Clinical trial NCT05060003
Conditions: Stage II Melanoma
Sponsor: Washington University School of Medicine
Start date: 2022-11-08; Completion date: 2023-11-27
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study's hypothesis is that patients with stage II melanoma who test positive for circulating tumor DNA are at a higher risk for recurrence and therefore adjuvant treatment is justified. In this study, the blood of consenting and eligible patients will be tested for ctDNA and those patients who test positive will be randomized on a 1:1 basis to either treatment with atezolizumab and tiragolumab or atezolizumab alone during Stage 1 of the study. If at least 3 patients in the atezolizumab + tiragolumab arm are shown to be ctDNA negative at C3D1, stage 2 of the study will begin enrollment. Stage 2 consists of 25 patients all enrolled to the atezolizumab + tiragolumab arm (no randomization and no atezolizumab monotherapy arm).Patients who test negative for ctDNA will be observed off protocol.

Detailed description:

Arms: arm 1: * Atezolizumab is given as an IV infusion every 4 weeks at a dose of 1680 mg over 60 minutes (+/- 15 minutes).
* Tiragolumab is given as an IV infusion every 4 weeks at a dose of 840 mg over 60 minutes (+/- 15 minutes).
* Treatment can continue for up to 13 cycles. arm 2: * Atezolizumab is given as an IV infusion every 4 weeks at a dose of 1680 mg over 60 minutes (+/- 15 minutes).
* Treatment can continue for up to 13 cycles.
Interventions: intervention 1: Atezolizumab intervention 2: Tiragolumab intervention 3: Signatera Assay
Intervention descriptions: intervention 1: Atezolizumab is provided by Genentech. intervention 2: Tiragolumab is provided by Genentech. intervention 3: * To detect residual disease or to determine cancer recurrence with ctDNA
* Step 2 screening (4-12 weeks after date of surgery), cycle 3 day 1, cycle 6 day 1, cycle 9 day 1, cycle 12 day 1, and end of treatment (optional)

Protocol documents:
Prot_SAP_000.pdf: 
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A phase II randomized study of tiragolumab plus atezolizumab versus atezolizumab in the 
treatment of stage II melanoma patients who are ctDNA-positive following resection 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 202111158 
Version Date: 09 January 2023 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
George Ansstas, M.D. 
Phone: (314) 362-5677 
E-mail:  gansstas@wustl.edu  
 
Sub-Investigators 
 
Institution 
 
 
 
 
Modality 
David Chen, M.D. 
 
 
Washington University 
 
 
Dermatology 
Ningying Wu, Ph.D.  
 
Washington University 
 
 
Biostatistics 
Meredith McKean, M.D., MPH Sarah Cannon Research Institute 
 
Medical Oncology 
Mario Sznol, M.D. 
 
 
Yale School of Medicine 
 
 
Medical Oncology 
Adil Daud, M.D. 
 
 
University of California – San Francisco 
Medical Oncology 
Yan Xing, M.D., Ph.D. 
 
City of Hope  
 
 
 
Medical Oncology 
Margaret Callahan, M.D., Ph.D. Memorial Sloan Kettering 
 
 
Medical Oncology 
 
Study Drugs:  
 
Atezolizumab (Tecentriq) 
                                                Tiragolumab 
 
IND#: 
159038 
IND Sponsor: 
George Ansstas, M.D. 
NCT#: 
NCT05060003 
Funded by: 
Genentech BioOncology 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 


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A phase II randomized study of tiragolumab plus atezolizumab versus atezolizumab in the 
treatment of stage II melanoma patients who are ctDNA-positive following resection 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
23 Nov 2021 
Amendment #1 Version 
 
 
 
 
 
 
19 Sep 2022 
Amendment #2 Version 
 
 
 
 
 
 
09 Jan 2023 
 
 
 


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A phase II randomized study of tiragolumab plus atezolizumab versus atezolizumab in the 
treatment of stage II melanoma patients who are ctDNA-positive following resection 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 
PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
● United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 


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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 8 
SCHEMA ...................................................................................................................................... 10 
SCHEDULE OF ACTIVITIES..................................................................................................... 11 
1.0 
INTRODUCTION ............................................................................................................. 13 
1.1 
Stage II Melanoma ......................................................................................................... 13 
1.2 
Circulating Tumor DNA and Risk of Relapse ............................................................... 14 
1.3 
Signatera Assay – Test Principle .................................................................................... 16 
1.4 
Atezolizumab ................................................................................................................. 16 
1.5 
Tiragolumab ................................................................................................................... 17 
1.6 
Background on Blockade of the TIGIT Pathway in Cancer as a Potential Anti-Cancer 
Therapy ..................................................................................................................................... 17 
1.7 
Combined Inhibition of the TIGIT and PD-L1/PD-1 Pathways as Potential Anti-Cancer 
Therapy ..................................................................................................................................... 18 
1.8 
Study Rationale and Benefit/Risk Assessment .............................................................. 19 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 22 
3.0 
STUDY POPULATION .................................................................................................... 24 
3.1 
Step One (Signatera Assay Development) Eligibility .................................................... 24 
3.2 
Step Two (Randomization and Treatment) Eligibility ................................................... 26 
3.3 
Inclusion of Women and Minorities............................................................................... 28 
4.0 
REGISTRATION PROCEDURES ................................................................................... 28 
4.1 
Confirmation of Patient Eligibility ................................................................................. 28 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 29 
4.3 
Assignment of UPN ....................................................................................................... 29 
4.4 
Screen Failures ............................................................................................................... 29 
4.5 
Measures to Minimize Bias: Randomization ................................................................. 29 
4.6 
Screening and Enrollment Considerations ..................................................................... 30 
5.0 
TREATMENT PLAN ........................................................................................................ 30 
5.1 
Study Intervention Description ...................................................................................... 30 
5.2 
Study Intervention Administration ................................................................................. 31 
5.3 
Definitions of Evaluability ............................................................................................. 33 
5.4 
Concomitant Therapy and Supportive Care Guidelines ................................................. 33 
5.5 
Women of Childbearing Potential .................................................................................. 35 
5.6 
Duration of Therapy ....................................................................................................... 36 
5.7 
Duration of Follow-up .................................................................................................... 37 


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5.8 
Lost to Follow-Up .......................................................................................................... 37 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 37 
6.1 
Dose Modifications ........................................................................................................ 38 
6.2 
Treatment Interruptions .................................................................................................. 38 
6.3 
Management Guidelines for Atezolizumab- and Tiragolumab-Specific Adverse Events
 
40 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 61 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 62 
7.2 
Secondary Site Reporting Requirements........................................................................ 66 
7.3 
Exceptions to Expedited Reporting ................................................................................ 67 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 67 
8.1 
Atezolizumab (Tecentriq) .............................................................................................. 67 
8.2 
Tiragolumab ................................................................................................................... 69 
9.0 
CORRELATIVE STUDIES .............................................................................................. 71 
9.1 
Tissue for Whole Exome Sequencing ............................................................................ 71 
9.2 
Blood for Whole Exome Sequencing ............................................................................. 72 
9.3 
Blood for ctDNA ............................................................................................................ 72 
9.4 
Shipping Instructions...................................................................................................... 72 
10.0 DATA SUBMISSION SCHEDULE ................................................................................. 72 
10.1 
Adverse Event Collection in the Case Report Forms ................................................. 73 
11.0 MEASUREMENT OF EFFECT........................................................................................ 73 
12.0 DATA AND SAFETY MONITORING ............................................................................ 74 
13.0 AUDITING ........................................................................................................................ 75 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 76 
14.1 
Study Design............................................................................................................... 76 
14.2 
Primary Endpoint ........................................................................................................ 76 
14.3 
Secondary Endpoints .................................................................................................. 76 
14.4 
Statistical Hypotheses ................................................................................................. 77 
14.5 
Sample Size Determination ........................................................................................ 77 
14.6 
Study Population......................................................................................................... 77 
14.7 
Statistical Analyses ..................................................................................................... 78 
15.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 79 
16.0 REFERENCES .................................................................................................................. 80 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 82 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 83 


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APPENDIX C: Reporting Timelines ............................................................................................ 86 
APPENDIX D: Washington University Unanticipated Problem Reporting Cover Sheet ............ 90 
 
 


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PROTOCOL SUMMARY 
 
Title: 
A phase II randomized study of tiragolumab plus atezolizumab 
versus atezolizumab in the treatment of stage II melanoma patients 
who are ctDNA-positive following resection 
Study Description: 
This study’s hypothesis is that patients with stage II melanoma who 
test positive for circulating tumor DNA are at a higher risk for 
recurrence and therefore adjuvant treatment is justified.  In this 
study, the blood of consenting and eligible patients will be tested for 
ctDNA and those patients who test positive will be randomized on a 
1:1 basis to either treatment with atezolizumab and tiragolumab or 
atezolizumab alone.  Patients who test negative for ctDNA will be 
observed off protocol. 
Objectives: 
Primary Objective: To determine the ctDNA clearance rate in 
patients with stage II melanoma who test positive for ctDNA and are 
treated with the combination of atezolizumab and tiragolumab. 
 
Secondary Objective: To determine the confirmed ctDNA negativity 
proportion with two consecutive negative results in patients with 
stage II melanoma who test positive for ctDNA and are treated with 
atezolizumab and tiragolumab, and those who are treated with 
atezolizumab alone. 
 
To determine the relapse-free survival in patients with stage II 
melanoma who test positive for ctDNA and are treated with 
atezolizumab and tiragolumab, and those who are treated with 
atezolizumab alone. 
 
To determine the distant metastasis-free survival in patients with 
stage II melanoma who test positive for ctDNA and are treated with 
atezolizumab and tiragolumab, and those who are treated with 
atezolizumab alone. 
 
To determine the overall survival of patients with stage II melanoma. 
 
To evaluate the safety and tolerability of atezolizumab and 
tiragolumab in patients with stage II melanoma. 
 
To assess the impact of ctDNA kinetics on outcomes (relapse-free 
survival, distant metastasis-free survival, and overall survival) in 
patients with surgically resected stage II melanoma. 
Endpoints: 
Primary Endpoint: ctDNA clearance rate, defined as the proportion 
of ctDNA-positive patients having a ctDNA-negative test at C3D1. 
 
Secondary Endpoint: Proportion of ctDNA-positive patients having 
a ctDNA-negative test at two consecutive measures, relapse-free 


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survival (RFS), distant metastasis-free survival (DMFS), overall 
survival (OS), treatment-related grade 3 or greater AEs 
Study Population: 
During stage 1 of this study, 18 patients with stage II melanoma who 
have undergone complete resection and who have tested positive for 
ctDNA will be enrolled in each arm (atezolizumab + tiragolumab 
(treatment) vs. atezolizumab monotherapy (reference)) for a total of 
36 patients randomized.  If at least 3 patients in the atezolizumab + 
tiragolumab arm are shown to be ctDNA negative at C3D1, stage 2 
of the study will begin enrollment.  Stage 2 consists of 25 patients 
all enrolled to the atezolizumab + tiragolumab arm (no 
randomization and no atezolizumab monotherapy arm). With an 
anticipated ctDNA positive rate of 25%, a total of approximately 144 
patients will need to be consented for ctDNA testing in stage 1 and 
100 in stage 2. 
Phase: 
II 
Description of Sites / 
Facilities Enrolling: 
This study will be open at the Siteman Cancer Center at Washington 
University School of Medicine as well as other cancer centers in the 
United States. 
Description 
of 
Study 
Intervention: 
Patients who test positive for ctDNA will be randomized on a 1:1 
basis during stage 1 to either treatment with atezolizumab and 
tiragolumab or treatment with atezolizumab alone.  If, after the 
completion of stage 1, it is determined that enrollment will continue 
in stage 2, patients will not be randomized and all will receive 
treatment with atezolizumab and tiragolumab. 
 
Atezolizumab is given as an IV infusion at a dose of 1680 mg every 
4 weeks and tiragolumab is given as an IV infusion at a dose of 840 
mg every 4 weeks. 
Study Duration: 
Study duration is anticipated to be 84 months (24 months for accrual 
+ 12 months for treatment + 36 months for follow-up + 12 months 
for data analysis). Primary analysis will take place after all patients 
have completed adjuvant therapy.  Additionally, an interim analysis 
will occur after 18 patients have been accrued to the treatment arm 
(atezolizumab + tiragolumab). 
Participant Duration: 
Forty-eight months (12 months for treatment + 36 months for follow-
up)  
 
 
 
 
 
 
 


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SCHEMA 
 
 
 


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SCHEDULE OF ACTIVITIES 
 
Cycles are 28 days in duration.  Step 2 screening may take place up to 28 days prior to C1D1 
except where noted.  Safety assessments may take place +/- 3 days from time point. 
 
Step 1 
Screening 
Step 2 
Screening 
D1 of each 
cycle 
Q12W1 
EOT 
F/U2 
Screening consent 
X 
 
 
 
 
 
Treatment consent 
 
X 
 
 
 
 
Review of medical record 
X 
 
 
 
 
 
Confirmation of resection 
X 
 
 
 
 
 
H&P, PS, wt 
 
X 
X 
 
X 
 
CBC 
 
X 
X 
 
 
 
CMP, LDH, amylase, lipase 
 
X 
X 
 
 
 
TSH, free T3 or total T3, free T4 
 
X 
X 
 
 
 
INR, aPTT9 
 
X 
 
 
 
 
EBV serology 
X11 
 
 
 
 
 
HIV serology 
X11 
 
 
 
 
 
HBV serology 
X11 
 
 
 
 
 
HCV serology 
X11 
 
 
 
 
 
Pregnancy test3 
 
X 
X 
 
 
 
Urinalysis reflex to micro and/or 
culture9 
 
X 
 
 
 
 
ECG 
 
X 
X12 
 
 
 
Randomization6 
 
X 
 
 
 
 
Blood for ctDNA (Signatera 
testing) 
 
X5 
X8 
 
X10 
 
Whole blood and tissue for 
whole exome sequencing (for 
design of Signatera assay) 
X13 
 
 
 
 
 
Atezolizumab 
 
 
X4 
 
 
 
Tiragolumab7 
 
 
X4 
 
 
 
CT scan 
 
X 
 
X2 
 
X 
AE assessment 
 
 
Baseline through 90 days after last day of treatment 
1. corresponds with the end of every 3rd cycle; if there are treatment delays, imaging should continue to be done very 12 weeks rather 
than waiting for the end of every 3rd cycle 
2. Q12W during Years 1 and 2 after surgery, Q24W during Year 3 after surgery; depending on when a patient discontinues treatment, 
follow-up may be Q12W or Q24W; follow-up will discontinue after 3 years have elapsed from date of surgery  
3. women of childbearing potential only 
4. treatment can continue for up to 13 cycles; refer to Section 5.2 for instructions regarding monitoring of vital signs and post-infusion 
observation 
5. must take place 4-12 weeks after surgery; if ctDNA positive, patients will be randomized to receive either atezolizumab and 
tiragolumab or atezolizumab monotherapy, and if ctDNA negative, patient will not continue in this study 
6. stage 1 only; randomization must occur no more than 16 weeks after date of surgery 
7. if randomized to receive tiragolumab during stage 1; all patients during stage 2. 
8. prior to dosing on C3D1, C6D1, C9D1, C12D1 – the collection of blood for ctDNA should be discontinued after 2 consecutive 
negative tests 
9. required at Step 2 screening and thereafter only as clinically indicated 
10. optional 


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11. may take place up to 42 days prior to C1D1 
12. ECG should be performed at Step 2 screening, C3D1, C6D1, C9D1, and C12D1 
13. should be collected around time of resection; blood may be drawn for WES and ctDNA testing at the same time to consolidate blood 
draws; if the blood draw for WES takes place before 4 weeks post-resection, a separate draw is required for ctDNA testing 
 


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1.0 
INTRODUCTION 
 
1.1 
Stage II Melanoma 
 
Recent clinical trials in melanoma have focused on treating high risk stage III patients with 
programmed cell death inhibitor-1 (PD-1) inhibitors and combination BRAF and MEK 
inhibitors in the adjuvant setting to decrease the risk of recurrence and improve distant 
metastasis-free 
survival 
(DMFS) 
and 
overall 
survival 
(OS) 
(S1404/KN053, 
EORTC1325/KN054, CheckMate 238, COMBI-AD). Adult patients with stage III A, B, 
or C melanoma who received 18 doses (~1 year) of pembrolizumab post-resection in 
EORTC1325/KN054 had a significantly longer recurrence-free survival (RFS) than 
placebo [hazard ratio (HR) = 0.57; 98.4% confidence interval (CI), 0.43-0.74; p<0.0001]1. 
In CheckMate 238, resected stage IIIB, IIIC and IV melanoma patients have improved RFS 
and fewer Grade 3 and 4 adverse events (AEs) after one year of adjuvant treatment with 
nivolumab compared to patients treated with ipilimumab, which was previously approved 
by the Food and Drug Administration as adjuvant therapy. COMBI-AD has shown RFS 
benefit with one year of adjuvant treatment using dabrafenib and trametinib in patients 
whose tumors harbor BRAF V600E or V600K mutations with Stage IIIA, B, and C 
melanoma.  
 
All stage II patients are at risk of recurrence after complete surgical resection, which is 
considered standard of care in this patient population. Interferon (IFN) alpha as adjuvant 
therapy in melanoma has shown modest results at best (consistent effect on RFS with a 
maintained HR of 0.86 and approximately a 3% absolute survival advantage at 5 years)2. 
IFN alpha is a regimen with well described significant toxicities, particularly at high-dose, 
and these can profoundly affect quality of life and can even be life threatening.  With high-
dose IFN, approximately 40% of patients have treatment-related AEs that lead to dose 
delays or reductions3.  Adjuvant IFN offers a reduction in RFS but is not universally 
recommended because of the significant toxicity associated with treatment that can affect 
quality of life4.  Pegylated IFN alpha 2b was approved by the Food and Drug 
Administration on 29-MAR-2011 for adjuvant therapy. Today IFN alpha has a limited role 
in adjuvant treatment of melanoma and is now recommended only to patients with 
ulcerated primary melanomas and to patients without access to more modern treatments1.  
 
Some patients with stage II melanoma have OS outcomes similar to those of stage III 
patients. Data from the American Joint Committee on Cancer suggest that 94% of stage 
IIA, 87% of stage IIB, and 82% of stage IIC patients will be alive at 5 years and by 10 
years 88, 82, and 75% respectively. 
   
The stage IIIB 5-year OS rate of 83% is comparable to stage IIC OS at 5 years (82%).  
Similarly, stage IIIA (88%) and IIIB (77%) OS at 10 years are comparable to stage IIA 
(88%) and IIC (75%) OS rate at 10 years, respectively5.  These data clearly show that 
survival outcomes can be as dismal for some stage II patients as for stage III patients.   
 
Despite the increased risk of recurrence, adjuvant therapy is not generally recommended 
for stage II melanoma because of the associated toxicity and the relatively favorable 


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prognosis. Therefore, we propose to treat these patients based on a biomarker (circulating 
tumor DNA) that can enrich for a group of patients with the highest risk of recurrence 
rather treating all comers and exposing some patients to unnecessary toxicities.   
 
This population of high risk of recurrence thus has an unmet medical need for adjuvant 
therapy with the goal of preventing disease recurrence and increasing survival by providing 
treatment with adjuvant atezolizumab and tiragolumab. 
 
1.2 
Circulating Tumor DNA and Risk of Relapse 
 
In the evolving paradigm of effective adjuvant therapy in melanoma, it is essential to 
develop biomarkers identifying patients at high risk of relapse. Currently, features of the 
primary tumor such as ulceration, Breslow and number of mitoses in addition to nodal 
classification and disease stage are with a poor outcome in stages I–III melanoma; 
however, patient numbers in these studies were small and have yet to be confirmed in larger 
cohorts6, 7. 
 
Lee et al. showed that detecting circulating tumor DNA (ctDNA) in plasma taken within 
12 weeks of curative intent surgery is highly predictive of relapse in patients with stage 
II/III melanoma. The majority of patients with detectable ctDNA relapsed within 1 year of 
surgery, suggesting that ctDNA in the plasma can reveal occult metastatic disease that is 
not evident on radiological imaging. Notably, they were able to identify melanoma patients 
at high risk of both distant metastatic relapse and local recurrence, which is consistent with 
studies showing that ctDNA can signal micrometastatic disease after neoadjuvant 
chemotherapy postsurgical resection in breast cancer and following surgery for stage II 
colorectal cancer8 
 
In the same study, ctDNA was independent of standard staging indices in predicting disease 
recurrence, demonstrating the value of this approach in melanoma.  
 
The ability to predict progression to stage IV disease is extremely important in light of 
recent findings that immune checkpoint inhibition improves RFS in stage III melanoma. 
Detection of ctDNA allows identification of a subgroup of patients at high risk of early 
relapse and inferior survival, allowing stratification of patients to adjuvant regimens 
associated with higher toxicity but greater potential for efficacy. Taken at a single time-
point following surgery, it can add to AJCC staging in informing individual prognosis and 
therefore discussion regarding risks and benefits of adjuvant therapy, while longitudinal 
sampling will likely improve the ability to detect disease progression before radiological 
imaging. 
 
We advocate that the findings from Lee et al. be confirmed in clinical trials investigating 
treatment responses in this population in order to evaluate whether it is also a predictive 
biomarker for response to immune or targeted therapy. 
 
Also, in stage IIIA-D, circulating tumor cell (CTC) detection was not associated with sub-
stage, or primary tumor characteristics. Multivariable analysis demonstrated that the 


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detection of ≥1 baseline CTC was significantly associated with decreased 6-month RFS 
[log-rank, P < 0.0001; HR, 3.62, 95% confidence interval (CI), 1.78-7.36; P < 0.0001] and 
54-month RFS (log-rank, P = 0.01; HR, 1.69; 95% CI, 1.13-2.54; P = 0.01).9 
 
In fact, the use of ctDNA and CTCs has been compared for KRAS mutation detection in 82 
patients with lung cancer.10 Results showed that at a diagnostic specificity of 95%, ctDNA 
had a diagnostic sensitivity (detection rate) of 96%. By contrast, CTCs had an inferior 
diagnostic sensitivity of 52% and a specificity of 88%. 
 
In addition, the prognostic value of BRAF mutation-positive ctDNA was investigated in 
patients with melanoma.11 BRAF mutations are observed in approximately 50% of the 
melanoma tumor samples. In this study, 732 patients with BRAF V600 mutation-positive 
melanoma treated mainly with dabrafenib were evaluated. The mutational status 
determined by BEAMing (Beads, Emulsification, Amplification, and Magnetics) 
technology and tumor tissue was compared. BRAF mutations were detectable in ctDNA in 
76%/81% of late-stage patients with BRAF V600E/V600K-positive tumors. Patients 
with BRAF mutation-positive tumors but negative for BRAF-mutant ctDNA at baseline 
had longer progression-free survival and overall survival compared to patients with a 
positive baseline ctDNA result. These results suggest that ctDNA alone seems not to be 
suitable as the principal screening method for patients with unknown BRAF mutation 
status, but the presence and amount of ctDNA has prognostic value. 
 
Thus, compared to CTCs, ctDNA containing tumor biomarkers is easier to isolate from 
blood. ctDNA is thought to contain single or double-stranded fragmented (~150 bp) DNA 
derived from populations of normal and tumor cells. DNA mutations and epigenetic 
modifications such as DNA methylation derived from ctDNA have been frequently studied 
in melanoma and its application in identifying MRD can complement detection and 
enumeration of melanoma CTCs. ctDNA detection of single biomarkers such 
as BRAF or NRAS hotspot mutations have been useful in predicting immunotherapy 
response. Levels of ctDNA mutations have been found to be associated with tumor burden 
and OS. 
 
Like the current CTC assays, ctDNA assays also face the same issue with need for       
increased sensitivity for detecting ctDNA biomarkers in early-stage melanoma patients 
where there is high tumor heterogeneity. One approach to overcome tumor heterogeneity 
is to utilize Signatera.  
 
Signatera is a personalized, custom-built ctDNA assay for MRD assessment and evaluation 
of disease recurrence and treatment response, with the ability to detect somatic variants at 
a variant allele frequency (VAF) of 0.01% in ctDNA isolated from plasma. 12-15 Signatera 
offers several advantages over static liquid biopsy panels. Given the heterogeneity of 
cancer, static liquid biopsy panels that target the same set of genes for each patient can 
track on average ~3 mutations from a given individual’s primary tumor. 16-18 Moreover, 
many mutations identified in these panels may not be tumor derived, making such 
approaches less specific.16-18 Also, the targeted mutations may be driver or subclonal 
mutations which may be susceptible to treatment. Thus, treatment may lead to selective 


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attrition of cancer cells that contain these susceptible mutations, thereby reducing the 
ability of that mutation to track overall cancer burden. In this regard, the Signatera assay 
has an advantage that it prioritizes the detection of clonal, passenger mutations. Clonal 
variants occur early in tumor evolution and remain present in every cancer cell as the tumor 
evolves.19 Most clonal variants are passenger mutations (not driver mutations), i.e. these 
mutations have no effect on the fitness of a clone but are associated with clonal expansion, 
and thus are truly representative of the overall tumor burden. These clonal variants are 
unique to each individual tumor. Identifying and tracking a subset of clonal variants 
provides an opportunity to detect residual disease with high sensitivity and specificity, 
irrespective of tumor heterogeneity. 
 
1.3 
Signatera Assay – Test Principle 
 
To detect residual disease or to determine cancer recurrence with ctDNA, the Signatera 
process starts with sequencing the tumor tissue (resection or shave biopsy) and matched 
normal (whole blood) sample for each patient. Based on the sequencing results, a list of 
somatic SNVs specific to each patient are identified bioinformatically. Next, 16 SNVs are 
selected for multiplex PCR primer design based on several factors, including the clonality, 
and detectability of the mutations identified in the tumor tissue DNA. Regardless of the 
tumor type, the 16 SNV targets selected are unique to each patient with <1% of patients 
sharing any SNV target. PCR primers targeting the personalized 16 SNVs are generated 
and stored for testing. Then, two tubes of blood are drawn from the patient, the plasma is 
isolated, and the DNA, possibly including some ctDNA, is extracted. A universal library 
is then generated from plasma ctDNA, wherein the ctDNA is amplified. An aliquot of the 
universal library is used as an input for amplification of 16 patient-specific targets using 
multiplex PCR (mPCR). The mPCR product is barcoded, pooled, and sequenced on the 
Illumina HiSeq 2500. Sequenced data that passes the quality control (QC) goes through 
ctDNA analysis algorithm followed by issuance of a signed report by a Lab Director that 
contains information on the analyzed data, indicating the presence or absence of ctDNA. 
12,15,17,19 
 
1.4 
Atezolizumab 
 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic blockade 
of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and quality 
of tumor-specific T-cell responses, resulting in improved anti tumor activity (Fehrenbacher 
et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding to fragment 
crystallizable (Fc) receptors, thus eliminating detectable Fc effector function and 
associated antibody-mediated clearance of activated effector T cells. 
 
Atezolizumab shows antitumor activity in both nonclinical models and cancer patients and 
is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and CIT. 


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Atezolizumab is approved for the treatment of urothelial carcinoma, NSCLC, small-cell 
lung cancer, and triple-negative breast cancer. 
 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
 
1.5 
Tiragolumab 
 
Tiragolumab is a fully human IgG1/kappa mAb that binds TIGIT (T-cell Immunoreceptor 
with Immunoglobulin and Immunoreceptor Tyrosine-Based Inhibition Motif [ITIM] 
domains) and prevents its interaction with PVR (Poliovirus Receptor). The available 
nonclinical and clinical data provide a strong rationale for evaluating the potential clinical 
benefit of tiragolumab in cancer patients. Blockade of TIGIT by tiragolumab represents a 
novel strategy for cancer therapy because its mechanism of action is complementary to that 
of other checkpoint inhibitors, such as anti-PD-L1/PD-1. Consequently, tiragolumab as a 
single-agent or in combination with anti-cancer therapies, may enhance the magnitude and 
quality of tumor-specific T-cell responses, which may result in meaningful anti-tumor 
activity in solid tumors and in hematological malignancies.  
 
In the Phase II GO40290 study (CITYSCAPE), the primary analysis (clinical cutoff of 30 
June 2019) showed that the combination of tiragolumab plus atezolizumab improved ORR 
and PFS compared to placebo plus atezolizumab in the ITT population. ORR for 
tiragolumab plus atezolizumab was 31.3% (95% CI: 19.5, 43.2) compared to placebo plus 
atezolizumab which was 16.2% (95% CI: 6.7, 25.7). Investigator-assessed PFS for 
tiragolumab plus atezolizumab was 5.4 months (95% CI: 4.2, not reached) compared to 
placebo plus atezolizumab which was 3.6 months (95% CI: 2.7, 4.4), with a HR of 0.57 
(95% CI: 0.37, 0.90). 
 
Based on the above findings and results, the combination of atezolizumab and tiragolumab 
is of interest to us to investigate in enriched group of stage II melanoma with positive 
ctDNA with the intent to maximize the benefit and render the toxicity of treatment only to 
those who are in most need for therapy. 
 
1.6 
Background on Blockade of the TIGIT Pathway in Cancer as a Potential Anti-
Cancer Therapy 
 
TIGIT is a novel immune inhibitory receptor that is a member of the Ig super family (Yu 
et al. 2009; Manieri et al. 2017).  TIGIT expression is elevated in the tumor 
microenvironment in many human tumors, is coordinately expressed with other checkpoint 
immune receptors such as PD 1 and is associated with impaired T cell function and anti 
tumor immunity (Johnston et al. 2014).  Activation of TIGIT on T cells and NK cells limits 
cellular proliferation, effector cytokine production, and killing of target tumor cells (TCs) 
(Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; Manieri et 
al. 2017). 
 
TIGIT is expressed in a wide variety of human tumors and is highly correlated with T cell 


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infiltration and PD-1 expression (Johnston et al. 2014).  Fluorescence activated cell sorting 
analysis of fresh tumor samples showed that TIGIT and PD-1 are also co expressed on 
tumor infiltrating T cells.  TIGIT expression ranges from 30% to 80% and from 50% to 
80% on tumor infiltrating CD4+ and CD8+ T cells, respectively (Johnston et al. 2014). 
 
Therefore, TIGIT is a potential target for therapeutic intervention aimed at restoring the 
immune response against the tumor.  Agents that inhibit the activity of TIGIT may relieve 
an important source of tumor associated immune suppression and may enhance the activity 
of other immune based therapies, such as atezolizumab, an inhibitor of PD-L1.  Early 
nonclinical results using genetically deficient mice and blocking antibodies reveal a key 
role for TIGIT in regulating T cell responses.  Together the data support the hypothesis that 
anti-TIGIT in combination with anti-PD-L1 may reactivate anti tumor immunity to provide 
clinical benefit to patients.  
 
1.7 
Combined Inhibition of the TIGIT and PD-L1/PD-1 Pathways as Potential 
Anti-Cancer Therapy 
 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of 
tumor associated lymphocytes.  Activation of TIGIT on T cells and NK cells limits 
proliferation, effector cytokine production, and killing of target TCs.  Therefore, in the 
context of the tumor microenvironment, TIGIT acts to limit anti-tumor immune responses.  
Interference with TIGIT-PVR interaction may enhance the magnitude and quality of the 
tumor specific T cell responses through increased expansion of T cells as well as improved 
T cell priming and/or effector function.  Because TIGIT and PD 1 are co-expressed by 
infiltrating T cells in several human tumors, inhibition of the TIGIT/PVR pathway may 
complement and potentiate the anti-tumor activity of a PD L1 pathway inhibitor such as 
atezolizumab. 
 
The combined inhibition of the TIGIT and PD-L1/PD-1 pathways by tiragolumab and 
atezolizumab, respectively, has demonstrated promising clinical activity in the Phase I 
study GO30103 and the Phase II study GO40290 (hereafter referred to as CITYSCAPE).  
Study GO30103 is a first-in-human, combined Phase Ia/Phase Ib, open-label, dose 
escalation, multicenter study.  The study evaluated the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of biologic 
activity of tiragolumab administered as a single agent (Phase Ia) or in combination with 
atezolizumab (Phase Ib) to patients with locally advanced or metastatic malignancies.  As 
of December 2, 2019, 171 patients with multiple tumor types, including NSCLC, had been 
enrolled in the Phase Ib portion of the study.  Objective responses, including complete 
responses (CR) in 4 patients, and partial responses (PR) in 23 patients, have been observed. 
 
No maximum tolerated dose (MTD), no dose-limited toxicities (DLTs), and no clear dose-
related trends in the incidence or severity of adverse events have been determined for 
single-agent tiragolumab (2-1200 mg Q3W) or tiragolumab (2-1200 mg Q3W) in 
combination with atezolizumab (1200 mg Q3W) in Study GO30103. 
 
Tiragolumab was further evaluated in patients with PD-L1 selected advanced NSCLC 


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(tumor proportion score [TPS] ≥ 1%) in the Phase II, global, randomized, double-blind, 
placebo-controlled CITYSCAPE study.  As of the clinical cutoff date of Dec 2, 2019, the 
confirmed ORR in the intent-to-treat (ITT) population was higher in the tiragolumab 
combined with atezolizumab arm (37%) than in the placebo combined with atezolizumab 
arm (21%).  Investigator assessed PFS was also improved with a stratified HR of 0.58 (95% 
CI: 0.38 to 0.89), with a median PFS not estimable and 3.9 months in the tiragolumab 
combined with atezolizumab arm compared to the placebo combined with atezolizumab 
arm, respectively.  Responses to tiragolumab in combination with atezolizumab were 
observed in patients with both squamous and non-squamous histology (Rodriguez-Abreu 
et al, 2020). 
 
As of the clinical cutoff date of December 2, 2019 in the CITYSCAPE study, there were 
135 safety evaluable patients.  The safety profile was comparable between the tiragolumab 
combined with atezolizumab arm and the placebo combined with atezolizumab arm in 
terms of all-grade adverse events (99% vs 96%), Grade ≥ 3 adverse events (48% vs 44%), 
Grade 5 adverse events (4.5% vs 7.4%), serious adverse events (37% vs 35%), and adverse 
events leading to study treatment withdrawal (10.4% vs 8.8%).  Study treatment related 
adverse events occurred at a higher frequency in the tiragolumab combined with 
atezolizumab arm (82%) compared to the placebo combined with atezolizumab arm (72%). 
 
Analyzed with a comprehensive medical concepts strategy, immune-mediated adverse 
events were reported with a higher frequency in the tiragolumab combined with 
atezolizumab arm (69%) compared to the placebo combined with atezolizumab arm (47%).  
The difference (≥ 10% difference between arms) was predominantly attributed to events of 
immune mediated rash (preferred terms of rash, rash maculopapular, dermatitis, erythema, 
eczema, pruritic rash, folliculitis and skin ulcer) (40% vs 15%) and infusion related 
reactions (preferred term of infusion related reaction) (30% vs 10%). 
 
Tiragolumab is being investigated in clinical studies as a potential therapy against various 
tumor types.  Refer to the Tiragolumab Investigator’s Brochure for details on the 
nonclinical and clinical studies for tiragolumab. 
 
1.8 
Study Rationale and Benefit/Risk Assessment 
 
1.8.1 Study Rationale  
 
TIGIT is an inhibitory immunoreceptor that can limit the effector function of tumor 
associated lymphocytes.  Unlike other inhibitory co receptors, TIGIT is often 
coordinately expressed with PD-1 on tumor-infiltrating T cells in multiple tumors.  
In the Phase Ib portion of Study GO30103, evaluating tiragolumab in combination 
with atezolizumab, partial responses (PRs) occurred in patients with metastatic 
cancers, with varying degrees of PD-L1 and/or TIGIT expression (Bendell et al. 
2020).  The combination of atezolizumab with tiragolumab was tolerated in the 
Phase Ib portion of the study, with a safety profile consistent with prior 
observations of atezolizumab.   
 


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In the primary analysis of the Phase II CITYSCAPE study, in all randomized 
patients whose lung cancer had a PD-L1 tumor proportion score (TPS) ≥ 1% (n = 
135), the confirmed objective response rate (ORR) was higher in the tiragolumab 
plus atezolizumab group (31.3%) than in the placebo plus atezolizumab group 
(16.2%) (Rodriguez-Abreu et al. 2020).  Furthermore, investigator-assessed 
progression-free survival (PFS) was improved in the tiragolumab plus 
atezolizumab group (n = 67) relative to placebo plus atezolizumab group (n = 68) 
(stratified HR = 0.57; 95% CI: 0.37 to 0.90; median PFS 5.4 vs. 3.6 months, 
respectively).  The greatest efficacy was observed in patients whose tumors had 
high PD-L1 expression (TPS ≥ 50%; n = 58) with clear separation of the Kaplan-
Meier curve (Rodriguez-Abreu et al. 2020) for whom the confirmed ORR was 
55.2% in the tiragolumab plus atezolizumab group and 17.2% in the placebo plus 
atezolizumab group (stratified HR = 0.33; 95% CI: 0.15 to 0.72; median PFS not 
yet reached vs. 3.88 months, respectively).   
 
Consistent with the Phase Ib portion of Study GO30103, the combination of 
atezolizumab with tiragolumab was tolerated in the Phase II study (for more details, 
refer to the Tiragolumab Investigator’s Brochure).  Atezolizumab plus tiragolumab 
demonstrated an overall safety profile similar to that of atezolizumab alone in terms 
of all Grade adverse events, Grade 3 and 4 adverse events, serious adverse events 
and adverse events leading to study treatment discontinuation.  While adverse 
events related to any study treatment and adverse events leading to dose 
interruption of any study treatment were higher in the tiragolumab plus 
atezolizumab arm, there was no increase in Grade 5 adverse events (see the 
Tiragolumab Investigator’s Brochure).  Adverse events with potentially immune-
mediated causes have been observed with a higher frequency for tiragolumab in 
combination with atezolizumab in the CITYSCAPE study.  However, the 
imbalance was mostly attributed to Grade 1 and 2 rashes and infusion-related 
reactions (IRRs).  Grade 3 and 4 immune-mediated adverse events were similar 
between the tiragolumab plus atezolizumab treatment group compared with 
atezolizumab treatment alone.  To date, immune-mediated adverse events have 
been 
manageable 
with 
standard 
medical 
practice 
supplemented 
with 
corticosteroids, immunosuppressive agents, and/or hormone replacement therapy. 
   
1.8.2 Rationale for Atezolizumab / Tiragolumab Dose and Schedule 
 
Atezolizumab will be administered at a fixed dose of 1680 mg Q4W (1680 mg on 
Day 1 of each 28-day cycle), which is an approved dosage for atezolizumab, as 
outlined in the prescribing information.  The average concentration following the 
1680 mg Q4W dosage is expected to be equivalent to that of 1200 mg Q3W.  Anti-
tumor activity has been observed across doses ranging from 1 mg/kg to 20 mg/kg 
Q3W.  In Study PCD4989g, the maximum tolerated dose of atezolizumab was not 
reached and no DLTs were observed at any dose.  The fixed dose of 1200 mg Q3W 
(equivalent to an average body weight-based dose of 15 mg/kg Q3W) was selected 
on the basis of both nonclinical studies (Deng et al. 2016) and available clinical 
pharmacokinetic, efficacy, and safety data (refer to the Atezolizumab Investigator's 


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Brochure for details). 
 
Tiragolumab will be administered to patients at a fixed dose of 840 mg Q4W by IV 
infusion on Day 1 of each 28-day cycle.  The 840-mg Q4W dosing regimen is 
supported by results from PK modeling and simulation and exposure-safety 
analyses.  Briefly, the average and trough concentrations following the 840-mg 
Q4W dosing regimen are predicted to be similar to those of the 600-mg Q3W 
dosing regimen, which was evaluated in Studies GO30103 and GO40290.  The 
predicted maximum serum concentration (Cmax) of the 840-mg Q4W dosing 
regimen is 28% higher at steady state relative to the predicted Cmax of the 600-mg 
Q3W dosing regimen, but falls within the range of observed exposure of the highest 
administered dose (1200 mg Q3W in Study GO30103).  A preliminary analysis of 
the tiragolumab exposure-safety relationship based on data from Study GO30103 
(tiragolumab doses of 2-1200 mg Q3W administered as monotherapy or in 
combination with 1200 mg atezolizumab Q3W) suggests that tiragolumab does not 
appear to have an exposure-safety relationship.  In summary, the 840-mg Q4W 
dosing regimen is expected to have comparable efficacy and safety as the 600-mg 
Q3W dosing regimen given that the predicted exposure is within the range of 
observed efficacious exposures and tiragolumab does not appear to have an 
exposure-safety relationship.  
 
The fixed tiragolumab dose of 600 mg IV Q3W was selected for Study GO40290 
on the basis of available PK, safety, and preliminary efficacy data from Study 
GO30103, in which patients received single-agent tiragolumab or tiragolumab plus 
atezolizumab.  In Study GO30103, the MTD was not reached, and no DLTs were 
observed with tiragolumab monotherapy or in combination with 1200 mg Q3W 
atezolizumab (tiragolumab doses of 2-1200 mg Q3W).  In addition, development 
of ADAs to tiragolumab was observed in < 5% of evaluable patients receiving 
tiragolumab (doses of 2-1200 mg Q3W) in combination with atezolizumab.  
Complete occupancy of peripheral TIGIT receptors on CD4+ CD8+ T cells and NK 
cells was observed beginning at the 30 mg Q3W dose of tiragolumab and remained 
sustained at all higher doses.  Anti-tumor activity (as demonstrated by radiographic 
PRs) was observed at tiragolumab doses of 30-600 mg Q3W when given in 
combination with 1200 mg atezolizumab Q3W. 
 
1.8.3 Benefit/Risk Assessment 
 
The toxicities of atezolizumab alone and the combination of atezolizumab plus 
tiragolumab are expected to be similar.  Immune-mediated adverse events, although 
reported at a higher frequency for the atezolizumab plus tiragolumab arm in the 
Phase II study GO40290, are generally mild, transient, monitorable, and 
manageable in nature.   
 
 


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2.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
To determine the ctDNA 
clearance rate in patients with 
stage II melanoma who test 
positive for circulating tumor 
DNA and are treated with 
atezolizumab and tiragolumab. 
ctDNA clearance rate, defined as 
the proportion of ctDNA-
positive patients having a 
ctDNA-negative test at C3D1. 
Immune checkpoint 
blockade (ICB) provides 
clinical benefit to a subset 
of patients with cancer. 
However, existing 
biomarkers do not reliably 
predict treatment response 
across diverse cancer 
types. Bratman et al 
showed how serial 
circulating tumor DNA 
(ctDNA) testing may 
perform as a predictive 
biomarker in patients 
receiving ICB. Authors ran 
a prospective phase II 
clinical trial to assess 
ctDNA in five distinct 
cohorts of patients 
(including melanoma) with 
advanced solid tumors 
treated with 
pembrolizumab 
(NCT02644369). They 
applied bespoke ctDNA 
assays to 316 serial plasma 
samples obtained at 
baseline and every three 
cycles from 94 patients. 
Baseline ctDNA 
concentration correlated 
with progression-free 
survival, overall survival, 
clinical response and 
clinical benefit. This 
association became 
stronger when considering 
ctDNA kinetics during 
treatment. All 12 patients 
with ctDNA clearance 
during treatment were alive 


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with median 25 months 
follow up. This study 
demonstrates the potential 
for broad clinical utility of 
ctDNA-based surveillance 
in patients treated with 
ICB.22 
Secondary 
To determine the confirmed 
ctDNA negativity proportion 
with two consecutive negative 
results in patients with stage II 
melanoma who test positive 
for circulating tumor DNA and 
are treated with atezolizumab 
and tiragolumab, and those 
who are treated with 
atezolizumab alone. 
Proportion of ctDNA-positive 
patients having a ctDNA-
negative test at two consecutive 
measures  
 
To determine the relapse-free 
survival in patients with stage 
II melanoma who test positive 
for circulating tumor DNA and 
are treated with atezolizumab 
and tiragolumab, and those 
who are treated with 
atezolizumab alone 
Relapse-free survival (RFS), 
defined as the duration of time 
from the date of randomization 
to the date of earliest disease 
relapse or death, whichever 
occurs first. 
RFS is an acceptable 
measure of clinical benefit 
for a late stage study that 
demonstrates superiority of 
a new antineoplastic 
therapy, especially if the 
magnitude of the effect is 
large and the therapy has 
an acceptable risk/benefit 
profile. 
To determine the distant 
metastasis-free survival in 
patients with stage II 
melanoma who test positive 
for circulating tumor DNA and 
are treated with atezolizumab 
and tiragolumab, and those 
who are treated with 
atezolizumab alone  (both 
circulating tumor DNA 
positive and negative). 
Distant-metastasis free survival 
(DMFS), defined as the duration 
of time from the date of positive 
ctDNA being confirmed to the 
date of appearance of a distant 
metastasis or death, whichever 
occurs first. 
The secondary efficacy 
objective of this study is to 
compare DMFS between 
the two treatment arms 
To determine the overall 
survival of patients with stage 
II melanoma. 
Overall survival (OS), defined as 
the duration of time from the 
date of positive ctDNA being 
confirmed to death from any 
cause. 
The secondary efficacy 
objective of this study is to 
compare OS between the 
two treatment arms 
To evaluate the safety and 
tolerability of atezolizumab 
Defined as the number of 
treatment-related grade 3 or 
Safety parameters 
commonly used for 


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and tiragolumab in patients 
with stage II melanoma. 
greater AEs and discontinuations 
due to treatment-related AEs. 
evaluating investigational 
systemic anticancer 
treatments are included as 
safety endpoints including, 
but not limited to, the 
incidence of, causality, and 
outcome of AEs/serious 
adverse events (SAEs); and 
changes in vital signs and 
laboratory values. Adverse 
events will be assessed as 
defined by CTCAE, 
Version 5.0. 
To assess the impact of ctDNA 
kinetics on outcomes (relapse-
free survival, distant 
metastasis-free survival, and 
overall survival) in patients 
with surgically resected stage 
II melanoma. 
 
 
 
 
3.0 
STUDY POPULATION 
 
3.1 
Step One (Signatera Assay Development) Eligibility 
 
3.1.1 Inclusion Criteria 
 
1. Surgically resected and histologically/pathologically confirmed stage II 
cutaneous melanoma.  No more than 16 weeks may elapse between final 
surgical resection and randomization.  Treatment should start only after 
complete wound healing from the surgery. 
 
2. Participants must not have been previously treated for melanoma beyond 
complete surgical resection.  
 
3. At least 18 years of age. 
 
4. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.1.2 Exclusion Criteria 
 
1. A history of other malignancy with the exception of malignancies for which all 
treatment was completed at least 2 years before registration and the patient has 
no evidence of disease or malignancies in situ (such as DCIS), basal cell 


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carcinoma, or localized cutaneous squamous cell carcinomas. 
 
2. Currently receiving any other investigational agents. 
 
3. Prior history of pneumonitis. 
 
4. A history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to atezolizumab and tiragolumab or other agents used in 
the study. 
 
5. 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. 
 
6. 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, with the exceptions 
listed below: 
a. Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid replacement hormone are eligible for the study. 
b. Patients with controlled Type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study. 
c. 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: 
i. Rash must cover < 10% of body surface area 
ii. Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids 
iii. 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 
 
7. Active tuberculosis. 
 
8. Prior allogeneic stem cell or solid organ transplantation 
 
9. Positive hepatitis B surface antigen (HBsAb) at screening. 
 
10. Positive hepatitis C virus (HCV) antibody test at screening (unless followed by 
a negative HCV RNA test). 
 


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11. Current treatment with anti-viral therapy for HBV 
 
12. Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M 
(IgM) test at screening.  An EBV PCR test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection.  
Patients with a positive EBV PCR test are excluded. 
 
13. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti-CTLA-4, anti-PD-1, anti-TIGIT, and anti-PD-L1 therapeutic 
antibodies. 
 
14. History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
15. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 
cells/mcL or they have a history of AIDS-defining opportunistic infection 
within the 12 months prior to registration.  Concurrent treatment with effective 
ART according to DHHS treatment guidelines is recommended. 
 
3.2 
Step Two (Randomization and Treatment) Eligibility 
 
3.2.1 Inclusion Criteria 
 
1. Positive ctDNA test. 
 
2. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,500/mcL 
b. Lymphocyte count ≥ 500/mcL 
c. Platelets ≥ 100,000/mcL 
d. Hemoglobin ≥ 9.0 g/dL (patients may be transfused to meet this criterion) 
e. Total bilirubin ≤ 1.5 x IULN or direct bilirubin ≤ IULN for participants with 
total bilirubin levels > 1.5 x IULN; patients with known Gilbert disease 
must have total bilirubin ≤ 3 x IULN 
f. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
g. Alkaline phosphatase ≤ 2.5 x IULN 
h. Creatinine clearance ≥ 45 mL/min by Cockcroft-Gault 
i. Serum albumin ≥ 2.5 g/dL 
j. INR or PT ≤ 1.5 x IULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of intended use 
of anticoagulants 
k. aPTT ≤ 1.5 x IULN unless participant is receiving anticoagulant therapy as 
long as PT or aPTT is within therapeutic range of intended use of 
anticoagulants 
 
3. ECOG performance status ≤ 1 (see Appendix A) 
 


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4. The effects of atezolizumab and tiragolumab on the developing human fetus are 
unknown.  For this reason, women of childbearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control, 
abstinence) prior to study entry and for the duration of study participation, for 
90 days after the final dose of tiragolumab, and for 5 months after the final dose 
of atezolizumab.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she must inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of the study, and 90 
days after completion of the study 
 
3.2.2 Exclusion Criteria 
 
1. Pregnant and/or breastfeeding.  Women of childbearing potential must have a 
negative pregnancy test within 14 days of study entry. 
 
2. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of 
study treatment, or anticipation of need for such a vaccine during study 
treatment, within 90 days after the final dose of tiragolumab, or within 5 months 
after the final dose of atezolizumab 
 
3. Treatment with systemic immunosuppressive medication (including, but not 
limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor-α [TNF-α] 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: 
a. 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 
b. 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. 
 
4. Major surgical procedure within 4 weeks prior to initiation of study treatment, 
or anticipation of need for a major surgical procedure during the study. 
 
5. 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, or any active infection that, in the opinion of the 
investigator, could impact patient safety 
 
6. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to 
initiation of study treatment.  Patients receiving prophylactic antibiotics (e.g., 


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to prevent a urinary tract infection or chronic obstructive pulmonary disease 
exacerbation) are eligible for the study.  
 
7. Treatment with systemic immunostimulatory agents (including, but not limited 
to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
Registration for this trial will be a two-step process.  Step One will be screening and confirmation 
of eligibility for Signatera assay development.  Step Two will be screening and confirmation of 
eligibility for randomization (if applicable) and treatment, which must occur no more than 16 
weeks after resection. 
 
Step One screening may occur as soon as pathology has confirmed that the patient has stage II 
cutaneous melanoma.  Step One enrollment will be “On Study” in the OnCore database.  Step Two 
screening will occur after the Signatera assay has been developed.  Blood for ctDNA testing must 
be drawn and sent for analysis between 4 and 12 weeks after resection.  It is possible for blood for 
assay development and blood for ctDNA testing to be drawn at the same time provided that time 
point is 4 to 12 weeks after resection.  Step Two enrollment will be “On Treatment” in the OnCore 
database. 
  
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least two business days prior to 
registering patient: 
 


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1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within two business days. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs.  UPN will be formatted as Site No. (XXX) 
– Patient No. (XXX).  Site No. will be assigned by the Siteman Cancer Center and is site-
specific; patient no. will be assigned by the Siteman Cancer Center and is patient-specific. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study (i.e. who do not subsequently undergo ctDNA 
testing).  A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (if applicable).   
 
4.5 
Measures to Minimize Bias: Randomization 
 
After enrollment to stage 1, patients who are determined to be ctDNA positive will be 
randomized to receive either atezolizumab and tiragolumab (treatment group) or 
atezolizumab monotherapy (reference group) on a 1:1 basis.  The study will use a simple 


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randomization method. This method is equivalent to tossing a coin (where the probability 
of a head is 0.5) to determine treatment assignment (i.e., heads - atezolizumab and 
tiragolumab, tails – atezolizumab). Using the computer, a sequence of random numbers 
will be generated which are uniformly distributed between 0 and 1 and independent of each 
other. For the i-th patient entering the trial, if the i-th random number ≤ 0.5,  a combined 
treatment of atezolizumab and tiragolumab will be assigned; if the i-th random number > 
0.5 then atezolizumab monotherapy will be assigned. 
 
If it is determined (after analysis of stage 1) that enrollment will continue to stage 2, 
randomization will discontinue.  All stage 2 patients will receive atezolizumab + 
tiragolumab. 
 
4.6 
Screening and Enrollment Considerations 
 
The screening and enrollment targets outlined below should be considered in order to 
maintain adequate momentum towards trial completion. If at any time a screening or 
enrollment milestone cannot be met, the sponsor may elect to employ additional screening 
enhancement strategies upon discussion with Genentech/Roche, and consider stopping the 
study altogether due to feasibility. 
 
 
Screening Target 
Sub-Site 
Participation 
Enrollment Target 
6-month milestone 
20% of Stage 1 
patients screened 
(n>28) 
1 additional sub-site 
added 
n>5 enrolled 
12-month milestone 
40% of Stage 1/II 
patients screened 
(n>97) 
1 additional sub-site 
added  
n>19 enrolled 
18-month milestone 
60% of Stage 1/II 
patients screened 
(n>144) 
1 additional sub-site 
(optional) 
n>29 enrolled 
24-month milestone 
80% of Stage I/II 
patients screened 
(n>195) 
-- 
n>39 enrolled 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Study Intervention Description 
 
Atezolizumab is a PD-L1 blocking antibody which is indicated for the treatment of: 
● some adult patients with locally advanced or metastatic urothelial carcinoma 
● adult patients with metastatic non-squamous non-small cell lung cancer with no 
EGFR or ALK genomic tumor aberrations (in combination with bevacizumab, 
paclitaxel, and carboplatin) 
● adult patients with metastatic non-small cell lung cancer who have disease 


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progression during or following platinum-containing chemotherapy 
● adult patients with extensive-stage small cell lung cancer (in combination with 
carboplatin and etoposide) 
 
Tiragolumab is a fully human IgG1/kappa mAb that binds TIGIT (T-cell Immunoreceptor 
with Immunoglobulin and Immunoreceptor Tyrosine-Based Inhibition Motif [ITIM] 
domains) and prevents its interaction with PVR (Poliovirus Receptor).  
 
5.2 
Study Intervention Administration 
 
Consenting and eligible patients will undergo a blood draw to test for ctDNA 4 to 12 weeks 
after surgery.  Twenty mL of blood will be drawn into 2 10-mL Streck tubes as described 
in Section 9.0. 
 
During stage 1 of the study, patients who are ctDNA-positive will be randomized on a 1:1 
basis either to receive atezolizumab + tiragolumab or atezolizumab alone.  If, after analysis 
of stage 1 data, it is determined that enrollment will continue to stage 2, all patients will 
receive atezolizumab + tiragolumab. 
 
Atezolizumab is given as an IV infusion every 4 weeks at a dose of 1680 mg over 60 
minutes (+/- 15 minutes).  If this rate of infusion is tolerated without an infusion-related 
reaction, subsequent infusions of atezolizumab may be given over 30 minutes (+/- 10 
minutes). Otherwise, the rate of infusion remains 60 minutes (+/- 15 minutes).  After the 
first infusion of atezolizumab, the patient begins a 60-minute observation period during 
which vital signs should be recorded at 30 (+/-10 minutes) after infusion.  If the patient 
tolerated the first infusion well without infusion-associated adverse events, the observation 
period after the next and following infusions may be reduced to 30 minutes.  If the patient 
experienced infusion-associated adverse events in the previous infusion, the observation 
period should be 60 minutes.  If clinically indicated, vital signs should be recorded at 30 
(+/- 10) minutes after the infusion of atezolizumab. 
 
Tiragolumab is given as an IV infusion every 4 weeks at a dose of 840 mg over 60 minutes 
(+/- 15 minutes).  If this rate of infusion is tolerated without an infusion-related reaction, 
subsequent infusions of tiragolumab may be given over 30 minutes (+/- 10 minutes).  
Otherwise, the rate of infusion remains 60 minutes (+/- 15 minutes).  After the first infusion 
of tiragolumab, the patient begins a 60-minute observation period during which vital signs 
should be recorded at 30 (+/-10 minutes) after infusion.  If the patient tolerated the first 
infusion well without infusion-associated adverse events, the observation period after the 
next and following infusions may be reduced to 30 minutes.  If the patient experienced 
infusion-associated adverse events in the previous infusion, the observation period should 
be 60 minutes.  If clinically indicated, vital signs should be recorded at 30 (+/- 10) minutes 
after the infusion of tiragolumab. 
 
Treatment can continue for up to 13 cycles.  For patients receiving both drugs, 
atezolizumab will be given first, followed by tiragolumab.  If either study drug is delayed 
for a related toxicity, it is recommended that the other study drug is also delayed (if 


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applicable) since the safety profiles for atezolizumab and tiragolumab are similar. 
 
All patients will receive CT scans every 12 weeks for the first two years after initiation of 
treatment, then every 24 weeks for the next year; frequency of scans will not be adjusted 
in the event of a treatment delay.   
 
Administration of First and Subsequent Infusions of Atezolizumab and Tiragolumab 
 
Study drug 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
 No premedication is permitted 
prior to the atezolizumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
recorded within 60 minutes 
prior to the infusion. 
 Atezolizumab should be 
infused over 60 ( 15) minutes. 
 If clinically indicated, vital 
signs should be recorded every 
15 ( 5) minutes during the 
infusion. 
 If the patient experienced an IRR with 
any previous infusion of atezolizumab, 
premedication with an antihistamine 
and/or antipyretic medication may be 
administered for subsequent doses at the 
discretion of the investigator. 
 Vital signs should be recorded within 
60 minutes prior to the infusion. 
 Atezolizumab should be infused over 
30 ( 10) minutes if the previous 
infusion was tolerated without an IRR or 
60 ( 15) minutes if the patient 
experienced an IRR with the previous 
infusion.  
 If the patient experienced an IRR with 
the previous infusion, or if clinically 
indicated, vital signs should be recorded 
during the infusion. 
Observation 
period after 
infusion of 
atezolizumab 
 After the infusion of 
atezolizumab, the patient begins 
a 60-minute observation period. 
 Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion of atezolizumab. 
 Patients will be informed about 
the possibility of delayed post-
infusion symptoms and 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient tolerated the previous 
atezolizumab infusion well without 
infusion-associated adverse events, 
the observation period after the next and 
following infusions may be reduced to 
30 minutes. 
 If the patient experienced infusion-
associated adverse events in the previous 
infusion, the observation period should 
be 60 minutes. 
 If clinically indicated, vital signs should 
be recorded at 30 ( 10) minutes after the 
infusion of atezolizumab. 
Infusion of 
tiragolumab 
 No premedication is permitted 
prior to the tiragolumab 
infusion. 
 Vital signs (pulse rate, 
respiratory rate, blood pressure, 
and temperature) should be 
recorded within 60 minutes 
prior to the infusion. 
 If the patient experienced an IRR during 
any previous infusion of tiragolumab, 
premedication with an antihistamine 
and/or antipyretic may be administered 
for subsequent doses, at the discretion of 
the investigator. 
 Vital signs should be recorded within 60 
minutes prior to the tiragolumab 
infusion. 


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Study drug 
First Infusion 
Subsequent Infusions 
 Tiragolumab should be infused 
over 60 ( 15) minutes. 
 Vital signs should be recorded 
every 15 ( 5) minutes during 
the infusion. 
 Tiragolumab should be infused over 
30 ( 10) minutes if the previous 
infusion was tolerated without an 
infusion-related reaction, or 
60 ( 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 Vital signs should be recorded during the 
infusion if clinically indicated. 
Observation 
period after 
infusion of 
tiragolumab 
 After the infusion of 
tiragolumab, the patient begins 
a 60-minute observation period. 
 Vital signs should be recorded 
at 30 ( 10) minutes after the 
infusion of tiragolumab. 
● Patients will be informed about 
the possibility of delayed post-
infusion symptoms and will be 
instructed to contact their study 
physician if they develop such 
symptoms. 
 If the patient tolerated the previous 
infusion of tiragolumab well without 
infusion-associated adverse events, the 
observation period may be reduced to 30 
minutes. 
 If the patient experienced an infusion-
associated adverse event in the previous 
infusion, the observation period should 
be 60 minutes. 
 If clinically indicated, vital signs should 
be recorded at 30 ( 10) minutes after the 
infusion of tiragolumab. 
● Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and will be instructed to 
contact their study physician if they 
develop such symptoms. 
IRR  infusion-related reaction. 
 
5.3 
Definitions of Evaluability 
 
In order to be evaluable for the primary objective (ctDNA negativity at C3D1), a patient 
must have blood drawn to assess ctDNA at that time point.  Patients in Stage 1 who 
discontinue treatment prior to C3D1 will be replaced; patients in Stage 2 who discontinue 
treatment prior to C3D1 will not be replaced. 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 90-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue participation prior 
to having any disease assessment. 
 
5.4 
Concomitant Therapy and Supportive Care Guidelines 
 
If a patient experiences an infusion-related reaction with any previous infusion of 
atezolizumab or tiragolumab, premedication with an antihistamine and/or antipyretic 
medication may be administered for subsequent doses at the discretion of the investigator. 


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5.4.1 Permitted Therapy  
 
Patients are permitted to use the following therapies during the study: 
● Oral contraceptives with a failure rate of < 1% per year 
● Hormone-replacement therapy 
● Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a 
stable dose or low-molecular-weight heparin) 
● Inactivated influenza vaccinations 
● Megestrol acetate administered as an appetite stimulant  
● Mineralocorticoids (e.g., fludrocortisone) 
● Corticosteroids administered for COPD or asthma 
● Low-dose corticosteroids administered for orthostatic hypotension or 
adrenocortical insufficiency 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second and subsequent infusions only, at the discretion of the 
investigator. 
 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients 
who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress 
should be managed with supportive therapies as clinically indicated (e.g., 
supplemental oxygen and β2-adrenergic agonists). 
 
5.4.2 Cautionary Therapy for Atezolizumab- and Tiragolumab-Treated 
Patients 
 
5.4.2.1 Corticosteroids, Immunosuppressive Medications, and TNF-α 
Inhibitors 
 
Systemic corticosteroids, immunosuppressive medications, and TNF-α 
inhibitors may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab.  Therefore, in situations in which systemic 
corticosteroids, immunosuppressive medications, or TNF-α inhibitors 
would be routinely administered, alternatives, including antihistamines, 
should be considered.  If the alternatives are not feasible, systemic 
corticosteroids, immunosuppressive medications, and TNF-α inhibitors 
may be administered at the discretion of the investigator. 
 


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Systemic 
corticosteroids 
or 
immunosuppressive 
medications 
are 
recommended, at the discretion of the investigator, for the treatment of 
specific adverse events when associated with atezolizumab and/or 
tiragolumab therapy. 
 
5.4.2.2 Herbal Therapies 
 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are 
generally unknown.  However, herbal therapies not intended for the 
treatment of cancer may be used during the study at the discretion of the 
investigator. 
 
5.4.3 Prohibited Therapy 
 
Use of the following concomitant therapies is prohibited as described below: 
● Concomitant therapy intended for the treatment of cancer (including, but 
not limited to, chemotherapy, hormonal therapy, immunotherapy, 
radiotherapy, and herbal therapy), whether health authority-approved or 
experimental, is prohibited for various time periods prior to starting study 
treatment, depending on the agent, and during study treatment, until disease 
progression is documented and the patient has discontinued study treatment. 
● Investigational therapy within 42 days prior to initiation of study treatment 
and during study treatment.  Of note, COVID vaccines are not considered 
an investigational therapy. 
● Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks 
prior to initiation of study treatment, during study treatment, for 90 days 
after the final dose of tiragolumab, and for 5 months after the final dose of 
atezolizumab. 
● Systemic immunostimulatory agents (including, but not limited to, 
interferons and IL 2) are prohibited within 4 weeks or 5 drug-elimination 
half-lives (whichever is longer) prior to initiation of study treatment and 
during study treatment because these agents could potentially increase the 
risk for autoimmune conditions when given in combination with 
atezolizumab and tiragolumab. 
 
5.5 
Women of Childbearing Potential 
 
Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per 
year during the treatment period and for 90 days after the final dose of tiragolumab and 5 
months after the final dose of atezolizumab.   
 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified 
cause other than menopause), and is not permanently infertile due to surgery (i.e., removal 
of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator 


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(e.g., Müllerian agenesis).  The definition of childbearing potential may be adapted for 
alignment with local guidelines or regulations. 
 
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices, and copper intrauterine devices. 
 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
adequate methods of contraception. 
 
With a female partner of childbearing potential, men who are not surgically sterile must 
remain abstinent or use a condom plus an additional contraceptive method that together 
result in a failure rate of < 1% per year during the treatment period, for 90 days after the 
final dose of tiragolumab.  Men must refrain from donating sperm during this same period. 
 
With a pregnant female partner, men must remain abstinent or use a condom during the 
treatment period for 90 days after the final dose of tiragolumab to avoid exposing the 
embryo.  
 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
adequate methods of contraception. 
 
5.6 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for up to 
13 cycles or until one of the following criteria applies: 
 
● Documented and confirmed disease progression 
● Death 
● Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
● General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
● Suspected pregnancy 
● Serious noncompliance with the study protocol 
● Lost to follow-up 
● Patient withdraws consent 


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● Investigator removes the patient from study 
● The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar with the exception of discontinuation due to disease 
recurrence; patients who stop treatment due to recurrence will be considered off study and 
will no longer be followed after the 90-day follow-up for adverse events is completed. 
 
5.7 
Duration of Follow-up 
 
Follow-up frequency is calculated from date of surgery.  After surgery, patients will be 
followed every 12 weeks for 2 years and every 24 weeks for 1 additional year.  Frequency 
and duration of follow-up after the end of treatment depends on when treatment is 
discontinued.  Patients will be followed for 3 years from date of surgery regardless of when 
treatment is discontinued unless treatment is discontinued due to disease recurrence, in 
which case the patient will be considered off study after the 90-day follow-up for adverse 
events is completed.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
5.8 
Lost to Follow-Up 
 
A patient will be considered lost to follow-up if he or she fails to return for 2 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the patient fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the patient and reschedule the missed visit 
within 2 weeks and counsel the patient on the importance of maintaining the 
assigned visit schedule and ascertain if the patient wishes to and/or should continue 
in the study. 
o Before a patient is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the patient (where possible, 3 telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address).  
These contact attempts should be documented in the patient’s medical record or 
study file. 
o Should the patient continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Other holds and modifications beyond what is described below may be made at the discretion of 
the PI. 
 
 
 


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6.1 
Dose Modifications 
 
There will be no dose modifications, including dose reductions, for atezolizumab or 
tiragolumab in this study. 
 
6.2 
Treatment Interruptions 
 
Study treatment may be temporarily suspended as appropriate for management of toxicity.  
On the basis of the available characterization of mechanism of action, tiragolumab may 
cause adverse events similar to but independent of atezolizumab, may exacerbate the 
frequency or severity of atezolizumab related adverse events, or may have non overlapping 
toxicities with atezolizumab.  Because these scenarios may not be distinguished from one 
another in the clinical setting, immune mediated adverse events should generally be 
attributed to both study drugs, and dose interruptions or treatment discontinuation in 
response to immune mediated adverse events should be applied to both atezolizumab and 
tiragolumab. 
 
In the adjuvant setting, atezolizumab and tiragolumab may be held for a maximum of 12 
weeks.  If tiragolumab is interrupted for > 12 weeks for any reason, the patient must 
permanently discontinue tiragolumab treatment, but may continue atezolizumab if there is 
no contraindication and after discussion with the PI to determine whether the toxicity is 
considered related to tiragolumab and/or to the combination.  An exception can be made if 
in the judgment of the investigator, the patient is likely to derive clinical benefit from 
resuming tiragolumab after a hold of > 12 weeks.  In this case, tiragolumab may be restarted 
with the approval of the PI.  If atezolizumab is interrupted for > 12 weeks, the patient must 
permanently discontinue atezolizumab.  However, if, in the judgment of the investigator, 
the patient is likely to derive clinical benefit from atezolizumab after a hold of > 12 weeks, 
atezolizumab may be restarted with the approval of the PI.  Continued dosing of patients 
with single agent atezolizumab will require that all other study eligibility criteria continue 
to be met.  Continued administration of single agent tiragolumab after permanent 
discontinuation of atezolizumab is not permitted.  
 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab and/or 
tiragolumab may be withheld for additional time beyond > 12 weeks from the last dose 
until steroids are discontinued, or until steroids are reduced to prednisone dose (or dose 
equivalent) ≤ 10 mg/day.  The acceptable length of interruption will depend on an 
agreement with the PI.  
 
Dose interruptions for reason(s) other than toxicity may be allowed with PI approval. 
 
6.2.1 Study treatment discontinuation criteria specific to tiragolumab or 
atezolizumab-related AEs 
 
 Any Grade ≥ 2 treatment-related uveitis, eye pain, or blurred vision that does 
not respond to topical therapy and does not improve to Grade 1 severity within 
8 weeks or requires systemic treatment. 


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 Any Grade ≥ 2 treatment-related pneumonitis or interstitial lung disease that 
does not resolve following dose delay and systemic steroids. 
 For Grade ≥ 3 adrenal insufficiency or Grade ≥ 4 hypophysitis, treatment needs 
to be discontinued regardless of control with hormone replacement (Note: 
Hospitalization for diagnostic workup of adrenal insufficiency without severe 
symptoms should not require discontinuation). 
 Any Grade ≥ 3 non-skin, treatment-related AE lasting > 7 days or recurs, with 
the following exceptions for uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reactions, infusion reactions, 
endocrinopathies, and laboratory abnormalities:  
o Grade 3 treatment-related uveitis, pneumonitis, bronchospasm, diarrhea, 
colitis, neurologic toxicity, hypersensitivity reaction, or infusion reaction of 
any duration requires discontinuation.  
o Grade 
3 
treatment-related 
endocrinopathies 
(excluding 
adrenal 
insufficiency and hypophysitis) adequately controlled with only 
physiologic hormone replacement do not require discontinuation.  
o Grade 3 treatment-related laboratory abnormalities do not require treatment 
discontinuation except:  
 Grade 3 treatment-related thrombocytopenia > 7 days or associated with 
clinically significant bleeding requires discontinuation.  
 In most cases of Grade 3 AST or ALT elevation, study treatment will be 
permanently discontinued. If the Investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion 
between the Investigator and the Medical Monitor/designee must occur.  
 Any treatment-related liver function test abnormality that meets the following 
criteria require discontinuation:  
o AST or ALT > 5 × ULN to 8 × ULN for > 2 weeks 
o AST or ALT > 8 × ULN 
o Total bilirubin > 5 × ULN 
o Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN  
 Grade 3 or 4 infusion reaction of any duration  
 Any Grade 4 treatment -related AE or laboratory abnormality, except for the 
following events, which do not require discontinuation:  
o Grade 4 neutropenia ≤ 7 days.  
o Grade 4 lymphopenia or leukopenia ≤ 14 days in duration.  
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to Grade 
< 4 or return to baseline within 7 days.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management within 72 hours of their onset.  
o Grade 4 treatment -related endocrinopathy AEs (except adrenal 
insufficiency or hypophysitis), such as hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with 
physiologic hormone replacement (corticosteroids at ≤ 10 mg of prednisone 
or equivalent per day, thyroid hormones) or glucose-controlling agents, 


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respectively, may not require discontinuation after discussion with and 
approval from the Medical Monitor.  
 Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of 
the Investigator, presents a substantial clinical risk to the patient with continued 
treatment. 
 Disease recurrence (local, regional, or distant), including new primary 
melanoma (except MMIS Stage 0) Note: Non-melanoma skin cancer does not 
require treatment discontinuation. In the absence of intolerable toxicity, patients 
with diagnosed MMIS Stage 0 melanoma will be eligible to continue study 
treatment using the same dose and schedule for their original melanoma of up 
to approximately 1 year of study treatment starting from first dose, at the 
discretion of the Investigator. 
 
6.3 
Management Guidelines for Atezolizumab- and Tiragolumab-Specific 
Adverse Events 
 
6.3.1 Respiratory Disorders and Pulmonary Events 
 
Immune-mediated pulmonary events are a potential risk with tiragolumab.   
 
Pulmonary events may present as new or worsening cough, chest pain, fever, 
dyspnea, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be 
assessed for pulmonary signs and symptoms throughout the study.   
 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or 
pulmonary hypertension. COVID-19 evaluation should be performed per 
institutional guidelines where relevant.  Management guidelines for pulmonary 
events are provided in the table below. 
 
Management Guidelines for Respiratory Disorders and Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Respiratory 
disorder or other 
pulmonary 
event, Grade 1  
● Continue atezolizumab and tiragolumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
Respiratory 
disorder or other 
pulmonary 
event, Grade 2 
● Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
● Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL with or without transbronchial biopsy. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 


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Event 
Management 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and tiragolumab and contact Medical Monitor. c 
● For recurrent events, treat as a Grade 3 or 4 event. 
Respiratory 
disorder or other 
pulmonary 
event, Grade 3 or 
4 
● Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. c 
● Oral or IV broad-spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 
● Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
● 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. 
BAL  bronchoscopic alveolar lavage. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator’s benefit risk assessment and 
in alignment with the protocol requirements for the duration of treatment and document 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 and tiragolumab 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 assessment of benefit risk assessment and documented by the investigator (or appropriate 
delegate).. 
d     In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 
 
6.3.2 Hepatobiliary Disorders or Events 
 
 
  Eligible patients must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will 
be monitored throughout study treatment.  Management guidelines for hepatic 
events are provided in the table below. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and 
reviewed before administration of the next dose of study drug(s). 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic 
or neoplastic etiologies should be considered and addressed, as appropriate. 
 
 


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Management Guidelines for Hepatobiliary Disorders or Events 
Event 
Management 
Hepatobiliary 
disorder or 
event, Grade 1 
● Continue atezolizumab and tiragolumab. 
● Monitor LFTs until values resolve to within normal limits or to baseline 
values.  
Hepatobiliary 
disorder or 
event, Grade 2 
All events: 
● Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
● Withhold atezolizumab and tiragolumab 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab. c 
Hepatobiliary 
disorder or 
event, Grade 3 
or 4 
● Permanently discontinue atezolizumab and tiragolumab. 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. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be 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 ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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. 
 
6.3.3 Gastrointestinal Disorders or Events 
 
Immune-mediated gastrointestinal events are a potential risk with tiragolumab. 
 
Management guidelines for diarrhea or colitis are provided in the table below. 
 
All events of diarrhea or colitis should be thoroughly evaluated for other more 
common etiologies.  For events of significant duration or magnitude or associated 
with signs of systemic inflammation or acute-phase reactants (e.g., increased C-
reactive protein, platelet count, or bandemia):  Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, with three to five specimens for 


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standard paraffin block to check for inflammation and lymphocytic infiltrates to 
confirm colitis diagnosis.  
 
Management Guidelines for Gastrointestinal Disorders or Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea 
or 
colitis, Grade 1 
● Continue atezolizumab and tiragolumab. 
● Initiate symptomatic treatment. 
● Endoscopy is recommended if symptoms persist for  7 days. 
● Monitor closely. 
Diarrhea 
or 
colitis, Grade 2 
● Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
● Initiate symptomatic treatment. 
● If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
● Patient referral to GI specialist is recommended. 
● For recurrent events or events that persist  5 days, initiate treatment with 
corticosteroids equivalent to 1−2 mg/kg/day oral prednisone. If the event 
does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact Medical Monitor. c 
Diarrhea 
or 
colitis, Grade 3 
● Withhold atezolizumab and tiragolumab 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 does not improve within 48 hours 
after initiating corticosteroids, consider adding an immunosuppressive 
agent. 
● If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact Medical Monitor. c 
Diarrhea 
or 
colitis, Grade 4 
● Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. c 
● 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 does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 


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Event 
Management 
 GI  gastrointestinal. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be 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 ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab and 
tiragolumab only after approval has been documented by the investigator. 
 
6.3.4 Endocrine Disorders or Events 
 
Immune-related endocrine events are a potential risk with tiragolumab. 
 
Management guidelines for endocrine events are provided in the table below. 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, 
impotence, constipation, or mental status changes should be investigated for the 
presence of thyroid, pituitary, or adrenal endocrinopathies.  The patient should be 
referred to an endocrinologist if an endocrinopathy is suspected.  Thyroid-
stimulating hormone (TSH) and free 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. 
 
Management Guidelines for Endocrine Disorders or Events 
Event 
Management 
Hypothyroidism, 
Grade 1 
● Continue atezolizumab and tiragolumab. 
● Initiate treatment with thyroid replacement hormone. 
● Monitor TSH closely. 
Hypothyroidism, 
Grade 2 
● Consider withholding atezolizumab and tiragolumab. 
● Initiate treatment with thyroid replacement hormone. 
● Monitor TSH closely. 
● Consider patient referral to endocrinologist. 
● Resume atezolizumab and tiragolumab when symptoms are 
controlled and thyroid function is improving. 
Hypothyroidism 
Grade 3 and 4 
● Withhold atezolizumab and tiragolumab 
● 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 


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Event 
Management 
function is improving. 
● Permanently discontinue atezolizumab.c 
Hyperthyroidism, 
Grade 1 
TSH ≥ 0.1 mU/L and  0.5 mU/L: 
● Continue atezolizumab and tiragolumab. 
● 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 
Hyperthyroidism, 
Grade 2 
● Consider atezolizumab and tiragolumab. 
● Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
● Consider patient referral to endocrinologist. 
● Resume atezolizumab and tiragolumab when symptoms are 
controlled and thyroid function is improving. 
Grade 
3 
and 
4 
hyperthyroidism 
● Withhold atezolizumab. 
● Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
● Refer to an endocrinologist. 
● Resume atezolizumab and tiragolumab when symptoms are 
controlled, and thyroid function is improving. 
● Permanently discontinue atezolizumab.c 
Adrenal insufficiency, 
Grade 2−4  
● Withhold atezolizumab and tiragolumab 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 and tiragolumab. b 
● If event does not resolve to Grade 1 or better or patient is not stable 
on replacement therapy while withholding atezolizumab and 
tiragolumab, 
permanently 
discontinue 
atezolizumab 
and 
tiragolumab and contact PI. c 
Hypophysitis 
(panhypopituitarism), 
Grade 2 or 3  
● Withhold atezolizumab and tiragolumab 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 and 
tiragolumab. b 


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Event 
Management 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab 
and 
tiragolumab, 
permanently 
discontinue 
atezolizumab and tiragolumab and contact PI. c 
● For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(panhypopituitarism), 
Grade 4  
● Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. c 
● Refer patient to endocrinologist. 
● Perform brain MRI (pituitary protocol). 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
● Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must bebased 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 ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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. 
 
6.3.5 Metabolic Disorders or Events 
 
Event 
Management 
Hyperglycemia, Grade 
1 or 2 
● Continue atezolizumab and tiragolumab. 
● Investigate for diabetes.  If patient has Type 1 diabetes, treat as 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 and tiragolumab. 
● Initiate treatment with insulin. 
● Monitor for glucose control. 
● Resume atezolizumab and tiragolumab when symptoms resolve and 
glucose levels are stable. 
 
6.3.6 Eye Disorders or Events 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in the table below. 
 
Management Guidelines for Eye Disorders or Events 
Event 
Management 
Eye 
disorders, 
Grade 1  
● Continue atezolizumab and tiragolumab. 
● Patient referral to ophthalmologist is strongly recommended. 


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Event 
Management 
● Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
● If symptoms persist, treat as a Grade 2 event. 
Eye 
disorders, 
Grade 2 
● Withhold atezolizumab and tiragolumab 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact PI. c 
Eye 
disorders, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and tiragolumab and contact PI. c 
● Refer patient to ophthalmologist. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.   
● If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  ≥ 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be 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 ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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.  
 
6.3.7 Immune-Mediated Cardiac Events 
 
IMMUNE-MEDIATED MYOCARDITIS 
 
Immune-mediated myocarditis should be suspected in any patient presenting with 
signs or symptoms suggestive of myocarditis, including, but not limited to, 
laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, 
dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Myocarditis may also be a clinical manifestation of myositis or associated with 
pericarditis (see section on pericardial disorders below) and should be managed 
accordingly. 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 


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cardiac MRI as appropriate per institutional guidelines.  A cardiologist should be 
consulted.  An endomyocardial biopsy may be considered to enable a definitive 
diagnosis and appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
 
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 the table below.  Withhold treatment with 
atezolizumab for Grade 1 pericarditis and conduct a detailed cardiac evaluation to 
determine the etiology and manage accordingly. 
 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 
2-4 
 
 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
● Withhold atezolizumab and tiragolumab for up to 12 weeks after 
event onset  and contact PI. 
● 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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6.3.8 Infusion-Related Reactions  
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab or 
tiragolumab.  However, patients who experience an infusion-related reaction (IRR) 
or (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 tiragolumab and atezolizumab.  These reactions, which are 
thought to be due to release of cytokines and/or other chemical mediators, occur 
within 24 hours of atezolizumab or tiragolumab administration and are generally 
mild to moderate in severity. 
 
Guidelines for medical management of IRRs during Cycle 1 are provided in the 
table below.  For subsequent cycles, IRRs should be managed according to 
institutional guidelines. 
 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1  
● Reduce infusion rate to half the rate being given at the time of event onset. 
● After the event has resolved, the investigator should wait for 30 minutes 
while delivering the infusion at the reduced rate. 
● If the infusion is tolerated at the reduced rate for 30 minutes after symptoms 
have resolved, the infusion rate may be increased to the original rate. 
IRR, Grade 2 
● Interrupt infusion. 
● Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
● After symptoms have resolved to baseline, resume infusion at half the rate 
being given at the time of event onset. 
● For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics and monitor 
closely for IRRs. 
IRR, Grade 3 or 
4 
● Stop infusion. 
● Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
● Permanently discontinue atezolizumab or tiragolumab and contact PI. a 
IRR  infusion-related reaction. 
a Resumption of atezolizumab or tiragolumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  Patients can be re-challenged with atezolizumab or tiragolumab only after 
approval has been documented by the investigator. 
 


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6.3.9 Cytokine-Release Syndrome 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab or 
tiragolumab.  However, patients who experience CRS with atezolizumab or 
tiragolumab may receive premedication with antihistamines, anti-pyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions. 
 
CRS is defined as a supraphysiologic response following administration of any 
immune therapy that results in activation or engagement of endogenous or infused 
T cells and/or other immune effector cells.  Symptoms can be progressive, always 
include fever at the onset, and may include hypotension, capillary leak (hypoxia), 
and end-organ 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. 
 
Severe SARS CoV 2 infection is 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. 
 
Guidelines for medical management of CRS are provided in the table below. 
 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
Event 
Management 
Grade 1 afever b 
with or without 
constitutional 
symptoms  
● Immediately interrupt infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
● In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
● For subsequent infusions, consider administration of oral premedication 
with antihistamines, antipyretic medications, and/or analgesics, and 
monitor closely for CRS. 
Grade 2 a 
fever b with at least 
one of the 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 


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


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Event 
Management 
Fever b with at least 
one of the 
following: 
● Hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
● Hypoxia 
requiring oxygen 
by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
● Administer symptomatic treatment. c 
● Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). 
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS as described in this appendix. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.  For patients who are refractory to anti-
cytokine therapy, experimental treatments f may be considered at the 
discretion of the investigator and in consultation with the PI. 
● Hospitalize patient until complete resolution of symptoms. 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive airway pressure; 
CAR  chimeric antigen receptor; CPAP  continuous positive airway pressure; CRS  cytokine-release syndrome; 
CTCAE  Common Terminology Criteria for Adverse Events; eCRF  electronic Case Report Form; 
HLH  hemophagocytic lymphohistiocytosis; ICU  intensive care unit; MAS  macrophage activation syndrome; 
NCCN  National Cancer Comprehensive Network; NCI  National Cancer Institute. 
The management guidelines have been adapted from the NCCN guidelines for the management of CAR T-cell−related 
toxicities (Version 2.2019). 
a 
Grading system for management guidelines is based on the ASTCT CRS Consensus Grading Scale. 
NCI CTCAE v5.0 and the ASTCT CRS Consensus Grading Scale should be used when reporting severity of CRS on 
the Adverse Event eCRF.  NCI CTCAE v5.0 should be used when reporting severity of organ toxicities associated 
with CRS on the dedicated Cytokine Release Syndrome 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, antipyretic medications, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment may be administered 
as per institutional practice. 
d 
Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at  6 
L/min. 
e 
Resumption of atezolizumab or tiragolumab may be considered in patients who are deriving benefit and have 
fully recovered from the event.  The decision to re-challenge patients with atezolizumab or tiragolumab should be 
based on the investigator’s benefit-risk assessment and documented by the investigator. The Medical Monitor is 
available to advise is needed.  For subsequent infusions, administer oral premedication with antihistamines, 
antipyretics medications, and/or analgesics, and monitor closely for CRS.  Premedication with corticosteroids and 
extending the infusion time may also be considered after consulting the PI and considering the benefit−risk ratio. 
f 
Refer to Riegler et al. (2019)  
 
6.3.10 Pancreatic Events 
 
  The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as 


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serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in the table below. 
 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or 
lipase elevation, 
Grade 2 
Amylase and/or lipase  1.5-2.0  ULN: 
● Continue atezolizumab and tiragolumab. 
● 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 and tiragolumab 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and tiragolumab and contact PI. c 
● For recurrent events, permanently discontinue atezolizumab and 
tiragolumab and contact PI. c 
Immune-mediated 
pancreatitis, Grade 
2 or 3 
 
● Withhold atezolizumab and tiragolumab 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and tiragolumab and contact PI. c 
● For recurrent events, permanently discontinue atezolizumab and 
tiragolumab and contact PI. c  
Immune-mediated 
pancreatitis, Grade 
4 
● Permanently discontinue atezolizumab and tiragolumab and contact PI.c 
● Refer patient to GI specialist. 
● Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
● If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 


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Event 
Management 
month. 
GI  gastrointestinal; ULN=upper limit of normal. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be 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 ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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. 
 
6.3.11 Skin and subcutaneous tissue disorders 
 
Immune-related dermatologic events are a potential risk with tiragolumab.  The 
majority of cases of rash reported with the use of atezolizumab were mild in 
severity and self limiting, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis have been reported with atezolizumab. A dermatologist 
should evaluate persistent and/or severe rash or pruritus.  A biopsy should be 
considered unless contraindicated.  Management guidelines for dermatologic 
events are provided in the table below. 
 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
● Continue atezolizumab and tiragolumab. 
● Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
● Continue atezolizumab and tiragolumab. 
● Consider patient referral to dermatologist for evaluation and, if indicated, 
biopsy. 
● Initiate treatment with topical corticosteroids. 
● Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
Dermatologic 
event, Grade 3  
● Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
● Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
● Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 1-2 mg/kg/day if event does not improve 
within 48−72 hours. 
● If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact PI. c 
Dermatologic 
event, Grade 4 
● Permanently discontinue atezolizumab and tiragolumab and contact PI. c 


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Event 
Management 
Stevens 
Johnson 
syndrome 
or 
toxic epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens Johnson syndrome or toxic epidermal 
necrolysis: 
● Withhold tiragolumab and atezolizumab for suspected Stevens Johnson 
syndrome or toxic epidermal necrolysis. 
● Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist or urologist as relevant) for evaluation and, if indicated, 
biopsy. 
● Follow the applicable treatment and management guidelines above. 
● If Stevens Johnson syndrome or toxic epidermal necrolysis, permanently 
discontinue tiragolumab and atezolizumab. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be 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 ≥ 1 month to the equivalent of ≤ 10 mg/day 
oral prednisone before atezolizumab and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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. 
 
6.3.12 Nervous System Disorders 
 
Immune-related neurologic events are a potential risk with tiragolumab.   
 
  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 the table below with specific guidelines for myelitis 
provided in a separate table. 
 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-
mediated 
neuropathy, 
Grade 1 
● Continue atezolizumab and tiragolumab. 
● 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 and tiragolumab for up to 12 weeks after event 
onset. a 
● Investigate etiology. 
● Initiate treatment as per institutional guidelines. 
● For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume atezolizumab 
and tiragolumab. b 
o If event does not resolve to Grade 1 or better while 
withholding atezolizumab and tiragolumab, permanently 
discontinue atezolizumab and tiragolumab and contact PI. c 
 For facial paresis: 


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Event 
Management 
o If event resolves fully, resume atezolizumab b 
o 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 and tiragolumab and contact PI. c  
● Refer patient to neurologist 
● Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis 
and 
Guillain-Barré 
syndrome (any 
grade) 
● Permanently discontinue atezolizumab and tiragolumab and contact PI. c 
● Refer patient to neurologist. 
● Initiate treatment as per institutional guidelines. 
● Consider initiation of corticosteroids equivalent to 1-2 mg/kg/day oral or 
IV prednisone. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator’s benefit-risk and in alignment 
with the protocol requirements for the duration and 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 and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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. 
 
6.3.13 Immune-Mediated Meningoencephalitis 
 
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 


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sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished 
from potential meningoencephalitis resulting from infection (bacterial, viral, or 
fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
 
All patients being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, 
inflammation, or edema.  If deemed safe by the treating physician, a lumbar 
puncture should be performed and a neurologist should be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in the 
table below. 
 
Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
● Permanently discontinue atezolizumab and tiragolumab and contact 
PI.  
● Refer patient to neurologist. 
● Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day 
IV methylprednisolone and convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
 
 
6.3.14 Renal and Urinary Disorders 
 
  Eligible patients must have adequate renal function.  Renal function, including 
serum creatinine, should be monitored throughout study treatment.  Patients with 
abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications 
such as nonsteroidal 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 the table below. 
 
Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
● Continue atezolizumab and tiragolumab. 
● Monitor kidney function, including creatinine, closely until values resolve 
to within normal limits or to baseline values.  


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Event 
Management 
Renal event, 
Grade 2 
● Withhold atezolizumab and tiragolumab 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact PI. c 
Renal event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and tiragolumab and contact PI.  
● 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 and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator’s benefit-risk and in 
alignment with the protocol requirements for the duration and 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 and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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.  
 
6.3.15 Immune-Mediated Myositis 
 
  Myositis or inflammatory myopathies are a group of disorders sharing the 
common feature of inflammatory muscle injury; dermatomyositis and polymyositis 
are among the most common disorders.  Initial diagnosis is based on clinical 
(muscle weakness, muscle pain, skin rash in dermatomyositis), biochemical (serum 
creatine kinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
 
Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, 
Grade 1 
● Continue atezolizumab and tiragolumab. 
● Refer patient to rheumatologist or neurologist.  
● Initiate treatment as per institutional guidelines. 


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Event 
Management 
Immune-
mediated 
myositis, 
Grade 2 
● Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset a and contact PI. 
● 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and tiragolumab and contact PI. c 
Immune-
mediated 
myositis, 
Grade 3 
● Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset a and contact PI. 
● 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 and 
tiragolumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and tiragolumab and contact PI. c 
● For recurrent events, treat as a Grade 4 event. Permanently discontinue 
atezolizumab and tiragolumab.c 
Immune-
mediated 
myositis, Grade 
4 
● Permanently discontinue atezolizumab and tiragolumab and contact PI. 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. 


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Event 
Management 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator’s benefit-risk and in 
alignment with the protocol requirements for the duration and treatment and documented by the investigator. 
agreed upon 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 and tiragolumab can be resumed. 
c Resumption of atezolizumab and tiragolumab 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 investigatorPatients can 
be rechallenged with atezolizumab and tiragolumab- only after approval has been documented by the 
investigator..  
 
6.3.16 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  109/L (100,000/L) 
– ANC  1.0  109/L (1000/L) 
● Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen 
 1.5 g/L (150 mg/dL) 
● Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
● Low or absent natural killer cell activity 
● Ferritin  500 mg/L (500 ng/mL) 
● Soluble 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) 


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● At least two of the following: 
– Platelet count ≤ 181  109/L (181,000/L) 
– AST ≥ 48 U/L 
– Triglycerides  1.761 mmol/L (156 mg/dL) 
– Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines 
in the table below.  
 
Management 
Guidelines 
for 
Suspected 
Hemophagocytic 
Lymphohistiocytosis 
or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
● Permanently discontinue atezolizumab and tiragolumab and contact PI. 
● Consider patient referral to hematologist. 
● Initiate supportive care, including intensive care monitoring if indicated 
per institutional guidelines. 
● Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
● If event does not respond to treatment within 24 hours, contact PI and 
initiate treatment as appropriate according to published guidelines (La 
Rosée 2015; Schram and Berliner 2015; La Rosée et al. 2019). 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 90 days after the last day of 
treatment with atezolizumab and tiragolumab.  All adverse events must be recorded on the toxicity 
tracking case report form (CRF) with the exception of: 
● Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 7.2. 
 


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7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Washington University Sponsor Investigator (or designee) is required to notify 
the QASMC of any unanticipated problems involving risks to participants or others 
occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University Sponsor 
Investigator (or designee) is required to notify the QASMC within 10 days of 
Washington University notification via email to qasmc@wustl.edu.  Submission to 
QASMC must include either the myIRB form and supporting documentation or (if 
not submitted to myIRB) the date of occurrence, description of the event, whether 
the event is described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be 
notified, and whether the informed consent document and/or any study procedures 
will be modified as a result of this event. 
 
7.1.3 Reporting to Genentech 
 
Certain events require immediate reporting.  The investigator must report such 
events to Genentech immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following 
is a list of events that the investigator must report to Genentech within 24 hours 
after learning of the event, regardless of relationship to study treatment: 
● Serious adverse events 
● Adverse events of special interest (defined in Section 7.1.3.1) 
● Pregnancies (within 90 days after the last dose of tiragolumab or within 5 
months after the last dose of atezolizumab) 
● Data related to the product usage during breastfeeding 


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● Data related to overdose, abuse, misuse, or medication error 
 
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. 
 
For serious adverse events and adverse events of special interest, the investigator 
must report new significant follow-up information to Genentech immediately (i.e., 
no more than 24 hours after becoming aware of the information).  New significant 
information includes the following: 
● New signs or symptoms or a change in the diagnosis 
● Significant new diagnostic test results 
● Change in causality based on new information 
● Change in the event's outcome, including recovery 
● Additional narrative information on the clinical course of the event 
 
The completed MedWatch form should be sent to the Genentech contact specified 
below.  Transmission of these reports will be either electronically via email or by 
vax and within the timelines specified below. 
 
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 
 
All product complaints (refer to Appendix B) without an AE should call via: 
 
PC hotline number: 800-334-0290 (M-F 5am-5pm PST) 
 
Investigators must report all of the above-mentioned single case reports adequately 
to Genentech on a MedWatch within one (1) business day of the awareness date. 
 
The Investigator will email Genentech a quarterly line-listing documenting single 
case reports sent by the Investigator to Genentech in the preceding time period.  
These will be sent to ctvist_drugsafety@gene.com.  Following Case Transmission 
Verification, single case reports which have not been received by Genentech shall 
be forwarded by the Investigator to Genentech within five (5) calendar days from 
request by Genentech. 
 
The investigator will forward listings of non-serious AEs originating from the study 
to Genentech/Roche as needed on an ad-hoc basis. 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: 888-835-2555 
Fax: 650-225-4682 or 650-225-4630 
 


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Additionally, all IND annual reports submitted to the FDA by the Sponsor-
Investigator should be copied to Genentech..  The Investigator will forward a 
copy of the Final Study Report to Genentech upon completion of the study. 
Finally, any literature articles that are a result of the study should be sent to 
Genentech.  Copies of such reports should be sent to the Genentech Drug Safety 
CTV oversight mailbox at: ctvist_drugsafety@gene.com and to the assigned 
Clinical Operations contact for the study: 
Erica Winsch (imCORE-USMA-OPS-d@gene.com) 
 
Post-Study Adverse Events 
   
The investigator should expeditiously report any SAE occurring after a subject 
has completed or discontinued study participation if attributed to prior to 
atezolizumab or tiragolumab exposure. If the investigator should become aware 
of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should 
be reported as an SAE adequately to Genentech drug Safety during follow up 
period. 
  
Investigators must report all the above mentioned single case reports adequately 
to Genentech on a MedWatch within one (1) business day of the awareness date. 
 
Batch ID/lot ID for biologics associated with AE/SSR/PC/AESI must be included 
when submitting the case reports to Genentech. 
 
For blinded studies, batch ID/lot ID for biologics associated with 
AE/SSR/PC/AESI must be submitted at the end of the study to Genentech. 
 
7.1.3.1 Adverse Events of Special Interest 
 
Adverse events of special interest are required to be reported by the 
investigator to Genentech immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2 for reporting instructions).  Adverse 
events of special interest for this study are as follows: 
● Cases of potential drug-induced liver injury that include an elevated 
ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined by Hy's Law (see Section 5.3.5.7) 
● Suspected transmission of an infectious agent by the study 
treatment, as defined as: Any organism, virus, or infectious particle 
(e.g., 
prion 
protein 
transmitting 
transmissible 
spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an 
infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that 
indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of study treatment is 
suspected. 


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● Pneumonitis 
● Colitis 
● Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal 
insufficiency, hyperthyroidism, and hypophysitis 
● Hepatitis, including AST or ALT > 10 x ULN 
● Systemic lupus erythematosus 
● Neurological disorders:  Guillain Barré syndrome, myasthenic 
syndrome or myasthenia gravis, and meningoencephalitis, facial 
paresis, myelitis 
● Events suggestive of hypersensitivity, infusion-related reactions, 
cytokine 
release 
syndrome, 
and 
hemophagocytic 
lymphohistiocytosis,  
● Pericardial disorders 
● Nephritis 
● Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
● Myositis 
● Myopathies, including rhabdomyolysis 
● Grade ≥ 2 cardiac disorders  
● Vasculitis 
● Autoimmune hemolytic anemia 
● Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, 
dermatitis bullous, toxic epidermal necrolysis) 
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University Sponsor-Investigator to report to 
the FDA as follows: 
 
● Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix B for definitions) no later than 7 calendar days after 
initial receipt of the information.   
● Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix B) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix B) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 


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indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
● Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
● Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
● Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.1.5 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator (or designee) will notify the 
research team at each secondary site of all unanticipated problems involving risks 
to participants or others that have occurred at other sites within 10 working days 
of the occurrence of the event or notification of the Sponsor-Investigator (or 
designee) of the event.  This includes events that take place both at Washington 
University and at other secondary sites, if applicable. Refer to Section 16.0 
(Multicenter Management) for more information. 
 
7.2 
Secondary Site Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the Washington 
University Sponsor-Investigator and designee of all serious adverse events (refer to 
Appendix B, Section D) within 1 working day of the occurrence of the event or notification 
of the secondary site’s PI of the event.  This notification may take place via email if there 
is not yet enough information for a formal written report (using FDA Form 3500a 


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(MedWatch) and Washington University’s cover sheet (Appendix D)).  A formal written 
report must be sent to the Washington University Sponsor-Investigator and designee within 
4 calendar days (for fatal or life-threatening suspected adverse reactions) or 11 calendar 
days (for serious unexpected adverse reactions) of the occurrence of the event or 
notification of the secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.  
The research team at Washington University is responsible for reporting all applicable 
events to the FDA and Genentech as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
7.3 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
● planned hospitalizations 
● hospitalizations < 24 hours 
● respite care 
● events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Atezolizumab (Tecentriq) 
 
8.1.1 Atezolizumab Description 
 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy 
chains (448 amino acids) and two light chains (214 amino acids). Atezolizumab 
targets human PD-L1 and inhibits its interaction with its receptor PD-1. 
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is 
reported to provide additional inhibitory signals to T cells (Butte et al. 2007). 
 
8.1.2 Clinical Pharmacology 
 
PD-L1 may be expressed on tumor cells and/or tumor infiltrating immune cells and 
can contribute to the inhibition of the anti-tumor immune response in the tumor 
microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T 
cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell 
proliferation and cytokine production.  


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Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its 
interactions with both PD-1 and B7.1 receptors. This releases the PD-L1/PD-1 
mediated inhibition of the immune response, including activation of the anti-tumor 
immune response without inducing antibody dependent cellular cytotoxicity. In 
syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased 
tumor growth. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Patients’ exposure to atezolizumab increased dose proportionally over the dose 
range of 1 mg/kg to 20 mg/kg, including a dose of 1200 mg administered every 3 
weeks. The clearance (CV%) was 0.20 L/day (29%), the volume of distribution at 
steady state was 6.9 L, and the terminal half-life was 27 days. Steady state was 
achieved after 6 to 9 weeks following multiple doses. The systemic accumulation 
ratio for every 2 weeks administration and every 3 weeks administration was 3.3-
and 1.9-fold, respectively. Atezolizumab clearance was found to decrease over 
time, with a mean maximal reduction (CV%) from baseline value of approximately 
17% (41%); however, the decrease in clearance was not considered clinically 
relevant. 
 
8.1.4 Supplier 
 
Atezolizumab is provided by Genentech. 
 
8.1.5 Dosage Form and Preparation 
 
The atezolizumab 840 mg drug product will be supplied in a single-use, 15-mL 
USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, 
preservative-free clear liquid solution intended for IV administration. The vial is 
designed to deliver 14 mL (840 mg) of atezolizumab solution, but may contain 
more than the stated volume to enable delivery of the entire 14-mL volume.  
Patients will receive 1680 mg of atezolizumab, so 2 vials will be used for each dose. 
 
The prescribed dose of atezolizumab should be diluted in 250 mL 0.9% NaCl and 
infused through a 0.2 micrometer in-line filter. The IV bag may be constructed of 
PVC or PO; the IV infusion line may be constructed of PVC or PE; and the 0.2 
micrometer in-line filter may be constructed of PES. The prepared solution may be 
stored at 2°C-8°C or room temperature for up to 8 hours. 
 
8.1.6 Storage and Stability 
 
2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
Stability studies are ongoing. 


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CAUTION: No preservative is used in atezolizumab; therefore, the vial is intended 
for single use only. Discard any unused portion of drug remaining in a vial. 
 
8.1.7 Administration 
 
Atezolizumab is administered as an intravenous infusion over 60 minutes. If the 
first infusion is tolerated, all subsequent infusions may be delivered over 30 
minutes. Do not administer atezolizumab as an intravenous push or bolus.  No 
premedication is indicated for administration of Cycle 1 of atezolizumab. Patients 
who experience an infusion related reaction with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g. 
acetaminophen) for subsequent infusions. 
 
8.2 
Tiragolumab 
 
8.2.1 Tiragolumab Description 
 
Tiragolumab is a fully human IgG1/kappa mAb that binds TIGIT and prevents its 
interaction with PVR. The blockade of TIGIT by tiragolumab represents a novel 
strategy for cancer therapy because its mechanism of action is complementary to 
that of other checkpoint inhibitors, such as anti-PD-L1/PD-1. Consequently, 
tiragolumab as a single-agent or in combination with anti-cancer therapies, may 
enhance the magnitude and quality of tumor-specific T-cell responses, which may 
result in meaningful anti-tumor activity in solid tumors and in hematological 
malignancies. 
 
8.2.2 Clinical Pharmacology 
 
The PK of tiragolumab was evaluated as a single-agent in the Phase Ia portion and       
in combination with atezolizumab in the Phase Ib portion of Study GO30103. As of 
2 December 2019, preliminary PK data at tiragolumab doses ranging from 2 to 1200 
mg every 21 days (Q3W) show that tiragolumab exposures increased approximately 
doseproportionally with increasing dose levels. Similarly, tiragolumab exposures 
increased approximately in a dose-proportional manner from 2 to 1200 mg in 
combination with 1200 mg atezolizumab Q3W. Further, the PK of tiragolumab in 
combination with atezolizumab appeared to be consistent with the PK of 
tiragolumab administered as a single-agent. The geometric mean Cycle 1 Cmax of 
tiragolumab ranged from 0.771 to 268 μg/mL and geometric mean Cycle 1 AUC0-
21 ranged from 2.61 to 2880 day ∙ μg/mL for the dose levels 2 to 1200 mg in the 
Phase Ia portion of the study. Similarly, the geometric mean Cycle 1 Cmax ranged 
from 0.582 to 339 μg/mL and geometric mean AUC0-21 ranged from 2.60 to 3000 
day ∙ μg/mL for tiragolumab dose levels 2 to 1200 mg in combination with 
atezolizumab. Preliminary population-PK analysis estimated tiragolumab clearance 
at 0.28 L/day and linear drug elimination half-life at approximately 15 days. 
 


Versi o n 0 1/ 0 9/ 2 3  
 
pa ge 7 0  of 9 0  
 
8. 2. 3  P h ar m a c o ki netics a n d Dr u g Met a b olis m i n A ni m als  
 
Tira g ol u ma b bi n ds t o rec o m bi na nt h u ma n a n d c y n o m ol g us m o n ke y TI GI T at 
c o m para ble affi nit y ( 0. 8 1 a n d 4. 4 2 n M, res pecti vel y) a n d bl oc ks bi n di n g t o its hi g h -
affi nit y rece pt or P V R at c o m p ara ble 5 0 % i n hi bit or c o n ce ntrati o n re d ucti o n (I C 5 0) 
( sta n dar d de viati o n [ S D]) val ues of 2. 1 5 0. 3 8 n M a n d 0. 4 4  0. 0 6 n M 
res pecti vel y. Tira g ol u ma b d oes n ot bi n d 
m o use or rat TI GI T. T he P K of 
tira g ol u ma b f oll o wi n g a si n gle I V i njecti o n t o c y n o m ol g us m o n ke ys was e val uate d. 
I n s u m mar y, all a ni mals de vel o pe d a nti-dr u g a nti b o dies ( A D As) fr o m Da y 1 0 
o n war d. U p t o Da y 7 p ost -d ose, pri or t o t he o nset of t he A D A res p o nse, tira g ol u ma b 
de m o nstrate d bi p hasi c dis p ositi o n, a n d P K para m eters s u c h as o bser ve d m a xi m u m 
o bse r ve d ser u m c o nce ntr ati o n ( C ma x) a n d area u n der t he c o n ce ntr ati o n-ti me c ur ve 
( A U C) fr o m ti me 0 t o 7 d a ys p ost-d os e ( A U C 0 -7) were si milar t o ot her I g G 1 m A bs 
a gai nst l o w -e x pressi n g t ar gets ( De n g et al. 2 0 1 1). T he t o xic o ki netics ( T K) of 
tira g ol u ma b were e val u ate d as part of t he re peat-d ose G o o d La b orat or y Practice 
( G L P) t o xicit y st u dies i n c y n o m ol g us m o n k e ys ( St u d y 1 5-1 3 3 4 a n d St u d y 1 7 -
2 9 1 0). After re p eate d a d mi nistrati o n of M TI G 7 1 9 2 A i n t he 1 -m o nt h st u d y ( St u d y 
1 5 -1 3 3 4), all a ni mals i n t he 1 0 a n d 3 0 m g/ k g d os e  gr o u ps d e vel o pe d a d et ecta ble 
A D A res p o nse t h at le d t o t he l oss of e x p os ure i n m ost a ni mals. H o we v er, o nl y 1 of 
1 0 a ni mals i n t h e 1 0 0 m g/ k g d os e gr o u p de v el o pe d a d etect a ble A D A res p o nse. I n 
t he 2 6-wee k st u d y ( St u d y 1 7 -2 9 1 0), 5 of 6 a ni mals i n t he 3 0 m g/ k g a n d 5 of 6 
a ni mals i n t he 1 0 0 m g/ k g d os e gr o u ps were A D A -p ositi ve a n d ha d sli g htl y l o wer 
M TI G 7 1 9 2 A ser u m c o nce ntrati o ns w he n c o m pare d t o a ni mals wit h ne gati ve A D A 
res ults. I n b ot h st u dies, s yste mic e x p os ure was mai ntai ne d i n t he A D A-ne gati ve 
a ni mals, a n d  t he T K pr ofile was c o nsiste nt wit h t hat e x pecte d base d o n t he si n gle-
d ose P K st u d y. T he ser u m c o nce ntrati o n ti me pr ofiles of all d ose gr o u ps e x hi bite d 
a p pare nt bi p hasic dis p ositi o n i n w hic h a ra pi d i nitial distri b uti o n p hase was 
f oll o we d b y a sl o wer eli minati o n p hase.  
 
8. 2. 4  S u p plier  
 
Tira g ol u ma b is pr o vi de d b y Ge ne ntec h.  
 
8. 2. 5  D os a ge F or m a n d Pre p ar ati o n  
 
Tira g ol u ma b (als o k n o w n as M TI G 7 1 9 2 A) is a f ull y h u ma n m A b t hat bi n ds t o 
TI GI T. T he rec o m bi na nt a nti b o d y is pr o d uce d i n C hi nese ha mster o var y ( C H O) 
cells, a n d c o nsists of t w o hea v y c h ai ns ( 4 5 6 a mi n o aci d resi d ues eac h) a n d t w o li g ht 
c hai ns ( 2 2 0 a mi n o aci d resi d ues eac h). T h ere are t w o N-li n ke d gl yc os ylati o n sites 
( As n 3 0 6) i n t he fra g me nt cr ystalliza ble ( Fc) d o mai n. Tira g ol u ma b  will be s u p plie d 
as a sterile li q ui d i n a si n gle-use , 1 5 -m L glass  vial.   T he vial c o ntai ns a p pr o xi matel y 
1 0  m L ( 6 0 0  m g)  of tira g ol u m a b s ol uti o n. 
 
Tira g ol u ma b is t o be a d mi nistere d b y I V i nf usi o n eit her n eat or after dil uti o n i n 
0. 9 % Na Cl.  T he c o n ce ntrati o n of tira g ol u m a b is 6 0 
m g/ m L.  Usi n g t his 


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concentration, calculate the appropriate volume of undiluted study drug according 
to patient dose and product concentration. 
 
Tiragolumab dose 
Tiragolumab (60 mg/mL, 600 mg) 
120 mg 
2.0 mL* 
300 mg 
5.0 mL 
420 mg 
7.0 mL 
600 mg 
10 mL 
840 mg 
14 mL 
1200 mg 
20 mL 
* doses must be administered to the gradation on syringes (e.g. 1 mL increments) 
 
The final concentration of drug in the IV bag should be between 0.2 and 12.0 
mg/mL.  It may be necessary to remove an amount of saline from the IV bag 
equivalent to the amount of study drug volume to be added. 
 
A 0.2 µm in-line filter must be used with the infusion set during administration.  
The compatibility of tiragolumab with diluents other than described is unknown. 
 
8.2.6 Storage and Stability 
 
Tiragolumab must be prepared for dosing under appropriate aseptic conditions as 
it does not contain antimicrobial preservatives. The dose solution should be used 
immediately. If not used immediately, the total storage time of the dose solution 
prior to administration should not exceed 24 hours to limit the risk of microbial 
growth in case of accidental contamination. The recommended storage condition 
for the drug product and dose solution is 2°C8°C, but dose solutions may be stored 
at room temperature for up to a maximum of 4 hours. The compatibility of 
tiragolumab with diluents other than described is unknown. 
 
8.2.7 Administration 
 
Tiragolumab must not be infused into the same line or cannula concomitantly with 
other drug infusions, including parenteral nutrition. Infusions of blood products and 
any electrolyte supplementation must not occur simultaneously with infusion of 
tiragolumab. A 0.2 micron in line filter must be used with the infusion set during 
administration. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Tissue for Whole Exome Sequencing 
 
At least 11 unstained positively charged 5µm slides from resection or shave biopsyplus 
one contiguous H&E stained slide will be shipped to Natera using the address in Section 


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9.4.  A de-identified copy of the associated pathology report should accompany the tissue 
specimen. 
 
9.2 
Blood for Whole Exome Sequencing 
 
Six mL of blood will be collected into a K2-EDTA tube for whole exome sequencing for 
development of the Signatera assay during Step 1 screening.  Immediately after the draw, 
thoroughly mix the blood with the anticoagulant by gently inverting the tube 8x.  Within 2 
hours of draw, the blood will be shipped at ambient temperature with a refrigerated gel 
pack overnight to Natera using the address in Section 9.4. 
 
9.3 
Blood for ctDNA 
 
Twenty mL of peripheral blood will be drawn into 2 pre-labeled circulating tumor DNA 
BCT tubes (Streck 218962, NAT-800632) at the following time points: 
● Step 2 screening (4 to 12 weeks after date of surgery) 
● C3D1 
● C6D1 
● C9D1 
● C12D1 
● End of treatment (OPTIONAL) 
 
We will follow ctDNA titers longitudinally and correlate level changes with treatment 
response and/or relapse based on clinical and/or radiographical assessments. Note that 
ctDNA testing will be discontinued after two consecutive negative tests. 
 
Immediately after blood is drawn, thoroughly mix the blood with the anticoagulant by 
gently inverting it 8 times.  Do not shake vigorously. 
 
Tubes should be shipped to Natera at ambient temperature within 24 hours of collection.   
 
9.4 
Shipping Instructions 
 
All specimens should be shipped to the following address: 
ATTN: Accessioning – Signatera 
Natera Inc. 
13011A McCallen Pass 
Austin, TX 78753 
(877) 869-3052 
 
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section.  Data may be up to 1 cycle behind at any given time. 
 


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Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Treatment Assignment Form 
Prior to starting treatment 
ctDNA Form 
Baseline, C3D1, C6D1, C9D1, C12D1, end of treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Frequency per study calendar  
Imaging Form 
Baseline, every 12 weeks for the first 2 years after surgery, 
every 24 weeks for the third year after surgery 
Recurrence Form 
Time of disease recurrence 
Death Form 
Time of death 
MedWatch Form 
See Section 7.0 for reporting requirements 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
10.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
11.0 
MEASUREMENT OF EFFECT 
 
Tumor imaging is strongly preferred to be acquired by CT. For the abdomen and pelvis, contrast-
enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when mandated 
by local practice.  The same imaging technique regarding modality, ideally the same scanner, and 
the use of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the accuracy of 
the assessment of response or progression based on imaging. 
 
For the purposes of this study, patients should be re-evaluated every 12 weeks (+/- 2 weeks) for 
the first two years then every 24 weeks (+/- 2weeks) x2 for the third year, in addition to a baseline 
scan. 
 
Relapse-free survival is defined as the time from randomization to any of the following events: 


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recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) 
or death due to any cause. New incident cases of melanoma and second cancer diagnoses are not 
counted as events for recurrence-free survival. 
 
 
12.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are 
subject to the Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMB will disclose any potential conflicts of interest to the 
trial principal investigator and/or appropriate university officials, in accordance with institution 
policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning six months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the six-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The 
DSMB must meet at least every six months beginning six months after enrollment of the first 
patient at a secondary site, no more than one month prior to the due date of the DSM report to 
QASMC.  This report will include: 
 
● HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
● Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
● History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
● Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
● Protocol activation date at each participating site 
● Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
● Expected accrual end date, accrual by site, and accrual by cohort 
● Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
● Measures of efficacy 


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● Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
● Summary of toxicities at all participating sites and separated by cohorts 
● Abstract submissions/publications 
● Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMB. This is located on the 
QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-
office-prmcqasmc/.   
 
 
13.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
● Subject screening and enrollment 
● Reporting of adverse events 
● Maintenance of HIPAA compliance 
● Completeness of regulatory documentation 
● Completeness of participant documentation 
● Acquisition of informed consent 
● IRB documentation 
● Issues of protocol adherence 
 


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Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This is an open-label, multi-center, Simon two-stage phase II study consisting of random 
allocation of a portion of patients to a small reference arm to offer some protection against 
the uncertainties and potential biases of a one-armed study while retaining some of the 
statistical efficiency.  The reference arm is not a control group in the traditional sense and 
there will not be a formal efficacy comparison between the treatment and reference groups 
(Herson and Carter, 1986; Rubinstein, et. al., 2009).  
 
The purpose of this study is to evaluate the efficacy and safety of atezolizumab and 
tiragolumab in stage II melanoma patients who had undergone complete resection and been 
tested positive for circulating tumor DNA (ctDNA).  In this study, the treatment arm (i.e., 
atezolizumab and tiragolumab) will not be compared with the reference arm (i.e., 
atezolizumab only); it will be analyzed against historical control as a one-armed study.  The 
reference arm is intended to only act as a check on the similarity of the current patients to 
the historical control for a descriptive estimation of ctDNA clearance. 
 
14.2 
Primary Endpoint 
 
ctDNA clearance rate, defined as the proportion of ctDNA+ patients having a ctDNA 
negative test at C3D1.   
 
14.3 
Secondary Endpoints 
 
• 
Confirmed ctDNA negative rate, defined as the proportion of ctDNA-positive patients 
having two consecutive negative ctDNA tests. 
 
• 
Relapse free survival (RFS), defined as the duration of time from the date of positive 
ctDNA being confirmed to the date of earliest disease relapse or death, whichever 
occurs first. Patients who neither relapse nor die by the data cutoff date will be censored 
at the last follow up date. 
 
• 
Distant metastasis free survival (DMFS), defined as the duration of time from the date 
of positive ctDNA being confirmed to the date of appearance of a distant metastasis or 
death, whichever occurs first. Patients who neither develop distant metastasis nor die 
by the data cutoff date will be censored at the last follow up date.  
 
• 
Overall survival (OS), defined as the duration of time from the date of positive ctDNA 
being confirmed to death from any cause. Patients who are alive by the data cutoff date 
will be censored at the last follow up date. 


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• 
Safety and tolerability will be defined as the number of treatment (i.e., atezolizumab 
and tiragolumab) related grade 3 or greater adverse events (AEs). Adverse events will 
be assessed using CTCAE v5.0 criteria. Safety will be monitored from the time of 
initiation of study treatment to 30 days after discontinuation of therapy. 
 
14.4 
Statistical Hypotheses 
 
We hypothesize that for ctDNA+ stage II melanoma patients, using atezolizumab and 
tiragolumab will lead to at least a 25% ctDNA clearance at C3D1, while a null ctDNA 
clearance rate is 10%. 22 
 
14.5 
Sample Size Determination 
 
Under Simon’s two-stage optimal design (Simon, 1989), with one-sided alpha = 0.05 and 
power = 0.8, assuming using atezolizumab and tiragolumab will have a ctDNA clearance 
rate of 25% and a null rate is 10%, in stage 1, 18 patients will be accrued for the treatment 
arm (atezolizumab + tiragolumab). If 3 or more patients are observed to be ctDNA-negative 
at C3D1 for the treatment arm, we will continue the treatment of atezolizumab and 
tiragolumab to stage 2 with an additional 25 patients being accrued. Otherwise the study 
will be stopped. If 8 or more ctDNA clearances are observed at the study completion, the 
combination of atezolizumab and tiragolumab will be considered promising for ctDNA-
positive stage II melanoma patients. 
 
Randomization will only happen in the stage 1. In total, 36 patients (18 per arm) will be 
randomly assigned in a 1:1 ratio to the treatment group (atezolizumab and tiragolumab) or 
reference group (atezolizumab monotherapy). There is no randomization in stage 2. Stage 
2 is single-arm (i.e., the treatment arm only), with a sample size of 25.  
 
According to PI’s personal communication with the Natera team, we assume the ctDNA 
positive rate will be 25%. In stage 1, it is expected that up to 144 patients will be screened 
in order to randomize 36 patients (18 to each arm). If we continue the study to stage 2 with 
the treatment arm only, an additional 100 patients will be screened (in order to enroll 25 
patients). In total, we expect to accrue 244 patients for ctDNA testing with 61 patients 
going on to treatment. 
 
14.6 
Study Population 
 
If the study stops after stage 1, we will screen 144 melanoma patients who had undergone 
complete resection. Among them, 18 ctDNA-positive patients being treated with the 
combination of atezolizumab and tiragolumab will be compared to a historical control and 
18 ctDNA-positive patients on atezolizumab monotherapy will be analyzed as a descriptive 
comparison.  
 
If we continue the study after stage 1, the study will screen 244 patients in total. Among 
them, 43 ctDNA-positive patients being treated with the combination of atezolizumab and 


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tiragolumab will be compared to a historical control and 18 ctDNA-positive patients on 
atezolizumab monotherapy will be analyzed as a descriptive comparison.  
 
14.7 
Statistical Analyses 
 
Descriptive statistics will be used to summarize the trial results. Statistics for continuous 
variables may include means, medians, ranges and appropriate measures of variability. 
Qualitative variables will be summarized by counts and percentages. The uncertainty of 
estimates will be assessed by confidence intervals (CIs). All analyses will be considered 
as exploratory, even if statistical tests will be used. 
 
ctDNA clearance and confirmed negative rate, as well as safety data will be summarized 
by the number and proportions.  RFS, DMFS, and OS will be presented via the Kaplan-
Meier method. Median survival and corresponding two-sided 95% CIs will be computed. 
Survival rates with 95% CIs will be estimated. The group survival difference (i.e., 
treatment vs. reference) will be examined by the log-rank test. Further exploratory 
correlative analyses will be performed via Fisher exact test, t-test, or nonparametric 
Wilcoxon–Mann–Whitney test, if needed. 
 
14.7.1 Safety Early Stopping Rule 
 
Early stopping of this trial is calculated based upon the report of study treatment 
(i.e., the combination of atezolizumab and tiragolumab, or atezolizumab 
monotherapy) related grade 3 or greater adverse events (AEs) (i.e., toxicities). A 
Bayesian safety-monitoring plan (Thall PF, Simon RM, Estey EH., 1996)21 will 
be implemented once the first 12 evaluable patients are available. A Bayesian 
sequential safety monitoring will be defined as Pr(θT > θ0 | data) > 0.80, where θT 
denotes the proportion of toxicity and θ0 (θ0=20%) represents the rate under null 
hypothesis (maximum probability of toxicity allowed). Enrollment will be 
stopped early whenever there is >80% chance that the event rate is larger than the 
null. The trial will be recommended to stop for excessive toxicities according to 
the toxicity stopping boundaries listed in the table below:  
 
Stop for excessive toxicities (grade 3 or greater) if: 
# patients who experience 
toxicity is  ≥: 
In first  # patients being 
determined ctDNA positive  
4 
12 
7 
24 
10 
36 
12 
48 
15 
61 
 
The above stopping boundaries were obtained using Bayesian Toxicity 
Monitoring 
online 
application 
version 
2.2.1.0 
(available 
at 
http://ibl.mdanderson.org/BTM/) developed by M.D. Anderson Cancer 
Center. We assume that the parameter θ0 is a constant and that θT follows a non-


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informative prior of beta (0.5, 0.5). Accrual will be stopped and the event will be 
reviewed by the Data Safety and Monitoring Board if a study treatment-related 
death is observed.  
 
 
15.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
● Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show 
which version of the protocol was approved by the IRB. 
● Documentation of IRB approval of an informed consent form. The consent must 
include a statement that data will be shared with Washington University, including the 
Quality Assurance and Safety Monitoring Committee (QASMC), the DSMC (if 
applicable), and the Washington University study team. 
● Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
● Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


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16.0 
REFERENCES 
 
1. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo 
in resected stage III melanoma. New Engl J Med 2018; 378: 1789–1801.Ives NJ et al 
2017 
2. Trinh VA, Zobniw C, Hwu WJ. The efficacy and safety of adjuvant interferon-alfa 
therapy in the evolving treatment landscape for resected high-risk melanoma. Expert 
Opin Drug Saf. 2017;16(8):933-40.  
3. Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, et al. Diagnosis and 
treatment of melanoma. European consensusbased interdisciplinary guideline - update 
2012. Eur J Cancer 2012;48:2375-90. 
4. Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. 
Melanoma staging: evidence-based changes in the American Joint Committee on Cancer 
eighth edition cancer staging manual. CA Cancer J Clin. 2017 Nov;67(6):472-92.  
5. Gerami, P., Cook, R.W., Russell, M.C. et al. Gene expression profiling for molecular 
staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am 
Acad Dermatol. 2015; 72: 780–785.e3 
6. John, T., Black, M.A., Toro, T.T. et al. Predicting clinical outcome through molecular 
profiling in stage III melanoma. Clin Cancer Res. 2008; 14: 5173–5180 
7. R. J. Lee, G. Gremel, A. Marshall , K. A. Myers Circulating tumor DNA predicts survival 
in patients with resected high-risk stage II/III melanoma 
8. Lucci A, et al. Clin Cancer Res. 2020 Feb 3. doi: 10.1158/1078-0432.CCR-19-2670. 
[Epub ahead of print] Circulating Tumor Cells and Early Relapse in Node-positive 
Melanoma.  
9. Freidin MB, Freydina DV, Leung M, et al. Circulating tumor DNA outperforms 
circulating tumor cells for KRAS mutation detection in thoracic malignancies. Clin 
Chem. 2015;61:1299–1304. 
10. Santiago-Walker A, Gagnon R, Mazumdar J, et al. Correlation of BRAF mutation status 
in circulating-free DNA and tumor and association with clinical outcome across four 
BRAFi and MEKi clinical trials. Clin Cancer Res. 2016;22:567–57 
11. Lin SY, Huang SK, Huynh Kelly T, Salomon MP, Chang S-C, Marzese D, Lanman R, 
Talasaz A, Hoon DS (2018) Multiplex Gene Profiling of Cell-Free DNA in metastatic 
melanoma patients for monitoring disease. J Clin Oncol Precision Oncol. 
12. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage 
lung cancer evolution. Nature. 04/26/online 2017;545:446. 
13. Sethi H, Salari R, Swenerton R, et al. Analytical Validation of the Signatera™ RUO Assay, 
a Highly Sensitive Patient-Specific Multiplex PCR NGS-Based Non-Invasive Cancer 
Recurrence Detection and Therapy Monitoring Assay. Paper presented at: Proceedings of 
the Annual Meeting of the American Association for Cancer Research; April 14-18, 2018; 
Chicago, IL. 
14. Reinert T, Henriksen TV, Rasmussen MH, et al. Personalized Circulating Tumor DNA 
Analysis to Monitor Colorectal Cancer. Paper presented at: Proceedings of the Annual 
Meeting of the American Association for Cancer Research; April 14-18, 2018; Chicago, 
IL. 
15. Birkenkamp-Demtröder K, Christensen E, Sethi H, et al. Sequencing of Plasma cfDNA 
from Patients with Locally Advanced Bladder Cancer for Surveillance and Therapeutic 


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Efficacy Monitoring. Paper presented at: Proceedings of the Annual Meeting of the 
American Association for Cancer Research; April 14-18, 2018; Chicago, IL. 
16. Reiman A, Kikuchi H, Scocchia D, et al. Validation of an NGS mutation detection panel 
for melanoma. BMC Cancer. Feb 22 2017;17(1):150. 
17. Simen BB, Yin L, Goswami CP, et al. Validation of a next-generation-sequencing cancer 
panel for use in the clinical laboratory. Arch Pathol Lab Med. Apr 2015;139(4):508-517. 
18. Singh RR, Patel KP, Routbort MJ, et al. Clinical massively parallel next-generation 
sequencing analysis of 409 cancer-related genes for mutations and copy number variations 
in solid tumours. Br J Cancer. Nov 11 2014;111(10):2014-2023. 
19. Zimmermann B, Salari R, Swenerton R. Personalized Liquid Biopsy: Patient-Specific 
Non-Invasive Cancer Recurrence Detection and Therapy Monitoring. Paper presented at: 
10th Circulating Nucleic Acids in Plasma and Serum (CNAPS) International Symposium; 
September 20-22, 2017, 2017; Montpellier, France. 
20. Weiand S, Schroeder G, O’Fallon JR. Stopping when the experimental regimen does not 
appear to help. Statistics in Medicine. 1994;13:1453–1458 
21. Thall PF, Simon RM, Estey EH. New statistical strategy for monitoring safety and 
efficacy in single-arm clinical trials. J Clin Oncol. 1996;14(1):296–303. 
22. Bratman, S.V., Yang, S.Y.C., Iafolla, M.A.J. et al. Personalized circulating tumor DNA 
analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. 
Nat Cancer 1, 873–881 (2020). https://doi.org/10.1038/s43018-020-0096-5 
23. HersonJ, Carter SK. Calibrated phase II clinical trials in oncology. Statistics in Medicine, 
1986; 5:441-7. 
24. Rubinstein L, Crowley J, Ivy P, LeBlanc M, Sargent D. Randomized phase II designs. 
Clin Canc Res 2009; 15:1883–90.  
25. Simon R (1989). Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled 
Clinical Trials 10: 1-10. 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
 AEs not previously observed in the subject that emerge during the protocol-specified  
 AE reporting period, including signs or symptoms associated with  
 {insert condition being studied} that were not present prior to the AE reporting period. 
 Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
 If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website.  The American 
Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading Scale 
should be used in addition to NCI CTCAE v5.0 when reporting the severity of CRS. 
 
ASTCT CRS Consensus Grading 
Grade 
Symptoms 
1 
● Fever a with or without constitutional symptoms  
● No hypotension 
● No hypoxia 
2 
● Fever a combined with at least one of the following: 
– Hypotension not requiring vasopressors 
– Hypoxia requiring low-flow oxygen b by nasal cannula or blow-by 
3 
● Fever a combined with at least one of the following: 
– Hypotension requiring a vasopressor (with or without vasopressin) 
– Hypoxia requiring high-flow oxygen b by nasal cannula, face mask, 
non-rebreather mask, or Venturi mask 
4 
● Fever a combined with at least one of the following: 
● Hypotension requiring multiple vasopressors (excluding vasopressin) 
● Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, 
intubation and mechanical ventilation) 
5 
● Death due to CRS in which another cause is not the principal factor 
leading to this outcome 


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ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive airway pressure; 
CPAP  continuous positive airway pressure; CRS  cytokine-release syndrome. 
a 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 CRS severity (grade).  In this case, the CRS grade is driven by the presence of hypotension and/or 
hypoxia. 
b Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen delivered at  6 L/min. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
16.1.1  
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 


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surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
G. Product Complaints 
 
Definition: 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 bene released and distributed to the 
commercial market or clinical trial. 
 


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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Genentech 
Serious AND unexpected 
suspected adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that 
the information qualifies for 
reporting 
 
Unexpected fatal or life-
threatening suspected adverse 
reaction 
 
 
Report no later than 7 calendar 
days after initial receipt of the 
information 
 
Serious adverse event 
 
 
 
Report within 24 hours of 
learning of the event 
Unanticipated problem 
involving risk to participants 
or others 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
WU/BJH/SLCH, report within 1 
working day. 
Report via email after 
IRB acknowledgment 
 
 
Adverse event of special 
interest 
 
 
 
Report within 24 hours of 
learning of the event 
Abnormal liver function tests 
defined as Hy’s law 
 
 
 
Report within 24 hours of 
learning of the event 
Accidental overdose or 
medication error (if fulfilling 
the seriousness criteria) 
 
 
 
Report within 24 hours of 
learning of the event 
Pregnancy of female patient or 
female partner of male patient, 
spontaneous abortion, 
therapeutic abortion, or 
congenital anomaly/birth 
defect 
 
 
 
Report within 24 hours of 
learning of the event 
Major deviation 
Report within 10 working days.  If 
the event results in the death of a 
participant enrolled at 
 
 
 


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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Genentech 
WU/BJH/SLCH, report within 1 
working day. 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working days.   
 
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important increase 
in the rate of a serious 
suspected adverse reaction of 
that list in the protocol or IB 
 
 
Report no later than 15 calendar 
days after it is determined that 
the information qualifies for 
reporting 
 
Complaints 
If the complaint reveals an 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at 
the time of continuing review. 
 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses 
a safety issue, report within 10 
working days.   
 
If withdrawing the participant does 
not represent a safety issue and the 
patient will be withdrawn, report at 
continuing review. 
 
 
 
 
 
 


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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Genentech 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Genentech 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to 
Genentech as needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 


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Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Genentech 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 


Version 01/09/23 
 
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APPENDIX D: Washington University Unanticipated Problem Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Admission Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
☐ yes  
 
☐ no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date