugs, tests or hospitalization that are part of research, so check 
with your insurer before you join this project. If you have questions regarding costs, please 
contact Dr. Awan. 
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
There is no payment for being in this project. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  
 
Your other choices may include: 
 
Routine care for NSCC 
 
Joining a different research project 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
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 
The procedure or drug offered to you may also be available without being in any 
research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about the intervention that might change your mind 
about being in the project, we will tell you about it right away.  You can then decide if you want 
to stay in the project. 
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Musaddiq Awan, MD, 414-805-6700 
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Musaddiq Awan, 
MD at 414-805-6700. 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); Versiti, Inc.; 
Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- Froedtert Hospital (FH), 
Inc.; Froedtert Menomonee Falls Hospital;  Froedtert West Bend Hospital;  Froedtert & The 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 20 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
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Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West Bend 
Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information to be collected and used for this project is:  
 
 
Past and present medical records 
 
Records about your study visits and results of tests done during the study 
 
Records about phone calls made as part of this research 
 
Research records 
 
E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital’s rules are followed. 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who don’t work at MCW/Froedtert 
Hospital. because they planned, pay for, or work with us on this project.  The federal Privacy 
Rule may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For 
this project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
 
Florence Healthcare, Inc. 
 
The pharmaceutical company providing study drug, Genentech, and its research 
partners; 
 
Government agencies in the U.S., such as the Food and Drug Administration (FDA), 
National Cancer Institute (NCI), and National Institutes of Health (NIH); 
 
Other federal and state agencies, such as the Office of Human Research Protections, 
(OHRP); 
 
Others required by law 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record.  As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information and/or biospecimens, the information and/or 
biospecimens may be used for future research or distributed to another investigator for future 
research without additional informed consent from you or your legally authorized representative. 
The information might also be used or released for other purposes without asking you. Results 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
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Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
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of the project may be presented in public talks or written articles, but no information will be 
presented that identifies you. 
 
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. If 
you have questions, you can talk to the research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information without any end-date in case we need to 
check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Musaddiq Awan, MD at  
 
Department of Radiation Oncology 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 
The letter must say that you have changed your mind and do not want the researcher to collect 
and share your health information. At that time, we will decide that you cannot continue to be 
part of the project. We may still use the information we have already collected. 
 
E6. Access to records 
 
You may not be able to see, or copy, your project-related health information until after the 
project has been completed; otherwise, it could affect the study.   
 
F1. FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You can look up this project by referring to the ClinicalTrials.gov number (NCT04477759) or by 
asking the research team for a printed copy.    
 


Medical College of Wisconsin  
Informed Consent for Research 
Clinical Interventions template - Version: November 1, 2019 
 
IRB Protocol Number: PRO 38841 
IRB Approval Period: 9/12/2023 – 6/11/2024 
Page 22 of 22 
Protocol Version: V5 v. 7/31/23 
ICF Version: 9/11/23 
EFFECTIVE 
 
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CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document.  
All of my questions have been answered to my satisfaction. 
 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date   
 
 
 
Name of Witness, if applicable 
please print 
Signature of Witness 
 
Date 
Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol. The Principal Investigator 
is responsible and accountable for the research project.