Clinical trial NCT03977467
Conditions: Non-Small Cell Lung Cancer Solid Tumor
Keywords: atezolizumab NSCLC Non-Small Cell Lung Cancer advanced solid tumors tiragolumab
Sponsor: SCRI Development Innovations, LLC
Start date: 2019-08-30; Completion date: 2024-08-09
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II, two part trial (A and B), open label study of Atezolizumab and tiragolumab, or atezolizumab combined with SOC chemotherapy in patients with NSCLC or advanced solid tumors that have had prior treatment with a PD-1 inhibitor (e.g. nivolumab or pembrolizumab).

Detailed description:
Arm A consists of approximately 20 patients with advanced NSCLC who received first-line anti-PD-1 therapy, who have subsequent disease progression. Arm B consists of approximately 15 patients per disease type (renal cell carcinoma \[RCC\] progressing on prior anti-PD-1 therapy, triple negative breast cancer \[TNBC\] progressing on prior anti-PD-1 therapy, NSCLC progressing on check-point inhibitors plus chemotherapy in the first-line setting; and microsatellite instability-high \[MSI-high\] solid tumors \[as determined by local testing for MSI/mismatch repair (MMR)\] progressing on prior anti-PD-1 therapy).

Arms: arm 1: Arm A NSCLC participants randomized to receive chemotherapy plus atezolizumab at a flat dose of 1200 mg intravenously (IV) every 3 weeks. Standard of care chemotherapy is defined as a platinum-doublet therapy (or triplet if bevacizumab is used) of the Investigator's choice. arm 2: In Arm B, non-randomized participants with specific advanced solid tumors will be treated with atezolizumab at a flat dose of 1200 mg IV every 3 weeks until progression or unacceptable toxicity. arm 3: Arm A NSCLC participants randomized to receive platinum-based standard of care doublet chemotherapy (or triplet if bevacizumab is used) will be given by IV every 3 weeks. Platinum chemotherapy may be cisplatin or carboplatin chosen based on histology and at the discretion of the treating investigator. Arm A2 closed early due to change in recommended Standard of Care therapies. arm 4: In Arm B, non-randomized participants with specific advanced solid tumors will be treated with atezolizumab at a flat dose of 1200 mg IV and tiragolumab at a flat dose of 600mg IVevery 3 weeks until progression or unacceptable toxicity. The addition of tiragolumab was a later update to protocol. No randomization into or within Arm B.
Interventions: intervention 1: Atezolizumab intervention 2: Standard of Care Chemotherapy intervention 3: Tiragolumab
Intervention descriptions: intervention 1: Atezolizumab at a flat dose of 1200 mg IV every 3 weeks intervention 2: Platinum-based standard of care doublet chemotherapy (or triplet if bevacizumab is used) will be given by IV every 3 weeks. Platinum chemotherapy may be cisplatin or carboplatin chosen based on histology and at the discretion of the treating investigator. It should be administered according to the directions in the approved labeling. intervention 3: Tiragolumab at a flat dose of 600 mg IV every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and is the property of Sarah Cannon Development Innovations, LLC.  No part of this 
document may be transmitted, reproduced, published, or used by other persons without prior written authorization 
from Sarah Cannon Development Innovations, LLC. 
MULTI 29 
A Phase II study of atezolizumab and tiragolumab in patients with NSCLC or 
advanced solid tumors who have had prior treatment with a PD-1 inhibitor 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY IDENTIFIER (ID): 
 
MULTI 29 
STUDY DRUGS: 
Atezolizumab and tiragolumab 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd.  Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
STUDY CHAIR: 
Melissa Johnson, MD 
Sarah Cannon Research Institute   
1100 Dr. Martin L. King Jr. Blvd.  Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
DATE FINAL: 
17 August 2018 
AMENDMENT 1 
28 August 2020 
AMENDMENT 2 
15 December 2021 
AMENDMENT 3 
11 July 2022 
AMENDMENT 4 
25 August 2022 
AMENDMENT 5 
19 December 2022 


 
CONFIDENTIAL 
STUDY DRUG(S):  ATEZOLIZUMAB AND TIRAGOLUMAB   
DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
FINAL PROTOCOL DATE:  19 DECEMBER 2022  
 
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Clinical Study Statement of Compliance 
A Phase II study of atezolizumab and tiragolumab in patients with NSCLC or 
advanced solid tumors who have had prior treatment with a PD-1 inhibitor 
 
 
This clinical study shall be conducted in compliance with the protocol, as 
referenced herein, and all applicable local, national, and international 
regulatory requirements to include, but not be limited to: 
• 
International Council for Harmonisation (ICH) Guidelines on Good 
Clinical Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
Food and Drug Administration (FDA) Code of Federal Regulation 
(CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human 
Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical 
Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance 
Portability and Accountability Act (HIPAA)  
 
As the Study Chair and/or Principal Investigator, I understand that my 
signature on the protocol constitutes my agreement and understanding of my 
responsibilities to conduct the clinical study in accordance to the protocol and 
applicable regulations.  Furthermore, it constitutes my understanding and 
agreement that any changes initiated by myself, without prior agreement in 
writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 


 
CONFIDENTIAL 
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Clinical Study Signature Approval Page 
A Phase II study of atezolizumab and tiragolumab in patients with NSCLC or 
advanced solid tumors who have had prior treatment with a PD-1 inhibitor 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY ID: 
MULTI 29 
STUDY DRUGS: 
Atezolizumab and tiragolumab 
DATE FINAL: 
17 August 2018 
AMENDMENT 1 
28 August 2020 
AMENDMENT 2 
15 December 2021 
AMENDMENT 3 
11 July 2022 
AMENDMENT 4 
25 August 2022 
AMENDMENT 5 
19 December 2022 
 
               __________________________               __________________________                       ______________ 
Study Chair 
Melissa Johnson, MD 
Sarah Cannon Research Institute 
Study Chair Signature 
Date 
 
__________________________                  __________________________                        ______________  
Marcy Vallone 
Sarah Cannon Development 
Innovations, LLC 
Sarah Cannon Development Innovations, 
LLC Representative Signature 
Date 


 
CONFIDENTIAL 
STUDY DRUG(S):  ATEZOLIZUMAB AND TIRAGOLUMAB   
DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
FINAL PROTOCOL DATE:  19 DECEMBER 2022  
 
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Clinical Study Principal Investigator Signature Form 
A Phase II study of atezolizumab and tiragolumab in patients with NSCLC or 
advanced solid tumors who have had prior treatment with a PD-1 inhibitor 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY ID: 
MULTI 29 
DATE FINAL: 
17 August 2018 
AMENDMENT 1 
28 August 2020 
AMENDMENT 2 
15 December 2021 
AMENDMENT 3 
11 July 2022 
AMENDMENT 4 
25 August 2022 
AMENDMENT 5 
19 December 2022 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
__________________________ _            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
Principal Investigator Signature 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd.  Suite 800 
Attn:  MULTI 29 IIT Study Team  
Nashville, TN 37203 


 
CONFIDENTIAL 
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DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
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MULTI 29 Summary of Changes 
AMENDMENT NUMBER: 
5 
AMENDMENT DATE:       19 DECEMBER 2022 
Additions are noted by bolding.  Deletions are noted by cross outs.  Only the parts of sections with changes are 
presented.  Please note that formatting changes and minor changes to punctuation, spelling, and abbreviations that 
do not affect meaning are not noted in this summary. 
 
Table of Contents was corrected to reflect the list of appendices. 
6.1 Management of Tiragolumab/Atezolizumab-Related Adverse Events 
Management of the following tiragolumab/atezolizumab-related AEs is located in Appendix F: 
Management of 
Tiragolumab/Atezolizumab-Specific Adverse Events: immune-mediated pericardial disorders, pulmonary (including 
pneumonitis), hepatic, gastrointestinal, endocrine, immune-mediated myocarditis, ocular, infusion-related reactions 
(IRRs), pancreatic (including pancreatitis), dermatologic, neurologic, and meningoencephalitis, immune-mediated 
myelitis, and immune-mediated facial paresis. 
 
7.2.1 
Day 1 of each cycle (± 3 days) 
• 
Physical examination, including measurement of weight and vital signs (including signs and symptoms of 
immune-mediated myelitis) 
 
8.1.3 Risks Associated With Atezolizumab 
Immune-mediated myelitis, immune-mediated facial paresis, and immune-mediated pericardial disorders, 
including pericarditis, pericardial effusion, and cardiac tamponade, are an identified risks for atezolizumab.   
 
11.4 
Adverse Events of Special Interest (AESIs) 
• 
Immune-mediated facial paresis 
• 
Immune-mediated myelitis 
 
Appendix C 
Schedule of Assessments  
Footnote c: Physical examination will include measurements of height (pretreatment visit only), weight, and vital 
signs.  Include monitoring for signs and symptoms of immune-mediated myelitis.   
 
Appendix F: 
Management of Tiragolumab/Atezolizumab-Specific Adverse Events 
Table 11 
Management Guidance for Immune-Mediated MyocarditisCardiac Events 


 
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Event 
Management 
Immune-mediated 
myocarditis, Grades 2-4 
 
Immune-mediated 
pericardial disorders  
Grade 2-4 
• Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator. a 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD, or pericardiocentesis as 
appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a 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 
and/or tiragolumab should be based on the investigator’s assessment of benefit-risk and documented by the 
investigator (or an appropriate delegate). 
 
Immune-Mediated Myelitis 
Immune-mediated myelitis is an identified risk with atezolizumab  
• 
Patients should be monitored for clinical signs and symptoms that are suggestive of myeltis.  
Diagnostic workup is essential for an accurate characterization to differentiate between alternative 
etiologies. 
• 
Refer patient to neurologist. 
• 
For Grade 1 myelitis, continue immunotherapy unless symptoms worsen or do not improve.  
• 
Initiate treatment as per institutional guidelines.  
• 
Atezolizumab should be permanently withdrawn for ≥Grade 2 immune-mediated myelitis. 
Immune-Mediated Facial Paresis 
Immune-mediated facial paresis is an identified risk with atezolizumab. 
• 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  Diagnostic 
workup is essential for an accurate characterization to differentiate between alternative etiologies.  
• 
Refer patient to neurologist.  
• 
Initiate treatment as per institutional guidelines.  
• 
Atezolizumab should be withheld for patients with Grade 1 or 2 immune-mediated facial paresis and 
permanently withdrawn for ≥Grade 3 immune-mediated facial paresis. 
 
 


 
CONFIDENTIAL 
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AMENDMENT NUMBER: 
4 
AMENDMENT DATE:       25 August 2022 
Additions are noted by bolding.  Deletions are noted by cross outs.  Only the parts of sections with changes are 
presented.  Please note that formatting changes and minor changes to punctuation, spelling, and abbreviations that 
do not affect meaning are not noted in this summary. 
 
Synopsis 
Updated Exclusion criteria numbering and text in the synopsis to match the numbering and text in Section 3.2 
Exclusion criteria. 
 
Section 1.2 Atezolizumab 
Atezolizumab has been generally well tolerated.  Adverse events (AEs) with potentially immune-mediated causes 
consistent with an immunotherapeutic agent, including pericardial disorders (pericarditis, pericardial effusion, 
and cardiac tamponade), rash, influenza-like illness endocrinopathies, hepatitis or transaminitis, pneumonitis, 
colitis, myasthenia gravis, myocarditis, myositis, neurological issues (including Guillain-Barré Syndrome), and 
severe cutaneous adverse reactions have been observed (see atezolizumab Investigator's Brochure [IB] for detailed 
safety results).  To date, the majority of these events have been manageable with treatment. 
 
Section 6 Dose Modifications, Table 3 
A new row for pericardial disorders was added to Table 3 as follows: 
Pericardial events 
• Guidelines for management of pericardial events are provided in 
the atezolizumab IB for atezolizumab and Table 5. 
 
Section 6.1 Management of Tiragolumab/Atezolizumab-related Adverse Events 
Management of the following tiragolumab/atezolizumab-related AEs is located in Appendix F: Management of 
Tiragolumab/Atezolizumab-Specific Adverse Events: immune-mediated pericardial disorders, pulmonary 
(including pneumonitis), hepatic, gastrointestinal, endocrine, immune-mediated myocarditis, ocular, infusion-related 
reactions (IRRs), pancreatic (including pancreatitis), dermatologic, neurologic, and meningoencephalitis. 
 
Section 8.1.3 Risks Associated with Atezolizumab 
Immune-mediated pericardial disorders, including pericarditis, pericardial effusion, and cardiac tamponade 
are an identified risk for atezolizumab.  Atezolizumab has also been associated with risks such as the following: 
IRRs and immune-mediated hepatitis, pneumonitis,… 
 
Appendix F Management of Tiragolumab/Atezolizumab-Specific Adverse Events 
Pericardial Events 
Immune-mediated pericardial disorders, including pericarditis, pericardial effusion, and cardiac tamponade 
are an identified risk with atezolizumab. 
Pericardial disorders encompass a range of diseases of the pericardium.  Underlying causes include infection 
(particularly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related (post 
myocardial infarction or iatrogenic), and autoimmune disorders.  Pericardial disorders are also known to be 
associated with drugs including immune-checkpoint inhibitors. 


 
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Pericarditis may be associated with pericardial effusion, which if significant in volume, may result in 
hemodynamic instability and progress to cardiac tamponade.  Cardiac tamponade is a life-threatening 
condition and should be treated as a medical emergency. 
The diagnosis of immune-mediated pericarditis should be considered in all patients presenting with chest 
pain. 
The diagnosis of immune-mediated pericardial effusion and cardiac tamponade should be considered in all 
patients presenting with chest pain associated with dyspnea or hemodynamic instability. 
Cardiac tamponade should be treated as a medical emergency and consultation with a cardiologist should be 
sought for further management. 
Caution should be used when considering the use of atezolizumab in a patient who has previously experienced 
a pericardial disorder on prior treatment with other immune-stimulatory anticancer agents. 
Management guidelines for pericardial events are presented in Table 5. 
Table 5 Management Guidelines for Pericardial Events, Including Pericarditis, Pericardial Effusion, and 
Cardiac Tamponade 
Event 
Management 
Immune-mediated 
pericardial disorders, 
including pericarditis, 
pericardial effusion, and 
cardiac tamponade, any 
grade 
• Withhold atezolizumab for any patient with suspected immune-mediated 
pericardial disorders and contact the principal investigator. 
• Permanently discontinue atezolizumab for any grade confirmed immune-
mediated pericardial disorders. 
• Refer patient to cardiologist. 
• 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. 
AMENDMENT 
NUMBER: 
3 
AMENDMENT DATE:       11 July 2022 
Additions are noted by bolding.  Deletions are noted by cross outs.  Only the parts of sections with changes are 
presented.  Please note that formatting changes and minor changes to punctuation, spelling, and abbreviations that 
do not affect meaning are not noted in this summary. 
The following changes were in response to FDA comments received on Wednesday, 06 July 2022: 
Section 1.4 Rationale for the Study: 
In Arm A, patients will be receiving an anti-PD-L1 inhibitor in combination with chemotherapy (or 
chemotherapy alone) after previously receiving an anti-PD-1 inhibitor.  While we assume anti-PD-1 and 
anti-PD-L1 antibodies are synonymous in clinical practice, in truth this has not been (and will never be) 
tested.  There are several reasons these two classes of antibodies may be at least slightly different.  Anti-
PD-1 antibodies and anti-PD-L1 antibodies target opposing sides the same the PD-1/PD-L1 interaction, 
and thereby have distinct downstream effectors (PD-1’s ligands are most commonly PD-L1 and PD-L2 
while PD-L1 most commonly binds to PD-1and B7-1 (CD80).  PD-1 is largely expressed on immune cells, 
while PD-L1 is expressed on tumor cells.  Finally, the impact of tumor heterogeneity on a tumor’s 
predilection to respond to a PD-1 inhibitor vs. PD-L1 is not well understood.  It is common in clinical 
practice for patients to be treated with serial PD-1 inhibitors or PD-1 followed by PD-L1 inhibitors, 
because these agents are well tolerated and because it is assumed that some portion of cells may remain 
sensitive to PD-1 blockade even as the therapy has been deemed over all to have lost its usefulness. . We 
see this in the treatment of renal cell carcinoma and melanoma, for example, where options beyond 


 
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immunotherapy are minimal.  Arm A of this study aims to test the effect of continued CPI blockade with 
the addition of chemotherapy in NSCLC.    
Section 2.2 Secondary Objectives and Synopsis 
• 
Estimate the 6-month disease control rate (DCR), progression-free survival (PFS), overall survival (OS) in 
patients with NSCLC and other advanced solid tumors. 
Section 2.3 Exploratory Objectives and Synopsis 
• 
Estimate the 6-month progression-free survival (PFS) and overall survival (OS) in patients with 
NSCLC and other advanced solid tumors. 
Section 3.1 General Inclusion Criteria and Synopsis 
1. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 – 1 2  
Section 3.1.1 Inclusion Criteria for Arm A and Synopsis 
17. PD-L1 Tumor Proportion Score ≥1% 
Section 3.2 Exclusion Criteria and Synopsis 
6. Treatment with chemotherapy in the first line setting. 
Section 5.1.4: Stopping Rules in Dose Expansion  
Arm A will enroll 20 patients and each of the four Arm B cohorts will enroll 15 patients. Should the first 7 
patients in Arm A or the first 5 patients consecutively enrolled in any single Arm B cohort develop PD in 2 
cycles, that cohort will be stopped and no additional patient enrollment will be allowed. 
 
All other changes as follows: 
Section 3.1.2 Crossover from Arm A to Arm B and Synopsis 
18. 
Last dose of atezolizumab is ≥21 days 
Section 5.4.2 Tumor Tissue Samples 
An optional tissue biopsy will be requested for crossover patients.  This sample should be collected prior to 
the start of treatment on Arm B. 
Section 7.3 Response Assessment Every 2 Cycles (± 7days) 
Appendix C: Schedule of Assessments 
Response every 2 cycles (± 3 7 days) 
Optional tumor sample has been added to baseline studies. 
Footnote t: Optional tissue biopsy for crossover patients only; sample should be collected prior to start of 
treatment on Arm B. 
 
 


 
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AMENDMENT NUMBER: 
2 
AMENDMENT DATE:       15 December 2021 
Additions are noted by bolding.  Deletions are noted by cross outs.  Only the parts of sections with changes are 
presented.  Please note that formatting changes and minor changes to punctuation, spelling, and abbreviations that 
do not affect meaning are not noted in this summary. 
Global Changes 
• 
Arm A has been revised; the solid tumor cohorts in place prior to Amendment #2 have been deleted and 
replaced with one NSCLC + standard of care chemotherapy cohort.  Approximately 20 NSCLC patients 
will receive atezolizumab in combination with chemotherapy. 
• 
The following Arm B cohorts have been removed from the Protocol: 
- 
Advanced SCLC, SCCHN, melanoma, urothelial tumors, or esophageal tumors progressing on anti-
PD-1 monotherapy. 
- 
Melanoma progressing on nivolumab plus ipilimumab 
- 
NSCLC progressing on anti-PD-1 monotherapy in ≥ second-line setting 
- 
NSCLC progressing on nivolumab plus ipilimumab in the first-line setting 
- 
NSCLC progressing on nivolumab plus ipilimumab in combination with 2 cycles of chemotherapy in 
the first-line setting 
• 
Tiragolumab has been added to Arm B; patients enrolling will receive atezolizumab in combination with 
tiragolumab. Approximately 60 patients total will be enrolled among the various disease types. 
• 
The number of patients to be enrolled on the study has been updated to 258 80. 
• 
Immune-related events has been changed to immune-mediated events. 
Section 1.3 Tiragolumab 
Tiragolumab is a fully human IgG1/қ monoclonal antibody that binds TIGIT (T-cell immunoreceptor with 
immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains), an inhibitory 
immunoreceptor.  TIGIT is highly expressed on the surface of activated T-cell and natural killer (NK)-cell 
subsets and interacts with high affinity with CD155 (also known as poliovirus receptor [PVR]) (Yu et al. 
2009).  Genetic ablation in T cells in mice results in exacerbated T cell responses, demonstrating the role of 
TIGIT in inhibiting T cell responses (Joller et al. 2014, Johnston et al. 2014).  Activation of TIGIT on T cells 
and NK cells was demonstrated to limit proliferation, effector cytokine production, and killing of target 
tumor cells (Stanietsky et al. 2009, Yu et al. 2009, Johnston et al. 2014). 
Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for cancer therapy and is 
expected to enhance the magnitude and quality of tumor specific T cell responses, which may result in 
improved meaningful anti-tumor activity when tiragolumab is combined with other cancer immunotherapy 
(CIT) and chemotherapy (Tiragolumab IB 2020).  The available nonclinical and clinical data provide a strong 
rationale for evaluating the potential clinical benefit of tiragolumab in patients with cancer.  Refer to the 
tiragolumab IB for details on nonclinical and clinical studies of tiragolumab. 
Section 1.4 Rationale for the Study  
Tiragolumab binds to the inhibitory immunoreceptor TIGIT, which 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 T cells.  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 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 


 
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(Tiragolumab IB 2020).  Tiragolumab and atezolizumab have been studied in a phase I clinical trial, and have 
been shown to be safe and tolerable in combination with signals of anti-tumor efficacy (Bendell et al. 2020).  
Tiragolumab and atezolizumab have also been combined in treatment-naïve NSCLC patient populations with 
responses and survival outcomes greater than with atezolizumab and placebo combinations, especially in 
PDL1-high expressing tumors (Rodriguez-Abreu et al. 2020). 
This study will investigate the use of atezolizumab and tiragolumab in patients with acquired resistance following 
prior treatment with anti-PD-1 therapy.  The main NSCLC cohort, Arm A, will determine whether adding 
atezolizumab to standard of care (SOC) chemotherapy will be efficacious. (group 1) results in a greater benefit 
when compared to SOC chemotherapy alone (group 2), measured by overall response rate (ORR), in patients with 
advanced NSCLC with acquired resistance to anti-PD-1 monotherapy. Efficacy of atezolizumab in combination 
with tiragolumab will be explored in a signal-finding cohort of anti-PD-1-treated tumor types and disease settings 
(Arm B) including RCC progressing on prior anti-PD therapy, triple-negative breast cancer (TNBC) tumors 
progressing on anti-PD-1 therapy, NSCLC progressing on check-point inhibitors plus chemotherapy in the first-
line setting and microsatellite-high (MSI-high) solid tumors [as determined by local testing for MSI/mismatch repair 
(MMR)] progressing on anti-PD-1 monotherapy therapy. 
Section 2.1 Primary Objectives 
• 
Assess the efficacy of combining atezolizumab with SOC chemotherapy compared to standard of care only 
in NSCLC patients who have progressed after prior exposure to anti-PD-1. 
• 
Assess the efficacy (ORR) of atezolizumab compared to standard of care, in patients with advanced solid 
tumors who have progressed after prior exposure to anti-PD-1 monotherapy.  
• 
Assess the efficacy (Overall Response Rate [ORR]) of atezolizumab combined with SOC therapy in 
NSCLC, and atezolizumab combined with tiragolumab in patients with advanced solid tumors who 
have progressed after prior exposure to anti-PD- treatment. 
Section 2.2 Secondary Objectives 
• 
Determine the safety of atezolizumab combined with SOC chemotherapy, and atezolizumab combined 
with tiragolumab, in patients with NSCLC and other advanced solid tumors. 
Section 2.3 Exploratory Objectives 
• 
In selected patients with paired biopsy samples (pre-anti-PD1-treated and pre-atezolizumab/tiragolumab-
treated; or pre- and post-atezolizumab/tiragolumab-treated tissue): 
Section 3.1 Inclusion Criteria 
2. Adequate hematologic function defined as: 
- 
Absolute neutrophil count (ANC) ≥1500/μL with one exception: 
Patients with benign ethnic neutropenia (BEN): ANC >1300/µL 
BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate 
neutropenia that is not associated with any increased risk for infections or other clinical 
manifestation (Atallah-Yunes et al., 2019).  BEN is referred to as ethnic neutropenia because 
of its increased prevalence in people of African descent and other specific ethnic groups. 
- 
Hemoglobin (Hgb) ≥9 g/dL (Patients may be transfused to meet this criterion.) 
- 
Platelets ≥100,000/µL (without transfusion, within 7 days of enrollment).   
4. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated creatinine 
clearance ≥350 mL/min as calculated by the Cockcroft-Gault formula. (for the solid tumor cohort receiving 
atezolizumab monotherapy, the threshold can be reduced to a creatinine clearance of ≥30 mL/min.) 
5. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤1.5 × ULN. For patients receiving 
therapeutic anticoagulation: stable anticoagulant regimen 
6. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive methods with a failure rate of <1% per year, during their participation in the study and for 5 


 
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months following last dose of study drug(s).  Women must refrain from donating eggs during the study and for 
5 months following last dose of study drug(s) 
- 
A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a 
postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than 
menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).  The definition 
of childbearing potential may be adapted for alignment with local guidelines or requirements.   
- 
Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male 
sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post ovulation methods), and withdrawal are not adequate methods 
of contraception.  
7. Male patients with a female partner of childbearing potential or a pregnant female partner must remain abstinent 
(refrain from heterosexual intercourse) or use a condom during the treatment period and for 5 months after the 
last dose of study drug. 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 post-ovulation methods) and withdrawal are not adequate methods of contraception.  Men 
must also agree to refrain from donating sperm during their participation in the study and for 5 months after the 
last dose of study drug.  
14. Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that all of the following 
criteria are met: 
- 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
- 
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
- 
The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, 
whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection 
within 28 days prior to initiation of study treatment. 
- 
The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. 
- 
If the patient is receiving anti-convulsant therapy, the dose is considered stable. 
Section 3.1.1 Inclusion Arm A – Non-small cell lung cancer 
• 
Previously received and tolerated nivolumab or pembrolizumab monotherapy or immunotherapy 
doublets such as nivolumab/ipilimumab therapy (and was the last therapy prior to enrollment). 
Section 3.1.2 Inclusion Arm B – Advanced Solid Tumors 
• 
Patients with: 
o 
Advanced RCC progressing on anti-PD-1 therapy 
o 
Advanced TNBC progressing on anti-PD-1 therapy 
o 
NSCLC progressing on check-point inhibitors plus chemotherapy in the first-line setting 
o 
MSI-high solid tumors, as defined by local testing for MSI/MMR, progressing on anti-PD-1 therapy.  
(Only MSI-high tumors will require MSI/MMR testing results). 
Previously received and tolerated nivolumab or pembrolizumab monotherapy or immunotherapy doublets such 
as nivolumab/ipilimumab (and was the last therapy prior to enrollment). 
• 
Evidence of PD after receiving clinical benefit, defined as having at least one scan demonstrating at least SD 
during most recent PD-1 inhibitor treatment 
Section 3.2 Exclusion Criteria 
3. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or 
tiragolumab formulations 
5. Use of systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) ≤28 
days or 5 half-lives (whichever is longer) prior to the first dose of study drugs.   
6. Treatment with investigational therapy within 28 days prior to initiation of study treatment. 


 
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7. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor atezolizumab 
[TNF]-α agents 
8. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of 
need for such a vaccine during the course of the study or within 5 months after the last dose of atezolizumab or 
tiragolumab 
9. Uncontrolled tumor-related pain 
- 
Patients requiring pain medication must be on a stable regimen at study entry. 
- 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to 
palliative radiotherapy should be treated prior to enrollment.  Patients should be recovered from the 
effects of radiation.  There is no required minimum recovery period. 
- 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with 
further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) 
should be considered for loco-regional therapy if appropriate prior to enrollment. 
10. Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study 
treatment. 
16. Pregnant or lactating females 
23. 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 (see Appendix E: Pre-existing Autoimmune Diseases and Immune Deficiencies 
for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following 
exceptions: 
• 
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement 
hormone are eligible for the study. 
• 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible 
for the study. 
27. Positive Epstein-Barr virus (EBV) viral capsid antigen (VCA) 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. 
29. In the opinion of the Investigator any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of 
the results, or may render the patient at high risk from treatment complications 
30. Has had malignancies other than NSCLC, RCC, TNBC, or MSI-high solid tumors within 5 years prior to 
enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year 
overall survival [OS] >90%) treated with an expected curative outcome (such as adequately treated carcinoma 
in situ of the cervix, basal- or squamous-cell skin cancer, localized prostate cancer treated surgically with 
curative intent, or ductal carcinoma in situ treated surgically with curative intent). 
32. Prior treatment with anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-
based inhibition motif domains (TIGIT) therapeutic antibodies.  
33. Major surgical procedure within 4 weeks prior to initiation of study treatment, or anticipation of need 
for a major surgical procedure during the study. 
Section 3.2.1 Exclusion Arm A – Non-small cell lung cancer 
34. NSCLC with an activating EGFR mutation or ALK fusion oncogene 
o 
For patients with non-squamous NSCLC histology: unknown EGFR and/or ALK status requires 
testing  


 
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o 
For patients with squamous NSCLC histology: unknown EGFR and/or ALK status does not require 
test results at screening.  However, exclusion is applied if the status of either driver oncogene is 
known to be positive. 
o 
For patients with NSCLC of mixed histology: unknown EGFR and/or ALK status requires testing at 
screening 
Note: ALK and/or EGFR status may be assessed locally or submitted for central laboratory testing.  If 
ALK and/or EGFR status is assessed locally, testing must be performed on tissue or cytology using a 
validated FDA-approved test. If samples are submitted for central laboratory testing, five additional 
slides are required.  
35. Known c-ros oncogene 1 (ROS1) rearrangement: ROS1 testing at screening is not required for study 
inclusion; however, patients with known ROS1 rearrangements are excluded. 
Section 3.2.2 Exclusion Arm B – Advanced Solid Tumors  
37. Prior treatment with anti-TIGIT therapeutic antibodies. 
38. Known hypersensitivity to any component of the tiragolumab formulation 
Section 4 Study Registration 
• 
Patients enrolling in Arm A will be assigned to atezolizumab and SOC chemotherapy for NSCLC.  
Patients enrolling in Arm B will be assigned into a cohort based on disease type to receive 
atezolizumab and tiragolumab for 4 solid tumor types. 
Section 5 Study Design 
• 
Figure 1 “Study Schema” has been updated.  
• 
Table 1 “Administration of First and Subsequent Atezolizumab Infusions” has been updated. 
This is an open-label, multi-center, Phase II study of atezolizumab and tiragolumab, or atezolizumab in 
combination with SOC chemotherapy in patients with NSCLC or advanced solid tumors that have had prior 
treatment with a PD-1 inhibitor (e.g., nivolumab or pembrolizumab). 
Arm A: Arm A will enroll approximately 20 patients. 
Arm B: The following solid tumors will be enrolled into Arm B: 
• 
RCC progressing on prior atni-PD-1 therapy 
• 
NSCLC progressing on check-point inhibitors plus chemotherapy in the first-line setting 
• 
MSI-high solid tumors [as determined by local testing for MSI/MMR] progressing on prior anti-PD-1 
therapy. 
In Arm B, patients with advanced solid tumors will be treated with atezolizumab at a flat dose of 1200 mg IV every 
3 weeks and tiragolumab at a flat dose of 600 mg IV every 3 weeks. 
For Arm B the precise sample size cannot be determined.  Approximately 60 patients total will be enrolled 
among the various disease types. 
Section 5.1.1 Atezolizumab 
On days of scheduled infusions, atezolizumab should be administered first, before chemotherapy or tiragolumab. 
Section 5.1.2 Tiragolumab has been added to the protocol 
Tiragolumab 
 
600 mg IV every 3 weeks 
On days of scheduled infusions, atezolizumab should be administered first, before chemotherapy or tiragolumab.  
Administration of tiragolumab will be performed in a monitored setting where there is immediate access to trained 
personnel and adequate equipment and medicine to manage potentially serious reactions.  Tiragolumab infusions 
will be administered per the instructions outlined in Table 2. 
Table 2 “Administration of First and Subsequent Tiragolumab Infusions” has been added to the protocol.   
Section 5.3.1 Permitted Concomitant Medications 


 
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• 
The following criterion has been added: “Premedication with antihistamines, antipyretics, and/or 
analgesics may be administered for the second and subsequent atezolizumab and/or tiragolumab 
infusions only, at the discretion of the Investigator.” 
Section 5.3.3 Prohibited Concomitant Medications 
• 
Investigational therapy within 42 days prior to initiation of study treatment and during study 
treatment 
• 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are prohibited 
within 4 weeks or five half-lives of the drug (whichever is longer shorter) 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. 
Section 6 Dose Modifications 
• 
Updated throughout to include dose modification instructions for both atezolizumab and tiragolumab. 
Including Table 3 “Dose Modifications for Study Drugs.”  
• 
Resume atezolizumab/tiragolumab if event resolves to Grade 1 or better within 21 days.  Permanently 
discontinue atezolizumab if event does not resolve to Grade 1 or better within 21 days.  If 
atezolizumab is discontinued, the Investigator may continue tiragolumab, provided AEs have 
returned to Grade 1 or better within 21 days.  Permanently discontinue both atezolizumab and 
tiragolumab if event does not resolve to Grade 1 or better within 12 weeks.  Any patient requiring a 
toxicity-related dose delay of more than 21 days from the intended day of the next scheduled dose must be 
discontinued from the study.” 
Section 6.1 Management of Tiragolumab/Atezolizumab-Related Adverse Events 
Management of the following tiragolumab/atezolizumab-related AEs is located in Appendix F: pulmonary 
(including pneumonitis), hepatic, gastrointestinal, endocrine, immune-mediated myocarditis, ocular, infusion-
related reactions (IRRs), pancreatic (including pancreatitis), dermatologic, neurologic, and meningoencephalitis. 
Section 8 Drug Formulation, Availability, Administration, and Toxicity Information   
• 
Updated to include Section 8.2.1 Tiragolumab Labeling, Packaging, and Supply, Section 8.2.2 Preparation 
and Administration of Tiragolumab, and Section 8.2.3 Precautions and Risks Associated with Tiragolumab.   
Section 8.1.3 Precautions and Risks Associated with Atezolizumab 
• 
Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, meningoencephalitis, myocarditis, nephritis, myositis, and severe cutaneous adverse reactions.  
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
Section 10 Statistical Considerations 
10.2 Sample Size Considerations 
No formal statistical power calculations to determine sample size were performed for this study. Hence the 
numbers of patients have been based on the desire to obtain adequate safety and efficacy data while exposing 
as few patients as possible to the investigational products and procedures. Approximately 80 patients are 
planned to be enrolled in this study. 
NSCLC Cohort 
In Arm A, in group 1 and 54 in group 2 achieve 80.761% power to detect a difference between the group 
proportions of 0.2500.  The proportion in group 1 (the treatment group) is assumed to be 0.2500 under the null 
hypothesis and 0.5000 under the alternative hypothesis.  The proportion in group 2 (the control group) is 0.2500.  
The test statistic used is the one-sided Fisher's Exact Test.  The significance level of the test is 0.0500. 


 
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Numeric Results for Testing Two Proportions using Fisher's Exact Test 
H0: P1 - P2 ≤ 0 vs. H1: P1 - P2 = D1 > 0. 
Target Actual  
 
 
 
 
Diff 
 
 
Power Power* N1 
N2 
N 
P1 
P2 
D1 
Alpha 
 
0.80 
0.80761 54 
54 
108 
0.5000 0.2500 0.2500 0.0500  
* Power was computed using the normal approximation method 
Exploratory Cohort: 
precise sample size cannot be determined. A sample size of approximately 20 patients will be enrolled to the 
cohort.  
Advanced Solid Tumor Cohort 
In Arm B, precise sample size cannot be determined.  Descriptive statistics will be used. A sample size of 
approximately 60 20 patients will be enrolled to the cohort 
Section 10.4.2 Efficacy Analysis 
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and the associated 95% CI  in 
each treatment group will be provided. The hazard ratio and the 95% CI for these endpoints between the two 
treatment groups will be calculated. 
Section 11 Safety Reporting and Analyses 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, adverse events of 
special interest (AESIs), performing protocol-specified safety laboratory assessments, measurement of 
protocol-specified hematology, clinical chemistry, and other protocol-specified tests that are deemed critical to the 
safety evaluation of the study drug. 
Section 11.1.6 Assessment of Adverse Events 
Expected AEs are those AEs that are listed or characterized in the US Package Insert (USPI) or current IB. 
Appendix C Guidelines for Female Patients of Childbearing Potential and Fertile Male Patients  
Section 11.3 Recording of Adverse Events and Serious Adverse Events 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on the Adverse Event 
eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release syndrome (CRS).  
While IRRs occur during or within 24 hours after treatment administration, time to onset of CRS may vary.  
Differential diagnosis should be applied, particularly for late-onset CRS (occurring more than 24 hours after 
treatment administration), to rule out other etiologies such as delayed hypersensitivity reactions, sepsis or 
infections, HLH, tumor lysis syndrome, early disease progression, or other manifestations of systemic 
inflammation. 


 
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Adverse events that occur during or within 24 hours after study treatment administration and are judged to 
be related to study treatment infusion should be captured on the Adverse Event eCRF as a diagnosis (e.g., 
"infusion-related reaction" or "cytokine-release syndrome").  Avoid ambiguous terms such as "systemic 
reaction".  Cases of late-onset CRS should be reported as "cytokine-release syndrome" on the Adverse Event 
eCRF.  Associated signs and symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF 
or Cytokine-Release Syndrome eCRF, as appropriate. 
If a patient experiences both a local and systemic reaction to the same dose of study treatment, each reaction 
should be recorded separately on the Adverse Event eCRF, with signs and symptoms also recorded separately 
on the dedicated Infusion-Related Reaction eCRF or Cytokine-Release Syndrome eCRF. 
NCI CTCAE v4.0 and the American Society for Transplantation and Cellular Therapy (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. 
Guidelines for medical management of IRRs and CRS are provided in Appendix F. 
11.3.9 Lack of Efficacy or Worsening of Cancer 
Deterioration that is judged by the Investigator to have unexpectedly worsened in severity or frequency, or 
changed in nature (i.e., deterioration beyond the expected pattern of progression of the underlying disease) 
should be recorded as an adverse event.  When recording an unanticipated worsening of cancer on the 
Adverse Event eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of non-small cell lung cancer” [spell out name of 
condition, do not use acronym]).  Events that are clearly consistent with the expected pattern of progression 
of the underlying disease should not be recorded as adverse events.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be based on RECIST v.1.1.  In 
rare cases, the determination of clinical progression will be based on symptomatic deterioration.  However, 
every effort should be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an adverse event. 
11.3.10 Atezolizumab and Tiragolumab Overdose 
For Information on how to manage an overdose of atezolizumab and tiragolumab, see the IBs. 
Section 11.4 Adverse Events of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the product, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor is required.  Such an 
event might require further investigation in order to characterize and understand it.  Depending on the 
nature of the event, rapid communication by the trial Sponsor to the other parties (e.g., regulatory 
authorities) may also be warranted. 
The following are events of special interest, and must be reported to Genentech Drug Safety expeditiously, 
irrespective of regulatory seriousness criteria (see Section 11.2).  These AESIs adverse events of special interests 
include the following: 


 
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• 
Data related to suspected transmission of an infectious agent via medicinal product (STIAMP), as 
defined below: 
11.5 Sponsor Serious Adverse Event Reporting Requirements 
Development Innovations will provide case information on a completed MedWatch form within 1 business 
day to the Genentech contact information specified above. 
Transmission of these reports (initial and follow-up) will be sent either electronically or by fax and within the 
timelines specified below: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
Additional reporting requirements to Genentech include the following: 
• 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported to Genentech as an SAE.  Similarly, any congenital anomaly/birth defect in a 
child born to a female subject exposed to atezolizumab should be reported to Genentech as an SAE. 
In addition to SAEs, pregnancy reports and AESIs, the following Special Situations Reports should be collected and 
transmitted to Genentech even in the absence of an AE within one (1) thirty (30) calendar days.  
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
The Sponsor of the study (Development Innovations), will be responsible for the expedited reporting of safety 
reports originating from the study to the regulatory authority (FDA) where it has filed a clinical trial 
approval, in compliance with local regulations.  
The Sponsor (Development Innovations) will be responsible for the expedited reporting of safety reports 
originating from the study to the Ethics Committees and Institutional Review Boards (IRB), where 
applicable. 
The Sponsor (Development Innovations) will be responsible for the distribution of safety information to its 
own investigators, where relevant, in accordance with local regulations. 
Section 11.5.2 Sponsor Reporting for Clinical Studies under an Investigational New Drug Application 
For investigator-initiated IND studies, some additional reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR § 600.80. 
 
Compliance with Pharmacovigilance Agreement/Audit 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE report 
timeliness in accordance with its own procedures. The Parties agree to provide written responses in a timely 
manner to inquiries from the other Party regarding AE reports received outside the agreed upon Agreement 
timelines. If there is any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct ad hoc or institute a regular joint 
meeting to address the issue. 


 
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In case of concerns related to non-compliance of processes, other than exchange timelines, with this 
Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the issues causing non-
compliance. Every effort will be made by the non-compliant Party to solve the non-compliance issues and 
inform the other Party of the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit under the 
provisions of this Agreement can be requested by either Party. The Parties will then discuss and agree in 
good faith upon the audit scope, agenda and execution of the audit. The requesting Party will bear the cost of 
the audit. 
Section 11.5.3  Signal Management and Risk Management  
Genentech is responsible for safety signal management (signal detection and/or evaluation) for their own 
product. However, it is agreed that Development Innovations, as Sponsor of the study, will be primarily 
responsible for assessment of the benefit-risk balance of the study. 
If Development Innovations issues a safety communication relevant for Genentech (i.e., a safety issue that 
notably impacts the benefit-risk balance of the study and/or triggers any changes to the study) this will be 
sent to Genentech within five (5) business days of its internal approval. 
As needed, Genentech will reasonably assist Development Innovations with signal and risk management 
activities related to the product within the study. 
Genentech will also provide Development Innovations with any new relevant information that may modify or 
supplement known data regarding the product (e.g., relevant Dear Investigator Letter). 
Section 11.6 Safety Crisis Management 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on the conduct of the 
Study, may lead to labeling changes or regulatory actions that limit or restrict the way in which the Products 
(atezolizumab and tiragolumab) are used, or where there is media involvement, the Party where the crisis originates 
will contact the other Party as soon as possible. 
The Parties agree that Genentech shall have the final say and control over safety crisis management issues relating to 
the Products (atezolizumab and tiragolumab).  Development Innovations agrees that it shall not answer such queries 
from media and other sources relating to the Products but shall redirect such queries to Genentech. 
Section 13.5 IND Annual Reports 
Or emailed to the Genentech Drug Safety CTV mailbox: ctvistsa@gene.com. 
Section 13.7 Study Close-out 
And to the Genentech Drug Safety CTV oversight mailbox: ctvistsa@gene.com 
Appendix C: Guidelines for Female Patients of Childbearing Potential and Fertile Male Patients 
Appendix C has been removed as the necessary and consistent information is now within the protocol. 
Appendix C: Schedule of Assessment 
Footnote p.: EOT evaluations must be completed within 30 days after the last dose of study treatment.  Patients must 
be followed for AEs for 30 calendar days after the last dose of study drug and serious adverse events and adverse 
events of special interest will continue to be reported until 90 days after the last dose of study treatment. 


 
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Thyroid Function Tests have been added for C1D1 and every 4th cycle thereafter.  
Footnote s: Thyroid function tests will include TSH, FT4, and T3. TFTs will be collected at C1D1 and every 
4th cycle thereafter. 
Appendix D: Immune-Modified Response evaluation Criteria in Solid Tumors (immune-Modified RECIST)  
Conventional response criteria may not be adequate to characterize the anti-tumor activity of immunotherapeutic 
agents like atezolizumab and tiragolumab, which can produce delayed responses that may be preceded by initial 
apparent radiographic progression, including the appearance of new lesions. 
Appendix E F Pre-existing Autoimmune Disease and Immune Deficiencies 
• 
Include patients with controlled Type 1 diabetes mellitus who are on an insulin regimen as an 
exception to the exclusion criteria 
• 
Include instructions to contact the Medical Monitor if there is any uncertainty over autoimmune 
exclusions  
Appendix F G Management of Tiragolumab/Atezolizumab-specific Adverse Events  
• 
The entire appendix has been updated to include management for adverse events specific to the study 
drugs.  Instructions for hypophysitis, immune-mediated myocarditis, and Stevens-Johnson syndrome have 
been added. 
• 
Table 11, footnote e: There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors, but data are limited, and the role of such treatment in the setting 
of antibody-associated CRS has not been established. 
• 
Table 18, footnote a: 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. 


 
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AMENDMENT NUMBER: 
1 
AMENDMENT DATE:       28 August 2020 
Additions are noted by bolding. Deletions are noted by cross outs. 
Synopsis and Section 1.3 
Arm B consists of approximately 10-15 patients per disease type (renal cell carcinoma [RCC], triple negative breast 
cancer [TNBC], small cell lung cancer [SCLC], squamous cell carcinoma of the head and neck [SCCHN], 
melanoma, urothelial tumors, or esophageal tumors progressing on anti-PD-1 monotherapy; melanoma 
progressing on  nivolumab plus ipilimumab; NSCLC progressing on anti-PD-1 monotherapy in ≥ second-line 
setting; NSCLC progressing on pembrolizumab plus chemotherapy in the first-line setting; NSCLC 
progressing on nivolumab plus ipilimumab in the first-line setting; NSCLC progressing on nivolumab plus 
ipilimumab in combination with 2 cycles of chemotherapy in the first-line setting; and microsatellite 
instability-high [MSI-high] solid tumors {as determined by local testing for MSI/mismatch repair (MMR) 
progressing on anti-PD-1 monotherapy}), as well as patients with NSCLC who were treated with a PD-1 antibody 
in ≥ second-line setting and who have had subsequent disease progression and NSCLC patients who have 
progressed after pembrolizumab plus chemotherapy in the first-line setting. 
Synopsis and Section 3.1 General Inclusion Criteria 
7.  Willingness to provide a mandatory new pre-treatment tumor biopsy.  (Archival tumor tissue collected 
following anti-PD-1 therapy may be used if there have been no subsequent treatment regimens following 
tissue collection and the tissue meets the criteria in Section 5.4.2). 
10. Measurable disease by RECIST v1.1. 
Synopsis and Section 3.1.1 Inclusion Arm A-Non-small cell lung cancer 
2. Disease progression after prior documented clinical benefit, defined as having at least one scan 
demonstrating at least stable disease (SD), on first-line treatment with anti-PD-1 monotherapy therapy, 
(pembrolizumab) for ≥ months. 
Synopsis and Section 3.1.2 Inclusion Arm B-Advanced Solid Tumors 
1. Patients withadvanced: 
1. Advanced RCC, TNBC, SCLC, SCCHN, melanoma, MSI-high solid tumors, and patients 
withurothelial tumors, or esophageal tumors progressing on anti-PD-1 monotherapy.  
2. Melanoma progressing on nivolumab plus ipilimumab 
3. NSCLC who were progressing on anti-PD-1 monotherapy in the ≥ second-line setting or 
4. NSCLC progressing on pembrolizumab plus chemotherapy in the first-line setting 
5. NSCLC progressing on nivolumab plus ipilimumab in the first-line setting 
6. NSCLC progressing on nivolumab plus ipilimumab in combination with 2 cycles of 
chemotherapy in the first-line setting Additional cohorts may be added 
7. MSI-high solid tumors, as defined by local testing for MSI/MMR, progressing on anti-PD-1 
monotherapy.  (Only MSI-high tumors will be included.require MSI/MMR testing results). 
2. Previously received and tolerated nivolumab or pembrolizumab monotherapy or immunotherapy doublets 
such as nivolumab/ipilimumab therapy (and was the last therapy prior to enrollment). 
3. Evidence of disease progression. after receiving clinical benefit defined as having at least one scan 
demonstrating at least stable disease (SD) during the most recent treatment. 
Synopsis and Section 3.2 Exclusion Criteria 


 
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4. Most recent immunotherapy ≤21 days and ≥ Grade 1 immunotherapy-related side effects, with the exception of 
alopeciaMost recent immunotherapy ≤21 days and ≥ Grade 2 immunotherapy-related side effects that are 
unresolved prior to enrollment on study.   
23. DiagnosisKnown active Hepatitis B or C infection; HBV and HCV testing is not required as part of this 
study.   
24. Known history of human immunodeficiency virus, hepatitis B, or hepatitis C. (HIV1 or 2); HIV testing is not 
required as part of this study. 
27 
Has a second primary malignancy that in the judgment of the investigator and sponsor may affect the 
interpretation of results.Has had malignancies other than NSCLC within 5 years prior to enrollment, with the 
exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival [OS] 
>90%) treated with an expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal- or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, or 
ductal carcinoma in situ treated surgically with curative intent). 
Section 3.3 Discontinue from Study Treatment  
• 
Intercurrent illness (this will be at the Investigator’s discretion and may also include COVID-19) 
Section 5 Study Design 
Arm A consists of patients with advanced NSCLC who received first-line anti-PD-1-monotherapy with prior 
documented clinical benefit (e.g. ≥ SD) prior to, who have subsequent disease progression.  In Arm A, patients 
with NSCLC will be randomized 1:1 to either chemotherapy plus atezolizumab at a flat dose of 1200 mg IV every 3 
weeks or chemotherapy alone.  Standard of care chemotherapy is defined as a platinum-doublet therapy (or triplet if 
bevacizumab is used) of the Investigator’s choice. 
Arm B consists of approximately 10-15 patients per disease type (which include the following solid tumors: 
● 
RCC, TNBC, SCLC, SCCHN melanoma, MSI-high solid tumors [as determined by local testing for 
MSI/MMR]), patients with urothelial tumors, or esophageal tumors progressing on prior anti-PD-1 
monotherapy 
● 
Melanoma progressing on nivolumab plus ipilimumab  
● 
NSCLC progressing on anti-PD-1 antibodymonotherapy in ≥ second-line setting  
● 
NSCLC patients who have progressed progressing on pembrolizumab plus chemotherapy in the first-line 
setting  
● 
NSCLC progressing on nivolumab plus ipilimumab in the first-line setting 
● 
NSCLC progressing on nivolumab plus ipilimumab in combination with 2 cycles of chemotherapy in 
the first-line setting 
● 
MSI-high solid tumors [as determined by local testing for MSI/MMR] who progressed following anti-
PD-1 monotherapy. 
Figure 1, Arm B has been updated 
Section 5.4.2 Tumor Tissue Samples 
All patients are requiredhighly encouraged to provide an archival tissue sample obtained prior to anti-PD-1 
CPItherapy, if available (approximately 50% of patients).  A paraffin block is preferred or at At least 15 slides 
containing unstained, freshly cut, serial sections not older than 18060 days upon submissionshould be submitted to 
the analytical laboratory.  Prior PD-L1 molecular profilingexpression results by IHC should be captured on the 
eCRF. 
All patients are required to submit a mandatory new pre-treatment tissue sample from a core biopsy prior to 
initiating anti-PD-L1 CPI therapytreatment (Cycle 1 Day 1) on this study for correlative research (see Section 7.2).  
Archival tissue collected following anti-PD-1 therapy may be used if there have been no subsequent treatment 


 
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regimens following tissue collection. Archival tissue must not be older than 180 days and provide at least 15 
slides containing unstained, freshly cut, serial sections.  One to three core needle biopsies (minimum diameter 18 
gauge; however, 16 gauge is desirable) embedded in a single formalin-fixed paraffin-embedded (FFPE) block are 
required.  Alcohol fixation, fine needle aspirates, cell blocks, or cytology specimens are not allowed.   
An optional tissue biopsy will be requested upon disease progression with anti-PD-L1 therapyCPI (approximately 
25% of patients).   
Section 7.2 Baseline Study Assessments 
● 
Pre-PD-1-treated archival tumor tissue sample provided as a formalin-fixed paraffin-embedded (FFPE) 
tumor specimen in a paraffin block (preferred) or ideally at least 15 slides (or whatever is available) 
containing unstained, freshly cut (not older than 18060 days) serial sections. 
● 
PD-L1 molecular profilingexpression status by IHC (prior PD-L1 molecular profilingtesting results 
should be captured in the eCRF and doesif available; however, PD-L1 testing is not need to be 
repeated).required as part of this study).   
● 
A mandatory new pre-treatment tumor sample after progression on a PD-1 CPIanti-PD-1 therapy (if 
available).(Archival tumor tissue collected following anti-PD-1 therapy may be used if there have 
been no subsequent treatment regimens following tissue collection and the tissue meets the criteria in 
Section 5.4.2).  
Section 10.1 Statistical Design 
This is a multi-center, open-label, Phase II study of atezolizumab in patients with NSCLC or advanced solid 
tumors that have had prior treatment with a PD-1 inhibitor.   (either nivolumab or pembrolizumab). 
Arm A consists of patients with advanced NSCLC who received first-line anti-PD-1-monotherapay with 
prior documentation of clinical benefit (e.g. ≥ SD) prior to disease progression.  Arm A consists of patients 
with advanced NSCLC who received first-line anti-PD-1 monotherapy, who have subsequent disease 
progression.  In Arm A, patients with NSCLC will be randomized 1:1 to either chemotherapy plus atezolizumab 
at a flat dose of 1200 mg IV every 3 weeks or chemotherapy alone until progression or unacceptable toxicity.  
Standard of care chemotherapy is defined as a platinum-doublet therapy of the Investigator’s choice. 
Arm B consists of approximately 10-15 patients per disease type RCC, TNBC, SCLC, SCCHN, melanoma, and 
MSI-high solid tumors [as determined by local testing for MSI/MMR]), patients withurothelial tumors, or 
esophageal tumors progressing on anti-PD-1 monotherapy, melanoma progressing on nivolumab plus 
ipilimumab; NSCLC who were progressing on anti-PD-1 antibodymonotherapy in ≥ second-line setting; 
NSCLC progressing on pembrolizumab plus chemotherapy in the first-line setting; NSCLC progressing 
on nivolumab plus ipilimumab in the first-line setting; NSCLC progressing on nivolumab plus 
ipilimumab in combination with 2 cycles of chemotherapy in the first-line setting; and MSI-high solid 
tumors [as determined by local testing for MSI/MMR]) progressing on anti-PD-1 monotherapy.  In Arm 
B, patients with advanced solid tumors will be treated with an atezolizumab flat dose of 1200 mg IV every 3 
weeks until progression or unacceptable toxicity.  Additional cohorts may be added as emerging clinical data 
becomes available. 
Section 11.1.2 Statistical Design 
• 
Death (i.e., the AE actually causes or leads to death) 
• 
A life-threatening AE (i.e., the AE, in the view of the Investigator, places the subject at immediate risk 
of death.  It does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
Table 3 Adverse Event Severity Grading Scale for Events Not Specifically Listed in NCI CTAE added.  
Section 11.2 Serious Adverse Event Reporting by Investigators 
Adverse events of special interest, special situation reports, and product complaints are added events to be reported 
to the Innovations Safety Department. 
Section 11.4 Adverse Events of Special Interest 


 
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• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release syndrome, influenza-like 
illness, macrophage activating syndrome and hemophagocytic lymphohistiocytosissystemic 
inflammatory response syndrome, and systemic immune 
Section 11.1.2 Statistical Design 
Guidance text for reporting SAEs, AESIs, and product complaints has been updated.  
Section 11.5.3 Reconciliation/Case Transmission Verification of Single Case Reports 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed time 
period. Confirmation of receipt should be received within the time period mutually agreed upon. 
Section 11.9 Study close out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. This 
includes all IND annual reports and the Clinical Study Report (final study report). Additionally, any 
literature articles that are a result of the study should be sent to Genentech. Copies of such reports should be 
mailed to the assigned Clinical Operations contact for the study: 
Atezolizumab IIS Clinical Operations: anti-pdl-1-mpd3280a-gsur@gene.com  
And to Genentech Drug Safety CTV oversight mail box at: ctvistsa@gene.com 
Appendix D Schedule of Assessments  
• 
aPPT has been added to the PT/PTT/INR SoA line and associated footnotes b and f.  
• 
Pre-PD-1 archival tumor tissue sample collection has been updated in the SoA and footnotes k, l, an n.  
Appendix G Management of Atezolizumab-specific Adverse Events 
Appendix updated with the most current data.  
Throughout the protocol 
Text with “PD-1” treatment and therapy has been updated to “anti-PD-1” treatment and therapy to clarify the 
protocol.  
First use of abbreviations has been updated throughout the document. 
“Genentech/Roche” has been updated to “Genentech”.  


 
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MULTI 29 PROTOCOL SYNOPSIS 
Title of Study: 
A Phase II study of atezolizumab and tiragolumab in patients with NSCLC or advanced 
solid tumors who have had prior treatment with a PD-1 inhibitor 
Sarah Cannon 
Development 
Innovations 
Study ID: 
MULTI 29 
Sponsor: 
Sarah Cannon Development Innovations, LLC – Nashville - TN 
Study Duration: 
The total duration of the study is planned to be 2 years. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at 7 sites.   
Number of 
Patients: 
Approximately 80 patients are planned to be enrolled in this study: Arm A will enroll 
approximately 20 patients, and Arm B will enroll approximately 60 patients. 
Objectives: 
Primary Objective 
The primary objective of this study is to: 
• 
Assess the efficacy (Overall Response Rate [ORR]) of atezolizumab combined 
with SOC chemotherapy in NSCLC, and atezolizumab combined with tiragolumab 
in patients with advanced solid tumors who have progressed after prior exposure to 
anti-PD-treatment. 
Secondary Objectives 
The secondary objectives of this study are to: 
• 
Determine the safety of atezolizumab combined with SOC chemotherapy, and 
atezolizumab combined with tiragolumab, in patients with NSCLC and other 
advanced solid tumors.  
• 
Estimate the 6-month disease control rate (DCR) in patients with NSCLC and 
other advanced solid tumors. 
Exploratory Objectives 
The exploratory objectives of this study are: 
• 
Estimate the 6-month progression-free survival (PFS) and overall survival (OS) in 
patients with NSCLC and other advanced solid tumors. 
• 
Correlation of programmed death ligand 1 (PD-L1) expression by 
immunohistochemistry (IHC) with response to therapy. 
• 
Characterization of the tumor microenvironment by IHC, ribonucleic acid (RNA) 
sequencing and/or reverse transcription polymerase chain reaction (RT-PCR) and 
correlation of immune gene signatures with response to therapy. 
• 
In selected patients with paired biopsy samples (pre-anti-PD-1-treated and pre-
atezolizumab/tiragolumab-treated; or pre- and post-atezolizumab/tiragolumab-
treated tissue):  
o 
Assessment of immune escape mechanisms, that may include but is not 
limited to neoantigen profiling and T cell receptor (TCR) sequencing.  
o 
Assessment of tumor mutation burden (TMB) by next-generation sequencing 
(NGS) and correlation with response to therapy. 
Study Design: 
This is an open-label, multi-center, Phase II study of atezolizumab and tiragolumab, or 
atezolizumab combined with SOC chemotherapy in patients with NSCLC or advanced solid 
tumors that have had prior treatment with a PD-1 inhibitor (e.g. nivolumab or 
pembrolizumab).  Arm A consists of approximately 20 patients with advanced NSCLC who 
received first-line anti-PD-1 therapy, who have subsequent disease progression.  Arm B 
consists of approximately 15 patients per disease type (renal cell carcinoma [RCC] 
progressing on prior anti-PD-1 therapy, triple negative breast cancer [TNBC] progressing 
on prior anti-PD-1 therapy, NSCLC progressing on check-point inhibitors plus 


 
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chemotherapy in the first-line setting; and microsatellite instability-high [MSI-high] solid 
tumors [as determined by local testing for MSI/mismatch repair (MMR)] progressing on 
prior anti-PD-1 therapy).  
Study Drugs, 
Doses, and Modes 
of 
Administration: 
In Arm A, patients with NSCLC will receive chemotherapy plus atezolizumab at a flat dose 
of 1200 mg intravenously (IV) every 3 weeks.  Standard of care chemotherapy is defined as 
a platinum-doublet therapy (or triplet if bevacizumab is used) of the Investigator’s choice.  
In Part B, patients with advanced solid tumors will be treated with atezolizumab at a flat 
dose of 1200 mg IV every 3 weeks in combination with tiragolumab at a flat dose of 600 
mg IV every 3 weeks until progression or unacceptable toxicity.   
Inclusion 
Criteria: 
Patients must meet all of the following criteria in order to be included in the research study: 
1. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 - 2 
(Appendix A). 
2. Adequate hematologic function defined as: 
- 
Absolute neutrophil count ≥1500/μL with one exception: 
Patients with benign ethnic neutropenia (BEN):  ANC >1300/ μL 
- 
Lymphocyte count ≥0.5 × 109/L (500/µL) 
- 
Hemoglobin ≥9 g/dL (patients may be transfused to meet this criterion) 
- 
Platelets ≥100,000/µL (without transfusion, within 7 days of enrollment) 
3. Adequate liver function defined as: 
- 
Alanine aminotransferase and aspartate aminotransferase ≤2.5 × the upper limit of 
normal (ULN) 
- 
Total bilirubin ≤1.5 × ULN (patients with known Gilbert syndrome: serum 
bilirubin level ≤ 3 × ULN) 
4. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) or 
calculated creatinine clearance ≥30 mL/min as calculated by the Cockcroft-Gault 
formula. 
5. For patients not receiving therapeutic anticoagulation:  INR or aPTT ≤1.5 × ULN.  For 
patients receiving therapeutic anticoagulation:  stable anticoagulant regimen. 
6. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per 
year, during their participation in the study and for 5 months following last dose of 
study drug(s).  Women must refrain from donating eggs during the study and for 5 
months following last dose of study drug(s). 
- 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (≥12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.   
- 
Examples of contraceptive methods with a failure rate of <1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  The reliability of sexual abstinence should be evaluated 
in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not adequate 
methods of contraception.  
7. Male patients with a female partner of childbearing potential or a pregnant female 
partner must remain abstinent (refrain from heterosexual intercourse) or use a condom 
during the treatment period and for 5 months after the last dose of study drug.  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 


 
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(e.g., calendar, ovulation, symptothermal or post-ovulation methods) and withdrawal 
are not adequate methods of contraception.  Men must also agree to refrain from 
donating sperm during their participation in the study and for 5 months after the last 
dose of study drug. 
8. Age ≥18 years. 
9. Willingness to provide a mandatory new pre-treatment tumor biopsy.  (Archival tissue 
collected following anti-PD-1 therapy may be used if there have been no subsequent 
treatment regimens following tissue collection and the tissue meets the criteria in 
Section 5.4.2).  
10. Willingness and ability to comply with study and follow-up procedures. 
11. Ability to understand the nature of this study and give written informed consent. 
12. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
13. Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that 
all of the following criteria are met: 
- 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
- 
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
- 
The patient has not undergone stereotactic radiotherapy within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment. 
- 
The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease. 
- 
If the patient is receiving anti-convulsant therapy, the dose is considered stable. 
Inclusion Arm A- Non-small cell lung cancer 
14. Advanced squamous or non-squamous NSCLC 
15. Disease progression after prior documented clinical benefit, defined as having at least 
one scan demonstrating at least stable disease (SD), on first-line treatment with anti-
PD-1 monotherapy 
16. Previously received and tolerated nivolumab or pembrolizumab monotherapy or 
immunotherapy doublets such as nivolumab/ipilimumab therapy (and was the last 
therapy prior to enrollment). 
17. PD-L1 Tumor Proportion Score ≥1% 
Crossover from Arm A to Arm B 
18. Last dose of atezolizumab is ≥21 days 
Inclusion Arm B – Advanced Solid Tumors 
19. Patients with: 
• 
Advanced RCC progressing on anti-PD-1 therapy 
• 
Advanced TNBC progressing on anti-PD-1 therapy 
• 
NSCLC progressing on check-point inhibitors plus chemotherapy in the first-
line setting 
• 
MSI-high solid tumors, as defined by local testing for MSI/MMR, progressing 
on anti-PD-1 therapy.  (Only MSI-high tumors will require MSI/MMR testing 
results.) 
20. Evidence of disease progression after receiving clinical benefit, defined as having at 
least one scan demonstrating at least SD, during most recent PD-1 inhibitor treatment.  
Exclusion 
Criteria: 
Patients who meet any of the following criteria will be excluded from study entry: 


 
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1. History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
2. History of any Grade 3 or 4 toxicities to a prior checkpoint inhibitor (CPI) 
treatment. 
3. Known hypersensitivity to Chinese hamster ovary cell products or to any 
component of the atezolizumab or tiragolumab formulations 
4. Most recent immunotherapy ≤21 days and ≥ Grade 2 immunotherapy-related side 
effects that are unresolved prior to enrollment on study 
5. Use of systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) ≤28 days or 5 half-lives (whichever is shorter) 
prior to the first dose of study drugs.   
6. Treatment with chemotherapy in the first line setting. 
7. Treatment with investigational therapy within 28 days prior to initiation of study 
treatment. 
8. Treatment with systemic immunosuppressive medication (including, but not 
limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor-α agents) within 2 weeks prior to 
initiation of study treatment, or anticipation of need for systemic 
immunosuppressive medication during the course of the study, with the following 
exceptions: 
a. 
Patients who receive 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 receive mineralocorticoids (e.g., fludrocortisone), inhaled 
corticosteroids for chronic obstructive pulmonary disease (COPD) or 
asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal 
insufficiency are eligible for the study. 
9. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of 
study treatment, or anticipation of need for such a vaccine during the course of the 
study or within 5 months after the last dose of atezolizumab or tiragolumab. 
10. Uncontrolled tumor-related pain 
- 
Patients requiring pain medication must be on a stable regimen at study 
entry. 
- 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior 
to enrollment.  Patients should be recovered from the effects of radiation.  
There is no required minimum recovery period. 
- 
Asymptomatic metastatic lesions that would likely cause functional 
deficits or intractable pain with further growth (e.g., epidural metastasis 
that is not currently associated with spinal cord compression) should be 
considered for loco-regional therapy if appropriate prior to enrollment. 
11. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation 
of study treatment. 
- 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or COPD exacerbation) are eligible for the study. 
12. Requirement for use of denosumab during the study.  Patients who are receiving 
denosumab for any reason (including hypercalcemia) must be willing and eligible 
to receive a bisphosphonate instead while in the study. 


 
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13. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to 
starting study drug or has not recovered from side effects of such therapy. 
14. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
15. Symptomatic, untreated, or actively progressing central nervous system (CNS) 
metastases.  Patients who have received radiation or surgery for brain metastases 
are eligible if therapy was completed at least 2 weeks prior to study entry and there 
is no evidence of CNS disease progression, mild neurologic symptoms, and no 
requirement for chronic corticosteroid therapy.  Anticonvulsant therapy at a stable 
dose is permitted. 
16. Prior allogeneic stem cell or solid organ transplantation 
17. Pregnant or lactating females 
18. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
a. 
History of radiation pneumonitis in the radiation field (fibrosis) is 
permitted. 
19. Uncontrolled diabetes mellitus.  Patients with Type II diabetes are eligible if they 
require only oral hypoglycemic agents and fasting blood glucose level is ≤120.  
Patients with Type I diabetes are eligible if HbAlc is ≤7%. 
20. 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 (see Appendix B) 
21. History of leptomeningeal disease 
22. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently). 
a. 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
23. Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or 
calcium > 12 mg/dL or corrected serum calcium >ULN) 
24. 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 (see Appendix E for a more comprehensive list of 
autoimmune diseases and immune deficiencies), with the following exceptions: 
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: 
d. Rash must cover ˂10% of body surface area 
e. 
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids 


 
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f. 
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 
25. Serious active infection within 4 weeks of treatment (including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia), 
or another serious underlying medical condition that would impair the ability of 
the patient to receive protocol treatment. 
26. Known active Hepatitis B (HBV) or C (HCV) infection; HBV and HCV testing is 
not required as part of this study.   
27. Known history of human immunodeficiency virus (HIV1 or 2); HIV testing is not 
required as part of this study. 
28. Positive Epstein-Barr virus (EBV) viral capsid antigen (VCA) 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. 
29. Active tuberculosis 
30. In the opinion of the Investigator, any other disease, metabolic dysfunction, 
physical examination finding, or clinical laboratory finding that contraindicates the 
use of an investigational drug, may affect the interpretation of the results, or may 
render the patient at high risk from treatment complications 
31. Has had malignancies other than NSCLC, RCC, TNBC, or MSI-high solid tumors 
within 5 years prior to enrollment, with the exception of those with a negligible 
risk of metastasis or death (e.g., expected 5-year OS >90%) treated with an 
expected curative outcome (such as adequately treated carcinoma in situ of the 
cervix, basal- or squamous-cell skin cancer, localized prostate cancer treated 
surgically with curative intent, or ductal carcinoma in situ treated surgically with 
curative intent). 
32. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
33. Prior treatment with anti-T-cell immunoreceptor with immunoglobulin and 
immunoreceptor tyrosine-based inhibition motif domains (TIGIT) therapeutic 
antibodies.  
34. Major surgical procedure within 4 weeks prior to initiation of study treatment, or 
anticipation of need for a major surgical procedure during the study. 
Exclusion Arm A Non-small cell lung cancer 
35. NSCLC with an activating EGFR mutation or ALK fusion oncogene  
- 
For patients with non-squamous NSCLC histology: unknown EGFR 
and/or ALK status requires testing  
- 
For patients with squamous NSCLC histology: unknown EGFR and/or 
ALK status does not require test results at screening.  However, exclusion 
is applied if the status of either driver oncogene is known to be positive. 
- 
For patients with NSCLC of mixed histology: unknown EGFR and/or 
ALK status requires testing at screening 
Note: ALK and/or EGFR status may be assessed locally or submitted for central 
laboratory testing.  If ALK and/or EGFR status is assessed locally, testing must be 
performed on tissue or cytology using a validated FDA-approved test.  If samples 
are submitted for central laboratory testing, five additional slides are required. 
36. Known c-ros oncogene 1 (ROS1) rearrangement: ROS1 testing at screening is not 
required for study inclusion; however, patients with known ROS1 rearrangements 
are excluded. 


 
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37. Intervening treatment with a regimen other than CPI prior to enrollment in this 
study. 
Exclusion Arm B – Advanced Solid Tumors  
38. Prior treatment with anti-TIGIT therapeutic antibodies. 
39. Known hypersensitivity to any component of the tiragolumab formulation. 
Correlative 
Testing: 
Correlative research in this study provides an opportunity to gain insight into factors 
contributing to immune escape of the tumor and to investigate biomarkers helping to 
identify patients deriving benefit from CPI treatment upon progression on anti-PD-1 agents.  
This research may include, but is not limited to, analysis of neoantigens and the assessment 
of TMB by whole exome sequencing in tumor samples obtained prior to and post anti-PD-
1/PD-L1 agents.  Furthermore, research will include the characterization of the tumor 
microenvironment using IHC to assess PD-L1 and tumor infiltrating immune cells as well 
as the assessment of gene expression signatures by RNA sequencing.  Additional analyses 
of the tumor tissue or blood samples obtained prior to atezolizumab or tiragolumab therapy 
and on-treatment may include, but is not limited to sequencing of the TCR repertoire, 
assessment of immune cell subsets by flow cytometry, genomic profiling of circulating 
tumor deoxyribonucleic acid (DNA), or RNA by PCR or NGS. 
All patients are highly encouraged to provide an archival tissue sample obtained prior to 
anti-PD-1 therapy if available (approximately 50% of patients).  All patients are required to 
submit a new pre-treatment tissue sample from a core biopsy to be taken after progression 
on anti-PD-1 therapy and prior to anti-PD-L1 therapy (Cycle 1 Day 1).  Archival tumor 
tissue collected following anti-PD-1 treatment may be used if there have been no 
subsequent treatment regimens following tissue collection and the tissue meets the criteria 
in Section 5.4.2.  An optional tissue biopsy will be requested upon disease progression with 
anti-PD-L1 therapy (approximately 25% of patients).  An optional tissue biopsy will be 
requested for crossover patients.  This sample should be collected prior to the start of 
treatment on Arm B. 
Statistical 
Methodology: 
This is a multi-center, open-label, Phase II study of atezolizumab and tiragolumab in 
patients with NSCLC or advanced solid tumors that have had prior treatment with a PD-1 
inhibitor.   
Main NSCLC Cohort: In Arm A, precise sample size cannot be determined. Approximately 
20 patients will be enrolled to the cohort.  
Advanced Solid Tumor Cohort: In Arm B, precise sample size cannot be determined.  
Approximately 60 patients will be enrolled to Arm B. 
• 
Overall Response Rate (ORR) is defined as the proportion of patients with 
confirmed complete response (CR) or partial response (PR (i.e., 2 CRs or PRs at 
least 4 weeks apart) according to the immune-modified RECIST criteria.  
• 
Disease Control Rate (DCR) is defined as the proportion of patients with CR, PR, 
or SD for at least 6 months according to the immune-modified RECIST criteria. 
For ORR and DCR, patients without a post-baseline tumor assessment will be classed as not 
evaluable (NE) and considered as non-responder. 
For ORR and DCR, the estimates and the associated 95% confidence interval (CI) (based 
on the Clopper-Pearson method) in each treatment group will be calculated.   
• 
Progression Free Survival (PFS), defined as the time from the first day of study 
drug administration (Day 1) to disease progression as defined by the immune-


 
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modified RECIST criteria, or death on study.  Patients who are alive and free from 
disease progression will be censored at the date of last tumor assessment. 
• 
Overall Survival (OS), defined as the time from the first day of study drug 
administration (Day 1) to death on study.  Patients who are alive will be censored 
at the date of last known date alive. 
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and 
the associated 95% CI in each treatment group will be provided.   
All efficacy analyses will be performed using the Full Analysis Set. 


 
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MULTI 29 CONTACT INFORMATION 
Sarah Cannon Development Innovations  
Contact Information: 
Sarah Cannon Development Innovations, LLC  
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
Study Chair: 
Melissa Johnson, MD 
Sarah Cannon Research Institute 
1100 Dr. Martin L. King Jr. Blvd.,Suite 800 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@sarahcannon.com 
Safety Dept. Fax #: 
Safety Dept. Email: 
1-866-807-4325 
CANN.SAE@SCRI-Innovations.com 
Regulatory Department Email: 
SCRIRegulatory@scri-innovations.com 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AR 
Adverse reaction 
AST (SGOT) 
Aspartate aminotransferase 
BEN 
Benign ethnic neutropenia 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMP 
Comprehensive metabolic profile 
CNS 
Central nervous system 
COPD 
Chronic obstructive pulmonary disease 
CPI 
Checkpoint inhibitor 
CR 
Complete response/remission 
CRS 
Cytokine release syndrome 
CT 
Computer tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
Development Innovations 
Sarah Cannon Development Innovations 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin  
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
Hemophagocytic lymphohistiocytosis 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IHC 
Immunohistochemistry 
IL-2 
Interleukin 2 
imAE 
Immune-mediated adverse event 
IND 
Investigational new drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ISF 
Investigator study file 
IV 
Intravenous 
MAS 
Macrophage activation syndrome 


 
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MMR 
Mismatch repair 
MSI-high 
Microsatellite instability-high  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
Next-generation sequencing 
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PHI 
Protected health information 
PR 
Partial response/remission 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVR 
Poliovirus receptor 
RCC 
Renal cell carcinoma 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SAS 
Safety Analysis Set 
SD 
Stable disease 
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TCR 
T-cell receptor 
TIGIT 
T-cell immunoreceptor with immunoglobulin and 
immunoreceptor tyrosine-based inhibition motif domains 
TMB 
Tumor mutation burden 
TNBC 
Triple-negative breast cancer 
TNF 
Tumor necrosis factor 
TSH 
Thyroid-stimulating hormone 
UAE 
Unexpected adverse event 
ULN 
Upper limit of normal 
USPI 
US Package Insert 
WES 
Whole exome sequencing 


 
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TABLE OF CONTENTS 
MULTI 29 SUMMARY OF CHANGES ................................................................................ 5 
MULTI 29 PROTOCOL SYNOPSIS .................................................................................... 25 
LIST OF ABBREVIATIONS ................................................................................................ 34 
TABLE OF CONTENTS ....................................................................................................... 36 
1. 
INTRODUCTION ................................................................................................. 41 
 
Background ........................................................................................................... 41 
 
Atezolizumab......................................................................................................... 41 
 
Tiragolumab .......................................................................................................... 42 
 
Rationale for the Study .......................................................................................... 42 
2. 
STUDY OBJECTIVES ......................................................................................... 43 
 
Primary Objective.................................................................................................. 43 
 
Secondary Objectives ............................................................................................ 44 
 
Exploratory Objectives .......................................................................................... 44 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 44 
 
General Inclusion Criteria ..................................................................................... 44 
 
Inclusion Arm A – Non-small cell lung cancer ..................................................... 46 
 
Crossover from Arm A to Arm B .......................................................................... 46 
 
Inclusion Arm B – Advanced Solid Tumors ......................................................... 46 
 
Exclusion Criteria .................................................................................................. 47 
 
Exclusion Arm A –Non-small cell lung cancer..................................................... 50 
 
Exclusion Arm B – Advanced Solid Tumors ........................................................ 51 
 
Discontinuation from Study Treatment ................................................................. 51 
4. 
STUDY REGISTRATION.................................................................................... 52 
5. 
STUDY DESIGN .................................................................................................. 52 
 
Treatment Plan ...................................................................................................... 54 
 
Atezolizumab......................................................................................................... 54 
 
Tiragolumab (Arm B only).................................................................................... 55 
 
Standard of Care Chemotherapy (Arm A only) .................................................... 56 
 
Stopping Rules in Dose Expansion ....................................................................... 57 
 
Treatment Duration ............................................................................................... 57 
 
Concomitant Medications...................................................................................... 57 
 
Permitted Concomitant Medications ..................................................................... 58 
 
Concomitant Medications to be used with Caution............................................... 58 
 
Prohibited Concomitant Medications .................................................................... 59 


 
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Correlative Studies ................................................................................................ 59 
 
Blood samples ....................................................................................................... 60 
 
Tumor Tissue Samples .......................................................................................... 60 
 
Handling, storage and destruction of biological samples ...................................... 61 
 
Informed consent for storage of donated biological samples ................................ 61 
6. 
DOSE MODIFICATIONS .................................................................................... 61 
 
Management of Tiragolumab/Atezolizumab-Related Adverse Events ................. 65 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 65 
 
Overview ............................................................................................................... 65 
 
Baseline Study Assessments ................................................................................. 65 
 
Day 1 of each cycle (± 3 days) .............................................................................. 66 
 
Response Assessment Every 2 Cycles (± 7days) .................................................. 67 
 
End of Study Treatment ........................................................................................ 67 
 
Follow-up .............................................................................................................. 67 
 
Follow-up for Patients Who Discontinue Prior to Disease Progression ............... 67 
 
Survival Follow-Up ............................................................................................... 68 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 68 
 
Atezolizumab......................................................................................................... 68 
 
Atezolizumab Labeling, Packaging, and Supply ................................................... 68 
 
Preparation and Administration of Atezolizumab ................................................. 68 
 
Risks Associated with Atezolizumab .................................................................... 68 
 
Tiragolumab .......................................................................................................... 69 
 
Tiragolumab Labeling, Packaging, and Supply .................................................... 69 
 
Preparation and Administration of Tiragolumab................................................... 69 
 
Risks Associated with Tiragolumab ...................................................................... 69 
 
Accountability for All Study drugs ....................................................................... 69 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 70 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 70 
 
Statistical Design ................................................................................................... 70 
 
Sample Size Considerations .................................................................................. 70 
 
Analysis Population ............................................................................................... 71 
 
Data Analysis ........................................................................................................ 71 
 
Demographics and Baseline Characteristics ......................................................... 71 
 
Efficacy Analysis .................................................................................................. 71 
 
Safety Analysis ...................................................................................................... 72 


 
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Analysis Time Points............................................................................................. 72 
 
Final Analysis ........................................................................................................ 72 
 
Safety Review........................................................................................................ 72 
 
Efficacy Review .................................................................................................... 73 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 73 
 
Definitions ............................................................................................................. 73 
 
Adverse Events ...................................................................................................... 73 
 
Serious Adverse Event .......................................................................................... 73 
 
Adverse Reaction .................................................................................................. 74 
 
Suspected Adverse Reaction ................................................................................. 74 
 
Recording and Reporting of Adverse Events ........................................................ 74 
 
Assessment of Adverse Events.............................................................................. 76 
 
Serious Adverse Event Reporting by Investigators ............................................... 76 
 
Recording of Adverse Events and Serious Adverse Events .................................. 77 
 
Diagnosis versus Signs and Symptoms ................................................................. 78 
 
Persistent or Recurrent Adverse Events ................................................................ 78 
 
Abnormal Laboratory Values ................................................................................ 78 
 
Deaths .................................................................................................................... 79 
 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 79 
 
Pre-Existing Medical Conditions .......................................................................... 79 
 
New Cancers.......................................................................................................... 80 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 80 
 
Lack of Efficacy or Worsening of Cancer............................................................. 80 
 
Atezolizumab and Tiragolumab Overdose ............................................................ 81 
 
Adverse Events of Special Interest (AESIs).......................................................... 81 
 
Sponsor Serious Adverse Event Reporting Requirements .................................... 82 
 
Sponsor Assessment of Unexpected...................................................................... 83 
 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application ............................................................................................................ 84 
 
Reconciliation/Case Transmission Verification of Single Case Reports .............. 87 
 
Queries................................................................................................................... 87 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 88 
 
Study Monitoring, Auditing, and Inspecting ......................................................... 88 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 88 
 
Institutional Review Board Approval.................................................................... 88 
 
Regulatory Approval ............................................................................................. 89 
 
Informed Consent .................................................................................................. 89 
 
Confidentiality ....................................................................................................... 89 


 
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Financial Information ............................................................................................ 90 
 
IND Annual Reports .............................................................................................. 90 
 
Aggregate Report .................................................................................................. 90 
 
Study Close-out ..................................................................................................... 91 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 91 
 
Amendments to the Protocol ................................................................................. 91 
 
Documentation Required to Initiate the Study ...................................................... 92 
 
Study Documentation and Storage ........................................................................ 92 
 
Data Collection ...................................................................................................... 94 
 
Disclosure and Publication Policy ......................................................................... 94 
15. 
REFERENCES ...................................................................................................... 96 
16. 
APPENDICES ....................................................................................................... 99 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions ........... 55 
Table 2 
Administration of First and Subsequent Tiragolumab Infusions ............. 56 
Table 3 
Dose Modifications for Arm A and Arm B ............................................. 61 
Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE ............................................................................. 75 
Table 5 
Management Guidelines for Pericardial Events, Including 
Pericarditis, Pericardial Effusion, and Cardiac Tamponade .................. 114 
Table 6 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis............................................................................................ 115 
Table 7 
Management Guidelines for Hepatic Events ......................................... 116 
Table 8 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis).................................................................................................... 118 
Table 9 
Management Guidelines for Endocrine Events ..................................... 120 
Table 10 
Management Guidelines for Ocular Events ........................................... 122 
Table 11 
Management Guidelines for Immune-Mediated Cardiac Events ........... 123 
Table 12 
Management Guidelines for Infusion – Related Reactions and 
Cytokine-Release Syndrome .................................................................. 124 
Table 13 
Management Guidelines for Pancreatic Events ..................................... 128 
Table 14 
Management Guidelines for Dermatologic Events ................................ 129 


 
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Table 15 
Management Guidelines for Neurologic Disorders ............................... 131 
Table 16 
Management Guidelines for Immune-Mediated Meningoencephalitis . 132 
Table 17 
Management Guidelines for Renal Events ............................................ 133 
Table 18 
Management Guidelines for Immune-Mediated Myositis ..................... 134 
Table 19 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome ................. 137 
LIST OF FIGURES 
Figure 1 
Study Schema........................................................................................... 54 
 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 99 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ................................................................................................... 100 
Appendix C: 
Schedule of Assessments ....................................................................... 101 
Appendix D: 
Immune-Modified Response Evaluation Criteria in Solid Tumors 
(Immune-Modified RECIST)................................................................. 103 
Appendix E: 
Pre-existing Autoimmune Diseases and Immune Deficiencies ............. 112 
Appendix F: 
Management of Tiragolumab/Atezolizumab-Specific Adverse Events 113 
Appendix G: 
Anaphylaxis Precautions ........................................................................ 139 
Appendix H: 
Biological Sample Laboratory Testing Information .............................. 140 
Appendix I: 
Safety Reporting Fax Cover Sheet ......................................................... 141 
 


 
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1. 
INTRODUCTION 
 
Background 
Immune checkpoint inhibitors (CPIs), which target the programmed cell death protein 1 (PD-1) 
receptor and programmed death ligand 1 (PD-L1) axis, have heralded a paradigm shift in the 
treatment landscape for many solid tumors.  Checkpoint inhibitors improve survival and provide 
remarkable benefit for 20-40% of patients with advanced malignancies (Brahmer et al. 2012).  
Benefit is typically associated with increased levels of PD-L1 expression in the tumor and/or 
infiltrating immune cells.  Mutational burden is an independent predictor of response to therapy 
(Topalian et al. 2012, Rizvi et al. 2015).  Currently there are two U.S. Food and Drug 
Administration (FDA)-approved anti-PD-1 agents: nivolumab (Opdivo® Bristol-Myers Squibb) 
and pembrolizumab (Keytruda® Merck), and one FDA-approved anti-PD-L1 agent: 
atezolizumab (Tecentriq® Genentech) with many other compounds in development.  In general, 
CPIs are well-tolerated, and side effects are mild compared to chemotherapy (Brahmer et al. 
2012).   
 
Atezolizumab 
Atezolizumab is a CPI which targets PD-L1, blocking its interaction with activated T cell 
receptors (TCRs), PD-1 and B7-1, enhancing immune-mediated tumor recognition and 
cytotoxicity.  The PD-L1 pathway serves as an immune checkpoint to temporarily dampen 
immune responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding to its 
two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells following T 
cell activation, and expression is sustained in states of chronic stimulation (Blank et al. 2005, 
Keir et al. 2008).  B7-1 is a molecule expressed on antigen presenting cells and activated T cells.  
Binding of PD-L1 to PD-1 and B7-1 inhibits T cell proliferation and activation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or exhaustion of T cells 
(Butte et al. 2007, Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported 
to impede anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for restoring 
tumor-specific T cell immunity. 
Atezolizumab has been generally well tolerated.  Adverse events (AEs) with potentially immune-
mediated causes consistent with an immunotherapeutic agent, including pericardial disorders 
(pericarditis, pericardial effusion, and cardiac tamponade), rash, influenza-like illness 
endocrinopathies, hepatitis or transaminitis, pneumonitis, colitis, myasthenia gravis, myocarditis, 
myositis, neurological issues (including Guillain-Barré Syndrome), and severe cutaneous adverse 
reactions have been observed (see atezolizumab Investigator's Brochure [IB] for detailed safety 
results).  To date, the majority of these events have been manageable with treatment. 
Atezolizumab has demonstrated efficacy as a single agent and in combinations in a variety of 
tumor settings and patient populations, and is FDA approved to treat non-small cell lung cancer 
(NSCLC; Barlesi et al. 2016, Besse et al. 2015, Vansteenkiste et al. 2015, Spira et al. 2015) and 
advanced bladder cancer (Rosenberg et al. 2016, Infante et al. 2016). Targeting the PD-L1 


 
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pathway with atezolizumab has demonstrated activity in patients with advanced malignancies 
who have failed on standard-of-care therapies.  Objective responses have been observed across a 
broad range of malignancies, including NSCLC, urothelial carcinoma, renal cell carcinoma 
(RCC), melanoma, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma (see atezolizumab IB for detailed efficacy results).    
 
Tiragolumab 
Tiragolumab is a fully human IgG1/қ monoclonal antibody that binds TIGIT (T-cell 
immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif 
domains), an inhibitory immunoreceptor.  TIGIT is highly expressed on the surface of activated 
T-cell and natural killer (NK)-cell subsets and interacts with high affinity with CD155 (also 
known as poliovirus receptor [PVR]) (Yu et al. 2009).  Genetic ablation in T cells in mice results 
in exacerbated T cell responses, demonstrating the role of TIGIT in inhibiting T cell responses 
(Joller et al. 2014, Johnston et al. 2014).  Activation of TIGIT on T cells and NK cells was 
demonstrated to limit proliferation, effector cytokine production, and killing of target tumor cells 
(Stanietsky et al. 2009, Yu et al. 2009, Johnston et al. 2014). 
Therapeutic blockade of TIGIT by tiragolumab represents an attractive strategy for cancer 
therapy and is expected to enhance the magnitude and quality of tumor specific T cell responses, 
which may result in improved meaningful anti-tumor activity when tiragolumab is combined 
with other cancer immunotherapy (CIT) and chemotherapy (Tiragolumab IB 2020).  The 
available nonclinical and clinical data provide a strong rationale for evaluating the potential 
clinical benefit of tiragolumab in patients with cancer.  Refer to the tiragolumab IB for details on 
nonclinical and clinical studies of tiragolumab. 
 
Rationale for the Study 
Despite impressive responses and survival improvements, patients who initially receive benefit 
with anti-PD-1 agents eventually experience disease progression, and optimal next-line 
treatments for patients with acquired resistance to PD-1 therapy are unknown.  This is 
particularly true for patients with NSCLC, where both pembrolizumab and nivolumab are 
approved for patients with advanced disease in the refractory setting.  The median progression-
free survival (PFS) for patients treated with nivolumab in the Checkmate-017 and Checkmate-
057 studies was 2.3 months and 3.5 months respectively, with 1-year PFS for both studies of 
~ 20%.  Overall survival was improved in each study when compared with docetaxel.  Findings 
from Keynote-010 with pembrolizumab were similar with a PFS and overall survival (OS) of 5.2 
months and 14.9 months, respectively, compared with docetaxel with a PFS and OS of 8.1 
months and 4.1 months, respectively (Brahmer et al. 2015,Borghaei et al. 2015,Herbst et al. 
2016).  Clinically, PD-L1 expression may change upon exposure to chemotherapy, targeted 
therapies, non-therapeutic immune irritants, or immunotherapeutic agents including PD-1 CPIs.  
Increased PD-L1 expression and PD-1/PD-L1-mediated immune tolerance may be a mechanism 
of acquired resistance to PD-1 inhibitors.  PD-L1 blockade with atezolizumab may restore anti-
tumor immunity in patients with acquired resistance to pembrolizumab or nivolumab. 
Tiragolumab binds to the inhibitory immunoreceptor TIGIT, which 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 T cells.  Therefore, in the 


 
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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 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 
(Tiragolumab IB 2020).  Tiragolumab and atezolizumab have been studied in a phase I clinical 
trial, and have been shown to be safe and tolerable in combination with signals of anti-tumor 
efficacy (Bendell et al. 2020).  Tiragolumab and atezolizumab have also been combined in 
treatment-naïve NSCLC patient populations with responses and survival outcomes greater than 
with atezolizumab and placebo combinations, especially in PDL1-high expressing tumors 
(Rodriguez-Abreu et al. 2020).  
This study will investigate the use of atezolizumab and tiragolumab in patients with acquired 
resistance following prior treatment with anti-PD-1 therapy.  The main NSCLC cohort, Arm A, 
will determine whether adding atezolizumab to standard of care (SOC) chemotherapy will be 
efficacious.  Efficacy of atezolizumab in combination with tiragolumab will be explored in a 
signal-finding cohort of anti-PD-1-treated tumor types and disease settings (Arm B) including: 
RCC progressing on prior anti-PD therapy, triple-negative breast cancer (TNBC) tumors 
progressing on anti-PD-1 therapy, NSCLC progressing on check-point inhibitors plus 
chemotherapy in the first-line setting and microsatellite-high (MSI-high) solid tumors [as 
determined by local testing for MSI/mismatch repair (MMR)] progressing on anti-PD-1 therapy. 
In Arm A, patients will be receiving an anti-PD-L1 inhibitor in combination with chemotherapy 
(or chemotherapy alone) after previously receiving an anti-PD-1 inhibitor.  While we assume 
anti-PD-1 and anti-PD-L1 antibodies are synonymous in clinical practice, in truth this has not 
been (and will never be) tested.  There are several reasons these two classes of antibodies may be 
at least slightly different.  Anti-PD-1 antibodies and anti-PD-L1 antibodies target opposing sides 
the same the PD-1/PD-L1 interaction, and thereby have distinct downstream effectors (PD-1’s 
ligands are most commonly PD-L1 and PD-L2 while PD-L1 most commonly binds to PD-1 and 
B7-1 (CD80).  PD-1 is largely expressed on immune cells, while PD-L1 is expressed on tumor 
cells.  Finally, the impact of tumor heterogeneity on a tumor’s predilection to respond to a PD-1 
inhibitor vs. PD-L1 is not well understood.  It is common in clinical practice for patients to be 
treated with serial PD-1 inhibitors or PD-1 followed by PD-L1 inhibitors, because these agents 
are well tolerated and because it is assumed that some portion of cells may remain sensitive to 
PD-1 blockade even as the therapy has been deemed over all to have lost its usefulness.  We see 
this in the treatment of renal cell carcinoma and melanoma, for example, where options beyond 
immunotherapy are minimal.  Arm A of this study aims to test the effect of continued CPI 
blockade with the addition of chemotherapy in NSCLC. 
2. 
STUDY OBJECTIVES 
 
Primary Objective 
The primary objective of this study is to: 


 
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• Assess the efficacy (overall response rate [ORR]) of atezolizumab combined with SOC 
chemotherapy in NSCLC, and atezolizumab combined with tiragolumab in patients with 
advanced solid tumors who have progressed after prior exposure to anti-PD-treatment. 
 
Secondary Objectives 
The secondary objectives of this study are to: 
• Determine the safety of atezolizumab combined with SOC chemotherapy, and 
atezolizumab combined with tiragolumab, in patients with NSCLC and other advanced 
solid tumors.  
• Estimate the 6-month disease control rate (DCR) in patients with NSCLC and other 
advanced solid tumors. 
 
Exploratory Objectives 
The exploratory objectives of this study are: 
• Estimate the 6-month PFS and OS in patients with NSCLC and other advanced solid 
tumors. 
• Correlation of PD-L1 expression by immunohistochemistry (IHC) with response to 
therapy 
• Characterization of the tumor microenvironment by IHC, ribonucleic acid (RNA) 
sequencing and/or reverse transcription-polymerase chain reaction (RT-PCR) and 
correlation of immune gene signatures with response to therapy. 
• In selected patients with paired biopsy samples (pre-anti-PD1-treated and pre-
atezolizumab/tiragolumab-treated; or pre- and post-atezolizumab/tiragolumab-treated 
tissue):  
o 
Assessment of immune escape mechanisms, that may include but is not limited to 
neoantigen profiling and TCR sequencing;  
o 
Assessment of tumor mutation burden (TMB) by next-generation sequencing 
(NGS) and correlation with response to therapy. 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
 
General Inclusion Criteria 
Patients must meet all of the following criteria in order to be included in the research study: 
1. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 - 2 
(Appendix A: ECOG Performance Status Criteria). 
2. Adequate hematologic function defined as: 
- Absolute neutrophil count (ANC) ≥1500/μL with one exception: 
Patients with benign ethnic neutropenia (BEN): ANC >1300/µL 


 
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BEN (also known as constitutional neutropenia) is an inherited cause of mild or 
moderate neutropenia that is not associated with any increased risk for infections 
or other clinical manifestation (Atallah-Yunes et al., 2019).  BEN is referred to as 
ethnic neutropenia because of its increased prevalence in people of African 
descent and other specific ethnic groups. 
- Lymphocyte count ≥0.5 × 109/L (500/µL) 
- Hemoglobin (Hgb) ≥9 g/dL (patients may be transfused to meet this criterion) 
- Platelets ≥100,000/µL (without transfusion, within 7 days of enrollment) 
3. Adequate liver function defined as: 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × the 
upper limit of normal (ULN) 
- Total bilirubin ≤1.5 × ULN (patients with known Gilbert syndrome: serum 
bilirubin level ≤3 × ULN) 
4. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR 
calculated creatinine clearance ≥30 mL/min as calculated by the Cockcroft-Gault 
formula. 
5. For patients not receiving therapeutic anticoagulation: INR or aPTT ≤1.5 × ULN.  For 
patients receiving therapeutic anticoagulation: stable anticoagulant regimen 
6. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per 
year, during their participation in the study and for 5 months following last dose of study 
drug(s).  Women must refrain from donating eggs during the study and for 5 months 
following last dose of study drug(s) 
- A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (≥12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.   
- Examples of contraceptive methods with a failure rate of <1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods), and 
withdrawal are not adequate methods of contraception.  
7. Male patients with a female partner of childbearing potential or a pregnant female partner 
must remain abstinent (refrain from heterosexual intercourse) or use a condom during the 
treatment period and for 5 months after the last dose of study drug.  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 post-ovulation methods) and withdrawal are not adequate 


 
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methods of contraception.  Men must also agree to refrain from donating sperm during 
their participation in the study and for 5 months after the last dose of study drug.  
8. Age ≥18 years. 
9. Willingness to provide a mandatory new pre-treatment tumor biopsy.  (Archival tumor 
tissue collected following anti-PD-1 therapy may be used if there have been no 
subsequent treatment regimens following tissue collection and the tissue meets the 
criteria in Section 5.4.2). 
10. Willingness and ability to comply with study and follow-up procedures. 
11. Ability to understand the nature of this study and give written informed consent. 
12. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
13. Asymptomatic patients with treated or untreated CNS lesions are eligible, provided that 
all of the following criteria are met: 
- Measurable disease, per RECIST v1.1, must be present outside the CNS. 
- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. 
- The patient has not undergone stereotactic radiotherapy within 7 days prior to 
initiation of study treatment, whole-brain radiotherapy within 14 days prior to 
initiation of study treatment, or neurosurgical resection within 28 days prior to 
initiation of study treatment. 
- The patient has no ongoing requirement for corticosteroids as therapy for CNS 
disease. 
- If the patient is receiving anti-convulsant therapy, the dose is considered stable. 
 
Inclusion Arm A – Non-small cell lung cancer 
14. Advanced squamous or non-squamous NSCLC 
15. Disease progression (PD) after prior documented clinical benefit, defined as having at 
least one scan demonstrating at least stable disease (SD), on first-line treatment with anti-
PD-1 monotherapy.  
16. Previously received and tolerated nivolumab or pembrolizumab monotherapy or 
immunotherapy doublets such as nivolumab/ipilimumab therapy (and was the last therapy 
prior to enrollment). 
17. PD-L1 Tumor Proportion Score ≥1%. 
 
Crossover from Arm A to Arm B  
18. Last dose of atezolizumab is ≥21 days  
 
Inclusion Arm B – Advanced Solid Tumors  
19. Patients with: 
• Advanced RCC progressing on anti-PD-1 therapy 
• Advanced TNBC progressing on anti-PD-1 therapy 


 
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• NSCLC progressing on check-point inhibitors plus chemotherapy in the first-line 
setting 
• MSI-high solid tumors, as defined by local testing for MSI/MMR, progressing on 
anti-PD-1 therapy.  (Only MSI-high tumors will require MSI/MMR testing 
results). 
20. Evidence of PD after receiving clinical benefit defined as having at least one scan 
demonstrating at least SD during the most recent PD-1 inhibitor treatment.  
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies 
or fusion proteins 
2. History of any Grade 3 or 4 toxicities to a prior CPI treatment 
3. Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab or tiragolumab formulations 
4. Most recent immunotherapy ≤21 days and ≥ Grade 2 immunotherapy-related side 
effects that are unresolved prior to enrollment on study   
5. Use of systemic immunostimulatory agents (including, but not limited to, interferon 
and interleukin 2 [IL-2]) ≤28 days or 5 half-lives (whichever is shorter) prior to the 
first dose of study drugs.   
6. Treatment with chemotherapy in the first line setting. 
7. Treatment with investigational therapy within 28 days prior to initiation of study 
treatment. 
8. Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor [TNF]-α agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive medication during 
the course of the study, with the following exceptions: 
• Patients who 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. 
• Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled 
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or 
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are 
eligible for the study. 
9. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during the course of the study or 
within 5 months after the last dose of atezolizumab or tiragolumab 


 
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10. Uncontrolled tumor-related pain 
- Patients requiring pain medication must be on a stable regimen at study entry. 
- Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the effects of radiation.  There is 
no required minimum recovery period. 
- Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for loco-regional 
therapy if appropriate prior to enrollment. 
11. Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior 
to initiation of study treatment. 
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or COPD exacerbation) are eligible for the study. 
12. Requirement for use of denosumab during the study.  Patients who are receiving 
denosumab for any reason (including hypercalcemia) must be willing and eligible to 
receive a bisphosphonate instead while in the study. 
13. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy. 
14. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
15. Symptomatic, untreated, or actively progressing central nervous system (CNS) 
metastases.  Patients who have received radiation or surgery for brain metastases are 
eligible if therapy was completed at least 2 weeks prior to study entry and there is no 
evidence of CNS disease progression, mild neurologic symptoms, and no requirement 
for chronic corticosteroid therapy.  Anticonvulsant therapy at a stable dose is 
permitted. 
16. Prior allogeneic stem cell or solid organ transplantation 
17. Pregnant or lactating females 
18. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
• History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
19. Uncontrolled diabetes mellitus.  Patients with Type II diabetes are eligible if they 
require only oral hypoglycemic agents and fasting blood glucose level is ≤120.  
Patients with Type I diabetes are eligible if HbAlc is ≤7%. 


 
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20. Significant cardiovascular disease, such as New York Heart Association (NYHA) 
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 (see Appendix B:New York Heart Association (NYHA) 
Classification of Cardiac Disease) 
21. History of leptomeningeal disease 
22. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
• Patients with indwelling catheters (e.g., PleurX®) are allowed. 
23. Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or 
calcium >12 mg/dL or corrected serum calcium >ULN). 
24. 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 (see Appendix E: 
Pre-existing Autoimmune 
Diseases and Immune Deficiencies for a more comprehensive list of autoimmune 
diseases and immune deficiencies), with the following exceptions: 
• Patients with a history of autoimmune-mediated hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
- 
Rash must cover ˂ 10% of body surface area 
- 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
- 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors, or high potency or oral corticosteroids within the previous 
12 months 
25. Serious active infection within 4 weeks of treatment (including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia), or 
another serious underlying medical condition that would impair the ability of the 
patient to receive protocol treatment. 
26. Known active hepatitis B (HBV) or C (HCV) infection; HBV and HCV testing are 
not required as part of this study.   


 
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27. Known history of human immunodeficiency virus (HIV1 or 2); HIV testing is not 
required as part of this study. 
28. Positive Epstein-Barr virus (EBV) viral capsid antigen (VCA) 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. 
29. Active tuberculosis 
30. In the opinion of the Investigator any other disease, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding that contraindicates the use of an 
investigational drug, may affect the interpretation of the results, or may render the 
patient at high risk from treatment complications 
31. Has had malignancies other than NSCLC, RCC, TNBC, or MSI-high solid tumors 
within 5 years prior to enrollment, with the exception of those with a negligible risk 
of metastasis or death (e.g., expected 5-year OS >90%) treated with an expected 
curative outcome (such as adequately treated carcinoma in situ of the cervix, basal- or 
squamous-cell skin cancer, localized prostate cancer treated surgically with curative 
intent, or ductal carcinoma in situ treated surgically with curative intent). 
32. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
33. Prior treatment with anti-T-cell immunoreceptor with immunoglobulin and 
immunoreceptor tyrosine-based inhibition motif domains (TIGIT) therapeutic 
antibodies 
34. Major surgical procedure within 4 weeks prior to initiation of study treatment, or 
anticipation of need for a major surgical procedure during the study. 
 
Exclusion Arm A –Non-small cell lung cancer 
35. NSCLC with an activating EGFR mutation or ALK fusion oncogene 
o For patients with non-squamous NSCLC histology: unknown EGFR and/or ALK 
status requires testing  
o For patients with squamous NSCLC histology: unknown EGFR and/or ALK status 
does not require test results at screening.  However, exclusion is applied if the status 
of either driver oncogene is known to be positive. 
o For patients with NSCLC of mixed histology: unknown EGFR and/or ALK status 
requires testing at screening 
Note: ALK and/or EGFR status may be assessed locally or submitted for central 
laboratory testing.  If ALK and/or EGFR status is assessed locally, testing must be 
performed on tissue or cytology using a validated FDA-approved test.  If samples are 
submitted for central laboratory testing, five additional slides are required. 


 
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36. Known c-ros oncogene 1 (ROS1) rearrangement: ROS1 testing at screening is not 
required for study inclusion; however, patients with known ROS1 rearrangements are 
excluded. 
37. Intervening treatment with a regimen other than CPI prior to enrollment in this study. 
 
Exclusion Arm B – Advanced Solid Tumors  
38. Prior treatment with anti-TIGIT therapeutic antibodies. 
39. Known hypersensitivity to any component of the tiragolumab formulation 
 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the Investigator’s discretion and may also include 
COVID-19) 
• 
Inability of the patient to comply with study requirements 
• 
Patient requests to discontinue treatment 
• 
Patient withdraws consent from the study  
• 
Non-compliance/lost to follow-up 
• 
Study termination  
After discontinuation from protocol treatment, patients must be followed for AEs for 30 days, 
after their last dose of study drug.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the Investigator, these values are not 
likely to improve, because of the underlying disease.  In this case, the Investigators must record 
his or her reasoning for this decision in the patients’ medical records and as a comment in the 
electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v 4.0.3) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the Investigator, not likely that these values are to improve.  In this 
case, the Investigator must record his or her reasoning for making this decision in the patients’ 
medical records and as a comment in the eCRF. 


 
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4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, treatment alternatives, side-effects, risks, 
and discomforts.  Institutional Review Board (IRB) approval of this protocol and informed 
consent form (ICF) is required.  Eligible patients who wish to participate in the study will be 
enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled by the site following the subject registration instructions provided 
by Sarah Cannon Development Innovations, LLC (Development Innovations) study contact.  
Patient registration follow-up and/or confirmation will be provided via email within 
approximately 24 hours, or by the next business day.  Patients enrolling in Arm A will be 
assigned to atezolizumab and SOC chemotherapy for NSCLC.  Patients enrolling in Arm B will 
be assigned into a cohort based on disease type to receive atezolizumab and tiragolumab for 4 
solid tumor types. 
5. 
STUDY DESIGN 
This is an open-label, multi-center, Phase II study of atezolizumab and tiragolumab, or 
atezolizumab in combination with SOC chemotherapy in patients with NSCLC or advanced solid 
tumors who have had prior treatment with a PD-1 inhibitor (e.g. nivolumab or pembrolizumab).   
Arm A 
Arm A consists of patients with advanced NSCLC who received first-line anti-PD-1-therapy 
with prior documented clinical benefit (e.g. ≥ SD) prior to PD.  In Arm A, patients with NSCLC 
will be assigned treatment to chemotherapy plus atezolizumab at a flat dose of 1200 mg IV every 
3 weeks.  Standard of care chemotherapy is defined as a platinum-doublet therapy (or triplet if 
bevacizumab is used) of the investigator’s choice.  Arm A will enroll approximately 20 patients.  
Arm B 
Arm B consists of approximately 15 patients per disease type.  The following solid tumors will 
be enrolled into Arm B: 
● RCC progressing on prior anti-PD-1 therapy 
● TNBC progressing on prior anti-PD-1therapy 
● NSCLC progressing on check-point inhibitors plus chemotherapy in the first-line setting  
● MSI-high solid tumors [as determined by local testing for MSI/MMR] progressing on 
prior anti-PD-1 therapy. 
In Arm B, patients with advanced solid tumors will be treated with atezolizumab at a flat dose of 
1200 mg IV every 3 weeks and tiragolumab at a flat dose of 600mg IV every 3 weeks.  
Additional cohorts may be added as emerging clinical data becomes available.   
For Arm B the precise sample size cannot be determined.  Approximately 60 patients total will 
be enrolled among the various disease types.   


 
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The study schema is presented in Figure 1. 


 
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Figure 1 
Study Schema 
Arm A - NSCLC: 
 
Arm B –Advanced Solid Tumors: 
 
 
Treatment Plan 
 
Atezolizumab 
Atezolizumab  
1200 mg IV every 3 weeks 
On days of scheduled infusions, atezolizumab should be administered first, before chemotherapy 
or tiragolumab.  Administration of atezolizumab will be performed in a monitored setting where 
there is immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see Appendix G: 
Anaphylaxis 
Precautions.  Atezolizumab infusions will be administered per the instructions outlined in Table 
1.  


 
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Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
Study Drug 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
• 
No premedication is permitted 
prior to the atezolizumab 
infusion. 
• 
Vital signs (heart 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 
through an intravenous line 
with or without a sterile, non-
pyrogenic, low-protein 
binding in-line filter (pore size 
0.2-0.22 micron). 
• 
If clinically indicated, vital 
signs should be recorded 
during the infusion at 15, 30, 
45, and 60 minutes (±5 
minutes for all timepoints) 
during the infusion and at 
30 (±10) minutes after the 
infusion. 
• 
If the patient experienced an infusion-related 
reaction with any previous infusion of 
atezolizumab, premedication with 
antihistamines, antipyretics, and/or analgesics 
may be administered for subsequent doses at 
the discretion of the Investigator. 
• 
Vital signs should be recorded within 
60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 30 (±10) 
minutes if the previous infusion was tolerated 
without an infusion-related reaction, or 60 
(±15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion through an intravenous line with or 
without a sterile, non-pyrogenic, low-protein 
binding in-line filter (pore size 0.2-0.22 
micron). 
• 
If the patient experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
recorded during the infusion and at 
30 (±5) minutes after 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 should be informed 
about the possibility of 
delayed post-infusion 
symptoms and instructed to 
contact their study physician if 
they develop such symptoms. 
• 
If the patient tolerated the previous 
atezolizumab infusion well without infusion-
associated adverse events, the observation 
period after the next infusions may be reduced 
to 30 minutes. 
• 
If the patient experienced infusion-associated 
adverse events during the previous infusion, the 
observation period for the next infusion should 
be 60 minutes. 
• 
If clinically indicated, vital signs should be 
recorded at 30 (±10) minutes after the infusion 
of atezolizumab. 
 
Tiragolumab (Arm B only) 
Tiragolumab  
600 mg IV every 3 weeks 
On days of scheduled infusions, atezolizumab should be administered first, before chemotherapy 
or tiragolumab.  Administration of tiragolumab will be performed in a monitored setting where 


 
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there is immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  Tiragolumab infusions will be administered per the instructions 
outlined in Table 2. 
Table 2 
Administration of First and Subsequent Tiragolumab Infusions 
Infusion of 
tiragolumab 
First Infusion 
Subsequent Infusions 
• 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. 
• Tiragolumab should be infused over 60 
(±15) minutes. 
• Vital signs should be recorded every 
15 (±5) minutes during 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. 
• 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 during the 
previous infusion, the observation period 
for the next infusion 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. 
 
 
Standard of Care Chemotherapy (Arm A only) 
Platinum-based SOC doublet chemotherapy (or triplet if bevacizumab is used) will be given by 
IV every 3 weeks.  Platinum chemotherapy may be cisplatin or carboplatin chosen based on 


 
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histology and at the discretion of the treating investigator.  It should be administered according to 
the directions in the approved labeling. 
 
Stopping Rules in Dose Expansion 
Arm A will enroll 20 patients and each of the four Arm B cohorts will enroll 15 patients.  Should 
the first 7 patients in Arm A, or the first 5 patients consecutively enrolled in any single Arm B 
cohort develop PD in 2 cycles, that cohort will be stopped and no additional patient enrollment 
will be allowed. 
 
Treatment Duration 
Patients will be evaluated for toxicity at the start of each cycle.  Every 2 cycles, restaging will 
occur using immune-modified RECIST v1.1 criteria (see Appendix D: 
Immune-Modified 
Response Evaluation Criteria in Solid Tumors (Immune-Modified RECIST)).  Because of the 
possibility of an initial increase in tumor burden caused by immune cell infiltration in the setting 
of a T cell response (termed “pseudoprogression”) with atezolizumab and/or tiragolumab 
treatment, radiographic progression per RECIST v1.1 may not be indicative of true PD.  In the 
absence of unacceptable toxicity, patients who meet criteria for PD per RECIST v1.1 while 
receiving atezolizumab and/or tiragolumab will be permitted to continue atezolizumab and/or 
tiragolumab if they meet all of the following criteria: 
• Evidence of clinical benefit, as determined by the Investigator following a review of all 
available data 
• Absence of symptoms and signs (including laboratory values, such as new or worsening 
hypercalcemia) indicating unequivocal progression of disease 
• Absence of decline in ECOG performance status that can be attributed to PD 
• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) 
that cannot be managed by protocol-allowed medical interventions. 
Patients who have objective response (OR) or SD will continue treatment with re-evaluations 
every 2 cycles, until the time of tumor progression or intolerable treatment-related side effects.   
The end of the study is expected to occur approximately 1 year after the last patient is enrolled.  
However, the Investigator or the Sponsor may decide to end the study at any time.  The total 
length of the study from screening the first patient to the end of the study is estimated to be 
approximately 2 years. 
 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he or she is taking or has taken after the start of the study drug. 


 
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Permitted Concomitant Medications 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
second and subsequent atezolizumab and/or tiragolumab infusions only, at the discretion of the 
Investigator. 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
• 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 vaccines (e.g., influenza) 
• 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 atezolizumab and/or tiragolumab infusions only, at the 
discretion of the Investigator. 
In general, Investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience infusion-associated 
symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, 
and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local 
standard practice.  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and β2-
adrenergic agonists; see Table 12). 
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the Investigator with the exception of those listed in Section 5.3.3. 
 
Concomitant Medications to be used with Caution 
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 except that systemic 


 
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corticosteroids may not be given as premedication to patients with an allergy to contrast agents 
used for tumor scans. 
 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
• Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), 
whether approved or investigational, is prohibited prior to starting study treatment, 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 
• Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation 
of study treatment, during treatment with atezolizumab and/or tiragolumab, and for 5 
months after the last dose of atezolizumab and/or tiragolumab. 
• Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are 
prohibited within 4 weeks or five half-lives of the drug (whichever is shorter) 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/or tiragolumab. 
• Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited during 
study treatment because these agents could potentially alter the efficacy and safety of 
atezolizumab and/or tiragolumab. 
 
Correlative Studies 
While cancer immunotherapy has been shown to provide a significant survival benefit to cancer 
patients across tumor types, patients eventually experience progression of their disease.  The 
understanding of the mechanisms underlying innate or acquired resistance to cancer 
immunotherapy is still evolving.  Mutations in JAK1, JAK2 or B2M were shown to be 
associated with acquired resistance to PD-1 blockade in melanoma (Zaretsky et al. 2016, Tumeh 
et al. 2014) showed that patients who progressed on PD-1 blockade experienced lower CD8+ cell 
densities at the invasive margin of the tumor compared to patients who responded to therapy.  A 
better understanding of changes on treatment in the tumor microenvironment and the restoration 
of anti-tumor immunity upon disease progression are crucial to the development of novel 
therapies and will help to better sequence cancer immunotherapy agents.  Furthermore, it will be 
imperative to understand which patients will derive benefit from CPI post progression on anti- 
PD-1 agents. 
Correlative research in this study provides an opportunity to gain insight into factors contributing 
to immune escape of the tumor and to investigate biomarkers helping to identify patients 
deriving benefit from CPI treatment upon progression on anti-PD-1 agents.  This research may 
include, but is not limited to, analysis of neoantigens and the assessment of TMB by whole 


 
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exome sequencing (WES) in tumor samples obtained both prior to and post anti-PD-1/PD-L1 
agents.  Furthermore, research will include the characterization of the tumor microenvironment 
using IHC to assess PD-L1 and tumor infiltrating immune cells as well as the assessment of gene 
expression signatures by RNA sequencing.  Additional analyses of the tumor tissue or blood 
samples obtained prior to atezolizumab and/or tiragolumab therapy and on treatment may 
include, but are not limited to sequencing of the TCR repertoire, assessment of immune cell 
subsets by flow cytometry, genomic profiling of circulating tumor deoxyribonucleic acid (DNA), 
or RNA by PCR or NGS. 
Given the complexity and exploratory nature of the analyses, data derived from correlative 
research will not be provided to study Investigators or patients unless required by law.  The 
aggregate results of any conducted research will be available in accordance with the effective 
Sponsor policy on study data publication. 
 
Blood samples 
All patients will have blood samples collected for peripheral blood mononuclear cells (PBMC), 
plasma, and serum isolation to enable exploratory biomarker research in the future.  Blood 
samples will be collected for PBMCs on Cycle 1 Day 1 and at the end of treatment visit.  Blood 
samples for plasma/serum isolation will be collected on Cycle 1 Day 1, Cycle 3 Day 1 and at the 
end of treatment visit.  Samples will be banked for future correlative studies aiming to determine 
changes in blood-based biomarkers including but not limited to analysis of circulating immune 
cell populations, cytokines, or TCR sequencing using NGS, flow cytometry or array-based 
immunoassays.  In addition, whole blood will be collected at baseline as a normal DNA control 
sample for WES of the tumor.  The maximum total amount of blood collected at any time point 
will be 50 mL. 
 
Tumor Tissue Samples 
All patients are highly encouraged to provide an archival tissue sample obtained prior to anti-PD-
1 therapy, if available (approximately 50% of patients).  At least 15 slides containing unstained, 
freshly cut, serial sections not older than 180 days should be submitted to the analytical 
laboratory.  Prior PD-L1 expression results by IHC should be captured on the eCRF. 
All patients are required to submit a mandatory new pre-treatment tissue sample from a core 
biopsy prior to initiating anti-PD-L1 therapy (Cycle 1 Day 1) on this study for correlative 
research (see Section 7.2).  Archival tissue collected following anti-PD-1 therapy may be used if 
there have been no subsequent treatment regimens following tissue collection.  Archival tissue 
must not be older than 180 days and provide at least 15 slides containing unstained, freshly cut, 
serial sections.  One to three core needle biopsies (minimum diameter 18 gauge; however, 16 
gauge is desirable) embedded in a single formalin-fixed paraffin-embedded (FFPE) block are 
required.  Alcohol fixation, fine needle aspirates, cell blocks, or cytology specimens are not 
allowed.   
An optional tissue biopsy will be requested for crossover patients.  This sample should be 
collected prior to the start of treatment on Arm B. 
An optional tissue biopsy will be requested upon disease progression with anti-PD-L1 therapy 
(approximately 25% of patients).   


 
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Handling, storage and destruction of biological samples 
For shipment, handling, etc. of blood and tissue samples see the laboratory reference manual.  
Samples may be sent to one or more laboratories for analysis. 
All blood and tissue samples will be stored for up to 15 years after finalization of the manuscript, 
with the following exception{s}: 
21. Residual material from normal control DNA blood samples will be stored until they are no 
longer needed for this study or until they are exhausted 
22. All storage periods will be in accordance with the IRB-approved ICF and applicable laws 
(e.g., health authority requirements). 
 
Informed consent for storage of donated biological samples 
If a patient withdraws consent to the use of required biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed, 
Development Innovations is not obliged to destroy the results of this research. 
As collection of these biological samples is a required part of the study, the patient may not 
continue in the study after withdrawing this consent. 
6. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v 4.0.3, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof.   
There will be no dose reduction of atezolizumab or tiragolumab; however, treatment delays are 
allowed.   
Resume atezolizumab/tiragolumab if event resolves to Grade 1 or better within 21 days.  
Permanently discontinue atezolizumab if event does not resolve to Grade 1 or better within 21 
days.  If atezolizumab is discontinued, the Investigator may continue tiragolumab, provided AEs 
have returned to Grade 1 or better within 21 days.  Permanently discontinue both atezolizumab 
and tiragolumab if event does not resolve to Grade 1 or better within 12 weeks. 
The dose modifications to be used in this study are presented in Table 3. 
Table 3 
Dose Modifications for Arm A and Arm B 
Event 
Action to Be Taken 
IRRs and anaphylaxis 
• Guidelines for management of IRRs are provided in the 
Atezolizumab IB for atezolizumab and Table 11.  For anaphylaxis 
precautions, see Appendix G: 
Anaphylaxis Precautions. 
Pericardial events 
• Guidelines for management of pericardial events are provided in the 
atezolizumab IB for atezolizumab and Table 5. 
Pulmonary events 
 
Pneumonitis, Grade 1 
• Continue atezolizumab/tiragolumab 
• For recurrent pneumonitis, treat as a Grade 3 or 4 event. 


 
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Event 
Action to Be Taken 
Pneumonitis, Grade 2 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days.   
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
• For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 3 or 4 
• Permanently discontinue atezolizumab.  The Investigator may 
continue tiragolumab provided adverse events have returned to Grade 
1 or better within 21 days.   
Hepatotoxicity 
 
Hepatitis, Grade 2 
Events of > 5 days’ duration: 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Hepatitis, Grade 3 or 4 
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 within 21 days.   
Gastrointestinal toxicity 
 
Diarrhea or colitis, Grade 2 or 3 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Diarrhea or colitis, Grade 4  
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days.   
Endocrine disorders 
 
Symptomatic hypothyroidism 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab when symptoms are controlled 
and thyroid function is improving. 
Asymptomatic hyperthyroidism 
TSH < 0.1 mIU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 


 
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Event 
Action to Be Taken 
Symptomatic hyperthyroidism 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab when symptoms are controlled 
and thyroid function is improving. 
• Permanently discontinue atezolizumab for life-threatening immune-
mediated hyperthyroidism.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days. 
Symptomatic adrenal insufficiency, 
Grade 2, 3, or 4 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Hyperglycemia, Grade 3 or 4 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab when symptoms resolve and 
glucose levels are stable. 
Ocular toxicity 
 
Grade 1 
• Continue atezolizumab/tiragolumab. 
• If symptoms persist, treat as a Grade 2 event. 
Grade 2 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Grade 3 or 4  
• Permanently discontinue atezolizumab. If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 within 21 days.   
Pancreatic toxicity 
 
Amylase or lipase elevation, Grade 3 
or 4 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
• For recurrent events, permanently discontinue atezolizumab.  The 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   


 
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Event 
Action to Be Taken 
Immune-mediated pancreatitis, Grade 
2 or 3 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
• For recurrent events, permanently discontinue atezolizumab.  The 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Immune-mediated pancreatitis, Grade 
4 
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days.   
Dermatologic toxicity 
 
Rash, Grade 3  
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Rash, Grade 4 
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days.   
Neurologic disorders 
 
Immune-mediated neuropathy, Grade 
2  
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to Grade 1 or 
better within 21 days. 
• Permanently discontinue atezolizumab if event does not resolve to 
Grade 1 or better within 21 days.  If atezolizumab is discontinued, the 
Investigator may continue tiragolumab, provided adverse events have 
returned to Grade 1 or better within 21 days.   
Immune-mediated neuropathy, Grade 
3 or 4  
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days. 
Myasthenia gravis and 
Guillain-Barré, all grades 
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days.   
Immune-mediated 
meningoencephalitis,  
all grades 
• Permanently discontinue atezolizumab.  If atezolizumab is 
discontinued, the Investigator may continue tiragolumab provided 
adverse events have returned to Grade 1 or better within 21 days. 


 
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Event 
Action to Be Taken 
Grade 3 or 4 or intolerable Grade 
2 treatment-related toxicities not 
described above, excluding e.g., 
alopecia, nausea, and vomiting 
• Withhold atezolizumab/tiragolumab. 
• Resume atezolizumab/tiragolumab if event resolves to baseline or 
Grade 1 or better within 21 days.  
IRR = infusion-related reaction; TSH = thyroid-stimulating hormone. 
Clinical trial experience to date suggests that tiragolumab may increase or accentuate the immune-mediated 
adverse events (imAEs) observed with atezolizumab; please see Table 3 for management of imAEs.  If 
atezolizumab is held for drug-related toxicity, a reasonable guiding principle would be to also hold 
tiragolumab.  If atezolizumab is discontinued, the Investigator may continue tiragolumab, provided adverse 
events have returned to Grade 1 or better within 21 days.   
 
Management of Tiragolumab/Atezolizumab-Related Adverse Events 
Management of the following tiragolumab/atezolizumab-related AEs is located in Appendix F:
 
Management of Tiragolumab/Atezolizumab-Specific Adverse Events: immune-mediated 
pericardial disorders, pulmonary (including pneumonitis), hepatic, gastrointestinal, endocrine, 
immune-mediated myocarditis, ocular, infusion-related reactions (IRRs), pancreatic (including 
pancreatitis), dermatologic, neurologic, meningoencephalitis, immune-mediated myelitis, and 
immune-mediated facial paresis. 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is shown in Appendix C: Schedule of 
Assessments.  The baseline physical examination, medical history, ECOG PS, complete blood 
counts (CBC), differential and platelets, comprehensive metabolic profile (CMP), urinalysis, and 
prothrombin time (PT)/ partial thromboplastin time (PTT) or activated partial thromboplastin 
time (aPTT)/ international normalized ratio (INR) should be done ≤7 days prior to initiation of 
treatment.  If these initial examinations are obtained within 72 hours of Cycle 1 Day 1 they do 
not have to be repeated.  A pregnancy test must be performed within 72 hours of Cycle 1 Day 1.  
CT scans should be performed ≤28 days prior to initiation of treatment.   
 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
screening (±7 days unless otherwise noted): 
• Written informed consent prior to any other study-related procedures (≤28 days prior to 
initiation of treatment) 
• Medical history 
• Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, blood pressure, respiratory rate, and oral temperature) 
• ECOG performance status (see Appendix A: ECOG Performance Status Criteria) 


 
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• 12-lead electrocardiogram (ECG) 
• Concomitant medication review 
• CBC including Hgb, hematocrit, white blood cell count with 3-part differential and 
platelets 
• CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT, total 
bilirubin, total protein, and albumin. 
• Coagulation analysis: PT/PTT or aPTT/INR  
• Urine dipstick (if abnormal, additional testing [e.g., microscopic examination, urine 
protein:creatinine ratio] should be performed, as clinically indicated) 
• Serum or urine pregnancy test (must be performed within 72 hours of Cycle 1 Day 1) 
• CT scans of the chest, abdomen/pelvis ≤4 weeks prior to initiation of study treatment is 
preferred. 
● Pre-PD-1-treated archival tumor tissue sample provided as at least 15 slides (or whatever 
is available) containing unstained, freshly cut (not older than 180 days) serial sections. 
● PD-L1 expression status by IHC (prior PD-L1 testing results should be captured in the 
eCRF if available; however, PD-L1 testing is not required as part of this study).   
● A mandatory new pre-treatment tumor sample after progression on anti-PD-1 therapy 
(Archival tumor tissue collected following anti-PD-1 therapy may be used if there have 
been no subsequent treatment regimens following tissue collection and the tissue meets 
the criteria in Section 5.4.2).  
● Study Treatment Assessments  
 
Day 1 of each cycle (± 3 days) 
• Physical examination, including measurement of weight and vital signs (including signs 
and symptoms of immune-mediated myelitis) 
• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• CBC, including 3-part differential and platelets  
• CMP  
• Blood samples collected for plasma/serum on Cycle 1 Day 1 and Cycle 3 Day 1 (prior to 
treatment) 
• Blood sample for PBMC isolation and correlative research (Cycle 1 Day 1) 
• Blood sample for whole blood (Cycle 1 Day 1 only) 


 
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Response Assessment Every 2 Cycles (± 7days) 
Patients will be evaluated for response to treatment after every 2 cycles of treatment.  The 
following assessments will be performed:  
• CT scans of chest, abdomen and pelvis is preferred; however, SOC assessment for 
disease subtype will be acceptable 
Patients with PD or unacceptable toxicity should be discontinued from the study; patients with 
SD or response to therapy will continue treatment. 
 
End of Study Treatment   
The follow-up evaluations required after treatment ends due to completion of the planned study 
treatment period, disease progression, or once the patient is discontinued due to unacceptable 
toxicity or decision to discontinue treatment by the patient or the study physician are specified in 
Appendix C: Schedule of Assessments and below. 
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfill the end-of-treatment visit. 
After withdrawal from or completion of protocol treatment, patients must be followed for AEs 
for 30 calendar days after the last dose of study drug.  The following assessments will be 
performed: 
• Physical examination, including measurement of weight and vital signs  
• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• CBC, including 3-part differential and platelets 
• CMP  
• Serum or urine pregnancy test 
• Blood sample for plasma/serum/PBMC isolation and potential correlative research 
• CT scans of chest, abdomen and pelvis if not taken within the last 6 weeks  
• Tissue biopsy upon disease progression (optional). 
 
Follow-up 
 
Follow-up for Patients Who Discontinue Prior to Disease Progression 
Patients who discontinue study treatment prior to the occurrence of disease progression will be 
followed every 3 months (±1 month) from the date of last dose of study drug until disease 
progression or for up to 1 year whichever comes first unless otherwise directed due to study 
termination.  Assessments at these visits will be performed as described in Appendix C:
 
Schedule of Assessments.   


 
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Survival Follow-Up 
After disease progression is documented, patients will be followed every 3 months (±1 month) 
for survival (e.g., date and cause of death) for up to 1 year or death whichever comes first unless 
otherwise directed due to study termination.  Patients may be contacted during outpatient visits 
or by telephone. 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
Investigational Product 
Dosage Form and 
Strength 
Timing 
Manufacturer 
Section 
atezolizumab 
1200 mg 
Q3 weeks 
Genentech, Inc. 
8.1 
tiragolumab 
600 mg 
Q3 weeks 
Genentech, Inc. 
8.2 
 
Atezolizumab 
 
Atezolizumab Labeling, Packaging, and Supply 
Atezolizumab will be supplied in as a sterile colorless to slightly yellow liquid in a single-use, 
20-mL glass vial.  The vial contains approximately 20 mL (1200 mg) of atezolizumab solution 
by Genentech, Inc. 
For information on the formulation and handling of atezolizumab, see the pharmacy manual and 
the atezolizumab IB. 
The immediate packaging will contain a statement to conform with U.S. FDA Investigational 
New Drug (IND) requirements as follows: Caution: New Drug - Limited by Federal (or United 
States) law to investigational use. 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for atezolizumab are included on the investigational product label. 
Development Innovations must be granted access on reasonable request to check drug storage, 
dispensing procedures, and accountability records. 
 
Preparation and Administration of Atezolizumab 
Atezolizumab is administered as an IV infusion. 
Preparation, administration, and storage instructions will be provided in the IB. 
 
Risks Associated with Atezolizumab 
Immune-mediated myelitis, immune-mediated facial paresis, and immune-mediated pericardial 
disorders, including pericarditis, pericardial effusion, and cardiac tamponade are an identified 
risk for atezolizumab.  Atezolizumab has also been associated with risks such as the following: 
IRRs and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, 


 
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myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, 
myositis, and severe cutaneous adverse reactions.  Immune-mediated reactions may involve any 
organ system and may lead to hemophagocytic lymphohistiocytosis (HLH) and macrophage 
activation syndrome (MAS). 
Precautions and risks are described in detail in the atezolizumab IB.  Management of 
atezolizumab-related AEs is provided in Appendix F: 
Management of 
Tiragolumab/Atezolizumab-Specific Adverse Events. 
 
Tiragolumab  
 
Tiragolumab Labeling, Packaging, and Supply 
Tiragolumab will be supplied by Genentech, Inc. as a sterile liquid in a single-use, 15 mL 
glass vial.  The vial contains approximately 10 mL (600 mg) of tiragolumab.  
For further information on the formulation and handling of tiragolumab, see the pharmacy 
manual and the tiragolumab IB. 
The packaging will contain a statement to conform with U.S. FDA IND requirements as follows: 
Caution: New Drug - Limited by Federal (or United States) law to investigational use. 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for tiragolumab are included on the investigational product label. 
Development Innovations must be granted access on reasonable request to check drug storage, 
dispensing procedures, and accountability records. 
 
Preparation and Administration of Tiragolumab 
Tiragolumab is administered as an IV infusion. 
Preparation, administration, and storage instructions will be provided in the IB. 
 
Risks Associated with Tiragolumab  
Infusion-related reaction is an identified risk of tiragolumab.  Although clinical evaluation of 
tiragolumab is limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is 
anticipated to enhance T-cell and NK-cell proliferation, survival, and function.  Therefore, 
tiragolumab may increase the risk of autoimmune inflammation (also described as 
immune-mediated AEs).  In addition, owing to the intact Fc-effector function of tiragolumab, 
lymphopenia by means of antibody dependent cell cytotoxicity (ADCC) is a theoretical risk.   
Precautions and risks are described in detail in the tiragolumab IB.  Because tiragolumab may 
increase or accentuate the immune-mediated AEs (imAEs) observed with atezolizumab, please 
see Table 3 for management of imAEs.   
 
Accountability for All Study drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 


 
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Throughout the study and at its completion, Drug Accountability Record Form(s) must be 
completed by the site and sent to Development Innovations.  Study drug supplies must not be 
destroyed unless prior approval has been granted by Development Innovations or its 
representative.  Please contact Development Innovations regarding disposal of any study drug. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Increasing clinical experience indicates that traditional response criteria (e.g., RECIST v1.1 and 
World Health Organization criteria) may not adequately assess the activity of immunotherapeutic 
agents because initial radiographic evidence of PD does not necessarily indicate therapeutic 
failure.  Patients can experience a response in the presence of new lesions or after an increase in 
tumor burden.  Thus, this study will employ immune-modified RECIST for tumor assessments to 
account for the possible appearance of new lesions and allow radiographic progression to be 
confirmed at a subsequent assessment (see Appendix D: 
Immune-Modified Response 
Evaluation Criteria in Solid Tumors (Immune-Modified RECIST)).   
It is recommended that radiographic progression be confirmed at a subsequent tumor assessment 
to take into account the potential for pseudoprogression (caused by immune cell infiltration).  
Given the proposed immunomodulatory mechanism of action of atezolizumab and tiragolumab 
and the possibility of observing delayed responses, use of immune-modified RECIST will allow 
for the capture of a greater proportion of potential responses and allow patients to derive 
maximum clinical benefit.   
10. 
STATISTICAL CONSIDERATIONS 
 
Statistical Design 
This is a multi-center, open-label, Phase II study of atezolizumab and tiragolumab in patients 
with NSCLC or advanced solid tumors that have had prior treatment with a PD-1 inhibitor.   
Arm A consists of patients with advanced NSCLC who received first-line anti-PD-1-
monotherapy with prior documentation of clinical benefit (e.g. ≥ SD) prior to disease 
progression.  In Arm A, patients with NSCLC will be treated with chemotherapy plus 
atezolizumab at a flat dose of 1200 mg IV every 3 weeks, until progression or unacceptable 
toxicity.  Standard of care chemotherapy is defined as a platinum-doublet therapy (or triplet if 
bevacizumab is used) of the Investigator’s choice. 
Arm B consists of approximately 15 patients per disease type: RCC and TNBC progressing on 
anti-PD-1 therapy; NSCLC progressing on check-point inhibitors plus chemotherapy in the first-
line setting; and MSI-high solid tumors [as determined by local testing for MSI/MMR]) 
progressing on anti-PD-1 therapy.  In Arm B, patients with advanced solid tumors will be treated 
with atezolizumab at a flat dose of 1200 mg IV every 3 weeks and tiragolumab at a flat dose of 
600mg IV every 3 weeks, until progression or unacceptable toxicity.  Additional cohorts may be 
added as emerging clinical data becomes available. 
 
Sample Size Considerations 
No formal statistical power calculations to determine sample size were performed for this study. 


 
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Hence the numbers of patients have been based on the desire to obtain adequate safety and 
efficacy data while exposing as few patients as possible to the investigational products and 
procedures. Approximately 80 patients are planned to be enrolled in this study. 
NSCLC Cohort: 
In Arm A, precise sample size cannot be determined.  A sample size of approximately 20 
patients will be enrolled to the cohort. 
Advanced Solid Tumor Cohort: 
In Arm B, precise sample size cannot be determined.  Approximately 60 patients will be enrolled 
to the cohort. 
 
Analysis Population 
The following analysis populations will be used: 
• The Full Analysis Set (FAS) is defined as all patients who received at least one dose of 
study treatment. 
• The Safety Analysis Set (SAS) is defined as all patients who have received at least one 
dose of study treatment.   
 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations, and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented.  Time to events endpoints will be reported using Kaplan-Meier 
estimates, with 95% confidence intervals (CI) for median time to event. 
 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized.  Data to be tabulated will 
include demographic features such as age, sex and race, as well as disease-specific 
characteristics. 
The number and percentages of patients screened, treated, completed the treatment/study and 
withdrawn from treatment/study for any reasons will be presented overall and also by treatment 
group. 
 
Efficacy Analysis 
All efficacy analyses will be performed using the FAS. 
• Overall Response Rate (ORR) is defined as the proportion of patients with confirmed 
complete response (CR) or partial response (PR (i.e. 2 CRs or PRs at least 4 weeks apart) 
according to the immune-modified RECIST criteria.  
 
• Disease Control Rate (DCR) is defined as the proportion of patients with CR, PR, or SD 
for at least 6 months according to the immune-modified RECIST criteria. 
 


 
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For ORR and DCR, patients without a post-baseline tumor assessment will be classed as not 
evaluable (NE) and considered as non-responder. 
 
• Progression Free Survival (PFS), defined as the time from the first day of study drug 
administration (Day 1) to PD as defined by the immune-modified RECIST criteria, or 
death on study.  Patients who are alive and free from disease progression will be censored 
at the date of last tumor assessment. 
 
• Overall Survival (OS), defined as the time from the first day of study drug administration 
(Day 1) to death on study.  Patients who are alive will be censored at the date of last 
known date alive. 
For ORR and DCR, the estimates and the associated 95% CI (based on the Clopper-Pearson 
method) in each treatment group will be calculated.  The absolute and relative difference in ORR 
and DCR between the two treatment groups will also be presented. 
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and the 
associated 95% CI in each treatment group will be provided.   
 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE 4.03.  A copy of CTCAE scoring system may be 
downloaded from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized using system organ class and preferred term by treatment group for all patients in 
the SAS.  In addition, summaries of serious adverse events (SAEs), AEs leading to treatment 
discontinuation, AEs by maximum NCI CTCAE grade, and AEs related to study treatment will 
also be presented by treatment group. 
Other safety endpoints including laboratory results, vital signs, and ECG findings will be 
summarized for all patients in the SAS.  
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized by treatment group. 
 
Analysis Time Points 
 
Final Analysis 
The final analysis of the study will occur following the last visit of the last patient in the 
treatment arm. 
 
Safety Review 
No formal safety review is planned. 


 
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Efficacy Review 
No formal interim analyses are planned. 
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, 
adverse events of special interest (AESIs), performing protocol-specified safety laboratory 
assessments, measurement of protocol-specified hematology, clinical chemistry, and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing and reporting SAEs to the Development 
Innovations Safety Department (see Section 11.2).  It is the Sponsor’s responsibility to report 
relevant SAEs to the applicable local, national, or international regulatory bodies.  In addition, 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of that IRB.  
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
 
Definitions   
 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE (also known as adverse experience) can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a drug, without any judgement about causality.  
An AE can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, dose or including overdose. 
 
Serious Adverse Event 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of 
the following outcomes: 
• Death (i.e., the AE actually causes or leads to death) 
• A life-threatening AE (i.e., the AE, in the view of the Investigator, places the subject 
at immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death) 
• Inpatient hospitalization of at least 24-hours or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 


 
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may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.   
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations; it is based on patient/event outcome or action usually associated with 
events that pose a threat to a patient’s life or vital functions.  For example, nausea which persists 
for several hours may be considered severe nausea, but may not be considered an SAE.  On the 
other hand, a stroke which results in only a limited degree of disability may be considered only a 
mild stroke, but would be considered an SAE.  Severity and seriousness should be independently 
assessed when recording AEs on the eCRF and SAEs on the SAE Report Form. 
 
Adverse Reaction 
An adverse reaction (AR) means any AE caused by a drug.  Adverse reactions are a subset of all 
SARs where there is a reason to conclude that the drug caused the event. 
 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A SAR implies a lesser degree of certainty about 
causality than AR, which means any AE caused by a drug. 
 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes a SAE or not, any action taken (e.g., changes to study 
treatment), and outcome, should be provided, along with the Investigator’s assessment of 
causality (i.e., the relationship to the study treatment[s]).  For an AE to be a suspected treatment-
related event there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 
4.0.3, and changes will be documented. 


 
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Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age‑appropriate 
instrumental activities of daily living 
3 
Severe or medically significant, but not immediately life‑threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self‑care activities of daily 
living 
4 
Life-threatening consequences or urgent intervention indicated 
5 
Death related to adverse event 
If the AE is serious, it should be reported immediately to Development Innovations Safety 
Department.  Other untoward events occurring in the framework of a clinical study are to be 
recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention, including invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
Any clinically significant signs and symptoms, abnormal test findings, changes in physical 
examination, hypersensitivity, and other measurements that occur will be reported as AEs, and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment, the test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the Investigator. 
Reporting Period for Adverse Events 
All AEs and SAEs, regardless of seriousness or relationship to atezolizumab and tiragolumab 
treatment (called study treatment), spanning from the start of study treatment, until 30 calendar 
days after discontinuation or completion of study treatment as defined by the clinical study for 
that patient, are to be recorded on the corresponding screen(s) included in the eCRF.   
All AEs and SAEs resulting in discontinuation from the study should be followed until resolution 
or stabilization.  All new AEs and SAEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the Investigator, the AE or laboratory 


 
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abnormality/ies are not likely to improve because of the underlying disease.  In this case, the 
Investigators must record his or her reasoning for this decision in the patient’s medical record 
and as a comment on the eCRF screen.   
Thirty (30) days after completion of protocol-specific treatment or discontinuation, only AEs, 
SAEs, or deaths assessed by the Investigator as treatment related are to be reported. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES (definitive, probable, possible, unlikely):  There is a plausible temporal 
relationship between the onset of the AE and administration of the study medication, and 
the AE cannot be readily explained by the patient’s clinical state, intercurrent illness, or 
concomitant therapies, and/or the AE follows a known pattern of response to the study 
drug, and/or the AE abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO (unrelated):  Evidence exists that the AE has an etiology other than the study drug 
(e.g., pre-existing medical condition, underlying disease, intercurrent illness, or 
concomitant medication), and/or the AE has no plausible temporal relationship to study 
drug administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
Expected AEs are those AEs that are listed or characterized in the US Package Insert (USPI) or 
current IB.  
For patients receiving combination therapy, causality will be assessed individually for each 
protocol-mandated therapy. 
 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as serious require expeditious handling and 
reporting to Development Innovations Safety Department in order to comply with regulatory 
requirements.  Determination of life-threatening or serious is based on the opinion of either the 
Sponsor or the Investigator.   
Serious AEs may occur at any time from the start of study treatment through the 30 days after 
their last dose of study drug.  The Development Innovations Safety Department must be 
notified of all SAEs, regardless of causality, within 24 hours of the first knowledge of the 
event by the treating physician or research personnel.   
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE, AEs of Special Interest (AESIs), and Special Situation Reports (including pregnancy 
reports), and Product Complaints (with or without an AE) originating from the Study for the 


 
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Product reports should be sent to Development Innovations Safety Department via fax or e-mail 
using the following contact information (during both business and non-business hours): 
Development Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE, AEs of Special Interest (AESIs), and Special Situation Reports 
(including pregnancy reports) and Product Complaints (with or without an AE) report should be 
confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to Development Innovations Safety Department as soon as it is available; these 
reports should be submitted using the Development Innovations SAE Report Form.  The detailed 
SAE reporting process will be provided to the sites in the SAE reporting guidelines contained in 
the study reference manual. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
 
Recording of Adverse Events and Serious Adverse Events 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on the 
Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release syndrome 
(CRS).  While IRRs occur during or within 24 hours after treatment administration, time to onset 
of CRS may vary.  Differential diagnosis should be applied, particularly for late-onset CRS 
(occurring more than 24 hours after treatment administration), to rule out other etiologies such as 
delayed hypersensitivity reactions, sepsis or infections, HLH, tumor lysis syndrome, early 
disease progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment administration and are 
judged to be related to study treatment infusion should be captured on the Adverse Event eCRF 
as a diagnosis (e.g., "infusion-related reaction" or "cytokine-release syndrome").  Avoid 
ambiguous terms such as "systemic reaction".  Cases of late-onset CRS should be reported as 
"cytokine-release syndrome" on the Adverse Event eCRF.  Associated signs and symptoms 
should be recorded on the dedicated Infusion-Related Reaction eCRF or Cytokine-Release 
Syndrome eCRF, as appropriate. 


 
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If a patient experiences both a local and systemic reaction to the same dose of study treatment, 
each reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF or 
Cytokine-Release Syndrome eCRF. 
NCI CTCAE v4.0 and the American Society for Transplantation and Cellular Therapy (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. 
Guidelines for medical management of IRRs, imAEs, and CRS are provided in Appendix F:
 
Management of Tiragolumab/Atezolizumab-Specific Adverse Events. 
 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as an 
SAE. 
 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form (if applicable) 
and/or the AE eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it 
should be recorded on a separate SAE Report Form (if applicable) and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form (if 
applicable) and/or AE eCRF screen. 
 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 


 
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eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if: the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment, the laboratory findings require 
additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the Investigator. 
 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Study Discontinuation” 
eCRF screen.  All other on study deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the Development Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event screen of the eCRF.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event 
screen.  During post-study survival follow-up, deaths attributed to progression of disease will be 
recorded only on the “After Progressive Disease Follow-Up” eCRF screen. 
 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency department or emergency room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, custodial care or respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as an SAE to the Development 
Innovations Safety Department. 
 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 


 
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condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.2).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form, not available within the eCRF) should be completed and faxed to the Development 
Innovations Safety Department.  Development Innovations Safety Department should be notified 
expeditiously, irrespective of whether or not it meets the criteria for expedited reporting.  
Abortions (spontaneous, accidental, or therapeutic) must also be reported to the Development 
Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Development Innovations Safety Department 
immediately.  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
 
Lack of Efficacy or Worsening of Cancer 
Deterioration that is judged by the Investigator to have unexpectedly worsened in severity or 
frequency, or changed in nature (i.e., deterioration beyond the expected pattern of progression of 
the underlying disease) should be recorded as an adverse event.  When recording an 
unanticipated worsening of cancer on the Adverse Event eCRF, it is important to convey the 
concept that the condition has changed by including applicable descriptors (e.g., "accelerated 
worsening of non-small cell lung cancer” [spell out name of condition, do not use acronym]).  
Events that are clearly consistent with the expected pattern of progression of the underlying 
disease should not be recorded as adverse events.  These data will be captured as efficacy 
assessment data only.  In most cases, the expected pattern of progression will be based on 
RECIST v.1.1.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document progression 
through use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event. 


 
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Atezolizumab and Tiragolumab Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the Development Innovations Safety Department no 
greater than 24 hours from first knowledge of the event using the corresponding screens in the 
eCRF and following the same process described for SAE reporting (see Section 11.1.2) if the 
overdose is symptomatic. 
For information on how to manage an overdose of atezolizumab and tiragolumab, see the IBs. 
 
Adverse Events of Special Interest (AESIs) 
AESIs are a subset of Events to Monitor (EtMs) of scientific and medical concern specific to the 
product, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is required.  Such an event might require further investigation in order to characterize 
and understand it.  Depending on the nature of the event, rapid communication by the trial 
Sponsor to the other parties (e.g., regulatory authorities) may also be warranted. 
The following are events of special interest, and must be reported to Genentech Drug Safety 
expeditiously, irrespective of regulatory seriousness criteria (see Section 11.2).  These AESIs 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law 
and based on the following observations: 
– 
Treatment-emergent ALT or AST >3 × baseline value in combination with total 
bilirubin >2 × ULN (of which ≥35% is direct bilirubin) 
– 
Treatment-emergent ALT or AST >3 × baseline value in combination with clinical 
jaundice, as defined by Hy’s Law 
• 
Data related to suspected transmission of an infectious agent via medicinal product 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical 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. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
• 
Hepatitis, including AST or ALT >10 × ULN 
• 
Systemic lupus erythematosus 


 
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• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, influenza-like 
illness, MAS and HLH 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal, necrolysis) 
• 
Immune-mediated facial paresis 
• 
Immune-mediated myelitis 
 
Sponsor Serious Adverse Event Reporting Requirements 
Development Innovations Safety Department will forward SAE and AESI information, whether 
related or unrelated to atezolizumab and tiragolumab, pregnancy reports, and Product 
Complaints (with AE) originating from the Study for the Product to Genentech Drug Safety 
within 1 business day of Development Innovations Safety Department personnel becoming 
aware at 
Email: usds_aereporting-d@gene.com 
OR 
Fax: (650) 238-6067 
Development Innovations will provide case information on a completed MedWatch form with 
GNE Safety Reporting Fax Cover Sheet (see Appendix I: 
Safety Reporting Fax Cover Sheet) 
within 1 business day to the Genentech contact information specified above. 
Transmission of these reports (initial and follow-up) will be sent either electronically or by fax 
and within the timelines specified below: 
All Product Complaints without an AE should be called at: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
Product Complaints  
All Product Complaints (with or without an AE) shall be forwarded to Genentech within one 
calendar day of the awareness date. 


 
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A Product Complaint is defined as any written or oral information received from a complainant 
that alleges deficiencies related to identity, quality, safety, strength, purity, reliability, durability, 
effectiveness, or performance of a product after it has been released and distributed to the 
commercial market or clinical trial. 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
Additional reporting requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with atezolizumab and within 
the follow-up period (for female patients within five months after the last dose of 
atezolizumab/tiragolumab or the partner of a male patient within five months of completing 
therapy) will be transmitted to Genentech within 1 business day of the Awareness Date.  
Pregnancies will be followed up until the outcome of the pregnancy is known, whenever 
possible, based upon due diligence taken to obtain the follow-up information. 
• 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported to Genentech as an SAE.  Similarly, any congenital 
anomaly/birth defect in a child born to a female subject exposed to atezolizumab should be 
reported to Genentech as an SAE. 
In addition to SAEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech even in the absence of an AE within one (1) 
calendar day: 
• 
Data related to product usage during pregnancy or breastfeeding 
• 
Data related to overdose, abuse, misuse, medication error (including potentially exposed or 
intercepted medication errors) 
In addition, reasonable attempts should 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 
Note:  Investigators should also report events to their IRB as required. 
Development Innovations is responsible for reporting relevant SAEs to the competent authority, 
other applicable regulatory authorities, and participating Investigators, in accordance with 
International Council for Harmonisation (ICH) guidelines, and FDA regulations. 
 
Sponsor Assessment of Unexpected 
The Sponsor is responsible for assessing an adverse event or suspected adverse event as 
“unexpected.” 
An AE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB (or current USPI) 
• Event(s) is not listed at the specificity or severity that has been observed 


 
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• An event(s) is not consistent with the General Investigative Plan or in the current 
application 
• Includes AEs or SAR that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation 
When applicable, an unexpected adverse event (UAE) may also apply to an event that is not 
listed in the current USPI or an event that may be mentioned in the USPI, but differs from the 
event because of greater severity or specificity.    
Known as Suspected Unexpected Serious Adverse Reactions (SUSARs), these events suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
IB or USPI), and are serious (as defined by the protocol) and require expedient submission to 
relevant health authorities within 7 days (fatal or life-threatening event) or 15 days (all serious 
events), or as defined by law.  The term SUSAR is used primarily in the reporting of events to 
regulatory authorities. 
Expected AEs are those events that are listed or characterized in the USPI or current IB. 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
The Sponsor of the study (Development Innovations), will be responsible for the expedited 
reporting of safety reports originating from the study to the regulatory authority (FDA) where it 
has filed a clinical trial approval, in compliance with local regulations.  
The Sponsor (Development Innovations) will be responsible for the expedited reporting of safety 
reports originating from the study to the Ethics Committees and Institutional Review Boards 
(IRB), where applicable. 
The Sponsor (Development Innovations) will be responsible for the distribution of safety 
information to its own investigators, where relevant, in accordance with local regulations. 
 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application 
All written IND Safety Reports submitted to the FDA by the Development Innovations Safety 
Department must also be faxed to the pharmaceutical company that is supporting the study with 
either funding or drug supply: 
Atezolizumab and tiragolumab: 
Genentech Drug Safety 
Fax: (650) 225-4682 or (650) 225-4630. 
Email: ctvistsa@gene.com 
And Sponsor-Investigator will be responsible for the distribution of safety information to Site 
IRB. 
For questions related to safety reporting, please contact Genentech Drug Safety: 


 
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Tel:  (888) 835-2555 
Fax:  (650) 225-4682 or (650) 225-4630 
For investigator-initiated IND studies, some additional reporting requirements for the FDA apply 
in accordance with the guidance set forth in 21 CFR § 600.80. 
Events meeting the following criteria need to be submitted to the FDA as expedited IND 
Safety Reports according to the following guidance and timelines: 
7 Calendar Day Telephone or Fax Report: 
Development Innovations Safety Department is required to notify the FDA of any fatal or life-
threatening AE that is unexpected and assessed by the Investigator to be possibly related to the 
use of atezolizumab and tiragolumab.  A UAE is one that is not already described in the 
atezolizumab IB.  Such reports are to be telephoned or faxed to the FDA and Genentech within 
7 calendar days of first learning of the event. 
15 Calendar Day Written Report 
Development Innovations Safety Department is also required to notify the FDA and all 
participating Investigators, in a written IND Safety Report, of any serious, unexpected AE 
that is considered reasonably or possibly related to the use of atezolizumab and tiragolumab.  
A UAE is one that is not already described in the atezolizumab and tiragolumab IBs. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with Code 
of Federal Regulations (CFR) regulation 21 CFR § 312.32.  All safety reports previously filed by 
the Investigator with the IND concerning similar events should be analyzed and the significance 
of the new report in light of the previous, similar reports should be commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating Investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
All written IND Safety Reports submitted to the FDA must also be faxed to Genentech Drug 
Safety and to the site IRB.  
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (Section 5) of 
the MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the AE to each investigational product 
and suspect medication 


 
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Follow-Up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form 
• 
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. date of birth, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up information is 
being submitted (The patient identifiers are important so that the new information is 
added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom an AE was reported.  For questions regarding SAE 
reporting, you may contact Genentech Drug Safety or the medical safety liaison (MSL) assigned 
to the study.  Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available and/or upon request. 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
Compliance with Pharmacovigilance Agreement/Audit 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide written 
responses in a timely manner to inquiries from the other Party regarding AE reports received 
outside the agreed upon Agreement timelines. If there is any detection of trends of increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve 
the non-compliance issues and inform the other Party of the corrective and preventative actions 
taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit. 


 
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Reconciliation/Case Transmission Verification of Single Case Reports 
Development Innovations Safety Department agrees to conduct reconciliation for the product.  
Genentech and Development Innovations Safety Department will agree to the reconciliation 
periodicity and format, but agree at minimum to exchange quarterly line listings of cases 
received by the other party.  The periodic line-listing will be exchanged within seven (7) 
calendar days of the end of the agreed time period.  Confirmation of receipt should be received 
within the time period mutually agreed upon. 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by Development Innovations Safety Department to Genentech 
within five (5) calendar days from request by Genentech. 
If discrepancies are identified, Development Innovations Safety Department and Genentech will 
cooperate in resolving the discrepancies.  The responsible individuals for each party shall handle 
the matter on a case-by-case basis until satisfactory resolution.  The Development Innovations 
Safety Department shall receive reconciliation guidance documents within the “Activation 
Package.”  At the end of the study, a final cumulative Case Transmission Verification report will 
be sent to Genentech. 
Signal Management and Risk Management  
Genentech is responsible for safety signal management (signal detection and/or evaluation) for 
their own product. However, it is agreed that Development Innovations, as Sponsor of the study, 
will be primarily responsible for assessment of the benefit-risk balance of the study. 
If Development Innovations issues a safety communication relevant for Genentech (i.e., a safety 
issue that notably impacts the benefit-risk balance of the study and/or triggers any changes to the 
study) this will be sent to Genentech within five (5) business days of its internal approval. 
As needed, Genentech will reasonably assist Development Innovations with signal and risk 
management activities related to the product within the study. 
Genentech will also provide Development Innovations with any new relevant information that 
may modify or supplement known data regarding the product (e.g., relevant Dear Investigator 
Letter). 
 
Queries 
Queries related to the Study will be answered by Development Innovations.  However, 
responses to all safety queries from regulatory authorities or for publications will be 
discussed and coordinated between the Parties.  The Parties agree that Genentech shall have 
the final say and control over safety queries relating to the Products (atezolizumab and 
tiragolumab).  Development Innovations agrees that it shall not answer such queries from 
regulatory authorities and other sources relating to the Products independently but shall 
redirect such queries to Genentech. 


 
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Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests for information or review of data are met.  The Parties will clearly indicate on the 
request the reason for urgency and the date by which a response is required.  
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
Study Monitoring, Auditing, and Inspecting 
The Investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor or its representative(s), government regulatory authorities, and the IRB of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The Investigator will ensure the capability for inspections of applicable 
study-related facilities.  The Investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the Sponsor’s discretion, Source Document Verification (SDV) may be performed on all or 
partial data as defined in study documents and/or plans. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor, or its representative(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable 
government regulations, institutional research policies and procedures and any other local 
applicable regulatory requirement(s). 
 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., study 
diary), patient recruitment procedures (e.g., advertisements), information about payments (i.e., 
Principal Investigator payments) and compensation available to the patients and documentation 
evidencing the Principal Investigator’s qualifications should be submitted to the IRB for ethical 
review and approval if required by local regulations, prior to the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the ICF.  Investigators will be advised by the 
Sponsor or designee whether an amendment is considered substantial or non-substantial and 
whether it requires submission for approval or notification only to an IRB. 
Safety updates for atezolizumab and tiragolumab, will be prepared by the Sponsor or its 
representative as required, for distribution to the Investigator(s) and submission to the relevant 
IRB. 


 
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Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
• The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 


 
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• The rights of a research patient to revoke his or her authorization 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data.  
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF.  No material bearing a patient’s name will 
be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Development 
Innovations database, and shall be treated in compliance with all applicable laws and regulations.  
When archiving or processing personal data pertaining to the Investigator or sub Investigator, 
Development Innovations shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized party. 
 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between Sarah 
Cannon Development Innovations, LLC, and applicable parties.  Any Investigator financial 
disclosures as applicable to 21CFR Part 54 shall be appropriately provided. 
 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by Sarah Cannon Development Innovations should 
be copied to Genentech.  Copies of such reports should be faxed to Genentech Drug Safety: 
Fax: (650) 225-4682 or (650) 225-4630 
Or emailed to the Genentech Drug Safety CTV mailbox: ctvistsa@gene.com. 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
Aggregate Report 
The Sponsor will forward a copy of the Publication to Genentech upon completion of the Study. 


 
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Study Close-out 
Any study report submitted to the FDA by Development Innovations should be copied to 
Genentech.  This includes all IND annual reports and the final study report.  Additionally, any 
literature articles that are a result of the study should be sent to Genentech.  Copies of such 
reports should be provided to the assigned Clinical Operations contact for the study: 
Atezolizumab IIS Clinical Operations: anti-pdl-1-mpd3280a-gsur@gene.com. 
And to the Genentech Drug Safety CTV oversight mailbox: ctvistsa@gene.com 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representatives.  All amendments require review and approval of all 
pharmaceutical companies and the Principal Investigator supporting the study.  The written 
amendment must be reviewed and approved by the Sponsor, and submitted to the IRB at the 
Investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable, and IRB approval obtained, and specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed; or, when the addition or removal of 
an Investigator is necessitated. 
Items requiring a protocol amendment approval from IRB and/or FDA or other regulatory 
authorities include, but are not limited to, the following: 
• Change to study design 
• Risk to patient 
• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and / or procedures 
• Addition/removal of a new Investigator 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 


 
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Documentation Required to Initiate the Study 
Before the study may begin certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations 
Regulatory Department 
ATTN: MULTI 29 Study 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Nashville, TN  37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current curricula vitae for the Principal Investigator and any associate Investigator(s) 
who will be involved in the study 
• Indication of appropriate accreditation for laboratories (as required) to be used in the 
study and the normal ranges for tests to be performed by that laboratory 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB-approved ICF containing permission for audit by representatives of 
Development Innovations, the IRB, and the FDA and other regulatory agencies (as 
applicable) 
• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable) 
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s)  
 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 


 
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The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or Investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed eCRFs, IRB approval documents, patient identification lists, 
enrollment logs, delegation of authority log, staff qualification documents, laboratory normal 
ranges, and records relating to the study drug including accountability records.  Drug 
accountability records should, at a minimum, contain information regarding receipt, shipment, 
and disposition.  Each form of drug accountability record, at a minimum, should contain 
Principal Investigator name, date drug shipped/received; and date, quantity and batch/code, or lot 
number for identity of each shipment.  In addition, all original source documents supporting 
entries in the eCRF must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by the FDA; or, in the event that the marketing application has not 
been approved by the FDA, for no less than 2 years after the last shipment/delivery of the drug 
for investigational use is discontinued and the FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation/records of IRB activities as per 21CFR Part 
56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21-CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by the FDA; or, in the event that the marketing 
application has not been approved by the FDA, for no less than 2 years after the last 
shipment/delivery of the drug for investigational use is discontinued and the FDA has been 
notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs, medical records), all 
original signed ICFs, and copies of all eCRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents.  The documents 
listed above must be retained by the Investigator for as long as needed to comply with national 
and international regulations (generally 2 years after discontinuing clinical development or after 
the last marketing approval).  Sponsor will notify the Investigator(s)/institutions(s) when the 
study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, both the 
Sponsor and its representative should be prospectively notified.  The study records must be 
transferred to an acceptable designee, such as another Investigator, another institution, or to the 
Sponsor.  The Investigator must obtain the Sponsor’s written permission before disposing of any 


 
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records, even if retention requirements have been met.  All ISFs will be maintained by the 
Sponsor (Development Innovations) throughout the study, and will be held by the Sponsor at the 
conclusion of the study. 
 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study identifier, and patient number along with initials 
and/or date of birth/year as allowed per institutional policy will identify the patient in the eCRF.  
If the patient’s name appears on any other document (e.g., laboratory report), it must be 
obliterated on the copy of the document to be supplied to Development Innovations and replaced 
instead with the patient number and other identifier as allowed per institutional policy.  The 
Investigator will maintain a personal patient identification list (patient numbers with 
corresponding patient identifiers) to enable records to be identified and verified as authentic.  
Patient data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations. 
All data requested in the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown.”  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The Investigator will electronically sign and date the patient eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the 
Principal Investigator, once all data for that patient is final. 
 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
Inclusion of the Investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the study design, analysis, interpretation of data, or the drafting and/or 
critically revising of any manuscript(s) derived from the study.  The Investigator acknowledges 
that the study is part of a multicenter study and agrees that any publication by the Investigator of 
the results of the study conducted at any research site shall not be made before the first 
multicenter publication.  In the event there is no multicenter publication within fifteen (15) 
months after the study has been completed or terminated at all study sites, and all data has been 
received, the Investigator shall have the right to publish its results from the study, subject to the 
notice requirements described herein and subject to acknowledgement of the Sponsor as 
appropriate.  Investigator shall provide the Sponsor thirty (30) days to review a manuscript or 
any poster presentation, abstract or other written or oral material which describes the results of 


 
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the study for the purpose only of determining if any confidential or patentable information is 
disclosed thereby.  If the Sponsor requests in writing, the Investigator shall withhold any 
publication or presentation an additional sixty (60) days solely to permit the Sponsor to seek 
patent protection and to remove any Development Innovations confidential information from all 
publications. 


 
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15. 
REFERENCES 
Barlesi et al. 2016 
Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study 
comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; 
October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA44. 
Bendell et al. 2020 
Bendell JC, Bedard P, Bang YJ, et al. Abstract CT302: Phase Ia/Ib dose-escalation study of the 
anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in 
patients with advanced solid tumors.  Presented at: 2020 American Association for Cancer 
Research (AACR) Virtual Annual Meeting. Besse et al. 2015 
Besse et al. 2015 
Besse B, Johnson M, Jänne PA, et al. Phase II, single-arm trial (BIRCH) of atezolizumab as first-
line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung 
cancer (NSCLC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, 
Austria. Abstract 16LBA. 
Blank et al. 2005 
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-
specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. 
Cancer Immunol Immunother. 2005;54:307-14. 
Blank and Mackensen 2007 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother. 2007;56:739-45. 
Borghaei et al. 2015 
Borghaei H, Paz-Ares L, Horn L, Spigel DR et al. Nivolumab versus docetaxel in advanced non-
squamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. 
Brahmer et al. 2012 
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients 
with advanced cancer. N Engl J Med. 2012;366:2455-65. 
Brahmer et al. 2015 
Brahmer J, Reckamp, KL, et al. Nivolumab versus docetaxel in advanced squamous-cell non-
small-cell lung cancer. N Eng J Med. 2015;Jul 9;373(2):123-35. 
Butte et al. 2007 
Butte MJ, Keir ME, Phamduy TB. Programmed death-1 ligand 1 interacts specifically with the 
B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111-22. 


 
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Herbst et al. 2016 
Herbst RS, Kim DW, Felip E et al. Pembrolizumab versus docetaxel for previously treated, PD-
L1-positive, advanced non-small-cell lung cancer (Keynote-010): a randomized controlled trial. 
Lancet. 2016 Apr 9;387(10027):1540-50. 
Infante et al. 2016 
Infante JR, Hansen AR, Pishvaian MJ, et al. A phase Ib dose escalation study of the OX40 
agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid 
tumors. J Clin Oncol. 2016;34(suppl 15):101. 
Johnston et al. 2014 
Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor 
and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923-37. 
Joller et al. 2014 
Joller N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory 
functions. J Immunol. 2011;186:1338-42. 
Keir et al. 2008 
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annual 
Rev Immunol. 2008;26:677-704. 
Rizvi et al. 2015 
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. 
Rodriguez-Abreu et al. 2020 
Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-
blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) 
versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC 
(CITYSCAPE). J Clin Oncol. 2020;38(15_suppl):9503.Rosenberg et al. 2016 
Rosenberg et al. 2016 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following treatment with 
platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 
7;387(10031):1909-20.  
Spira et al. 2015 
Spira AI, Park K, Mazières J, et al. Efficacy, safety and predictive biomarker results from a 
randomized phase II study comparing atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J 
Clin Oncol. 2015;33(suppl15):8010. 


 
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Stanietsky et al. 2009 
Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits 
human NK cell cytotoxicity. Proc Natl Acad Sci USA. 2009;106:17858-63. 
Tiragolumab IB 2020 
Tiragolumab [Investigator Brochure]. Basel, Switzerland: F. Hoffmann-La Roche LTD 
Topalian et al. 2012 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012;366:2443-54. 
Tumeh et al. 2014 
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting 
adaptive immune resistance. Nature. 2014 Nov 27;515(7528):568-71. 
Vansteenkiste et al. 2015 
Vansteenkiste J, Fehrenbacher L, Spira AI, et al. Atezolizumab monotherapy vs docetaxel in 
2L/3L non-small cell lung cancer: primary analyses for efficacy, safety and predictive 
biomarkers from a randomized phase II study (POPLAR). Presented at: 2015 European Cancer 
Congress; September 25-29; Vienna, Austria. Abstract 14LBA. 
Yang et al. 2011 
Yang J, Riella LV, Chock S. The novel costimulatory programmed death ligand 1/B7.1 pathway 
is functional in inhibiting alloimmune responses in vivo. J Immunol. 2011;187:1113-9. 
Yu et al. 2009 
Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by 
promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 
2009;10:48-57. 
Zaretsky et al. 2016 
Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to 
PD-1 blockade in melanoma. N Engl J Med. 2016 Sep 1;375(9):819-29.


 
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16. 
APPENDICES 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
 
 


 
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Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 


 
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Appendix C: Schedule of Assessments  
ASSESSMENTS 
Baselinea 
 
STUDY TREATMENT (Cycles repeated every 3 weeks) 
Day 1 of every cycle (± 3 
days) 
Response every 2 cycles(± 7 
days) 
End of Treatmentp(± 3 
days) 
Follow-Upq,r 
(±3 days) 
Tests and Observations 
Informed consenta 
X 
 
 
 
 
Medical history 
Xb 
 
 
 
 
Physical examc    
Xb 
X 
 
X 
 
Vital Signsd 
Xb 
X 
 
X 
 
ECOG PS  
Xb 
X 
 
X 
 
12-lead ECG 
Xb 
 
 
 
 
Adverse event evaluation 
 
X 
 
X 
 
Concomitant medication review 
X 
X 
 
X 
 
Laboratory Observations 
CBC, 3-part differential, and platelets 
Xb 
X 
 
X 
 
CMPe 
Xb 
X 
 
X 
 
Thyroid Function Testss 
Xs 
Xs 
 
 
 
PT/PTT or aPTT/INRf  
Xb 
 
 
 
 
Urine Dipstick 
X 
 
 
 
 
Serum or Urine Pregnancy Testg 
Xb 
 
 
Xg 
 
Plasma/serum blood sampleh 
 
X 
 
X 
 
PBMC blood samplei 
 
X 
 
X 
 
Whole blood samplej 
 
X 
 
 
 
Pre-PD-1 archival tumor tissuek 
X 
 
 
 
 
PD-L1 Testing Results (if available)l 
X 
 
 
 
 
Fresh tumor samplen 
X 
 
 
 
 
Optional tumor sample 
Xt 
 
 
 
 
Optional tumor sample at PDo 
 
 
 
X 
 
Staging 
 
 
 
 
 
CT scan 
Xb 
 
Xm 
X 
Xq 
Survival 
 
 
 
 
Xr 
 


 
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Appendix C: 
Schedule of Assessments (continued)   
 
a 
Informed consent must be obtained ≤28 days prior to the initiation of treatment. 
b 
The baseline physical examination, medical history, ECOG PS, complete blood counts (CBC) with 3-part differential and platelets, comprehensive 
metabolic profile (CMP), urinalysis, and PT/PTT or aPTT/INR should be done ≤7 days prior to initiation of treatment.  However, if these initial 
examinations are obtained within 72 hours of Cycle 1 Day 1 they do not have to be repeated.  A pregnancy test must be performed within 72 hours of 
Cycle 1 Day 1.  CT scans should be performed ≤28 days prior to initiation of treatment.  ECG and research samples should be performed ≤28 days prior 
to initiation of study treatment. 
c 
Physical examination will include measurements of height (pretreatment visit only), weight, and vital signs.  Include monitoring for signs and symptoms 
of immune-mediated myelitis.   
d 
Vital signs will include resting heart rate, blood pressure, respiratory rate, and oral temperature. 
e 
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT), ALT (SGPT), total 
bilirubin, total protein, and albumin.   
f 
If PT/PTT or aPTT/INR are normal at baseline they do not need to be repeated.  Patients requiring the initiation of an anti-coagulation therapy during 
study treatment should have coagulation tests performed according to standard practice guidelines. 
g 
Serum or urine pregnancy tests are to be conducted in women of childbearing potential.    
h 
Blood samples collected for plasma/serum on Cycle 1 Day 1, Cycle 3 Day 1 (prior to treatment), and EOT. 
i 
Blood sample for PBMC isolation and correlative research will be collected on Cycle 1 Day 1 and EOT. 
j 
Blood sample for whole blood will be collected on Cycle 1 Day 1 only. 
k 
Pre-PD-1 archival tumor tissue sample (highly recommended if available) provided as at least 15 FFPE slides (or whatever is available) containing 
unstained, freshly cut (not older than 180 days) serial sections. 
l 
If prior PD-L1 testing results by IHC are available it should be captured in the eCRF and does not need to be repeated. 
m 
Patients should have CT scans done  
n 
A mandatory fresh tumor sample will be collected from each patient prior to treatment.  Archival tissue collected following PD-1 therapy may be used if 
there have been no subsequent treatment regimens following tissue collection. 
o 
Tissue biopsy upon disease progression (optional) 
p 
EOT evaluations must be completed within 30 days after the last dose of study treatment.  Patients must be followed for AEs for 30 calendar days after 
the last dose of study drug and serious adverse events and adverse events of special interest will continue to be reported until 90 days after the last dose 
of study treatment. 
q 
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 3 months (±1 month) from the date of 
last dose of study drug until disease progression or for up to 1 year whichever comes first unless otherwise directed due to study termination.   
r 
After disease progression is documented, patients will be followed every 3 months (±1 month) for survival (e.g., date and cause of death) for up to 1 
year or death whichever comes first unless otherwise directed due to study termination.  Patients may be contacted during outpatient visits or by 
telephone. 
s 
Thyroid function tests will include TSH, FT4, and T3. TFTs will be collected at C1D1 and every 4th cycle thereafter. 
t 
Optional tissue biopsy for crossover patients only; sample should be collected prior to start of treatment on Arm B. 


 
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Appendix D: Immune-Modified Response Evaluation Criteria in Solid Tumors (Immune-
Modified RECIST) 
Conventional response criteria may not be adequate to characterize the anti-tumor activity of 
immunotherapeutic agents like atezolizumab and tiragolumab, which can produce delayed 
responses that may be preceded by initial apparent radiographic progression, including the 
appearance of new lesions.  Therefore, immune-modified response criteria have been developed 
to incorporate new lesions into the assessment of total tumor burden and allow radiographic 
progression to be confirmed at a subsequent assessment.  Immune-modified RECIST, as 
described within this appendix, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer et al. 
2009), in the same manner that immune-mediated response criteria were adapted from WHO 
criteria (Wolchok et al. 2009) and RECIST v1.0 (Nishino et al. 2014).  When not otherwise 
specified, RECIST v1.1 conventions will apply.  Differences between immune-modified 
RECIST and RECIST v1.1 are summarized below. 
 
RECIST v1.1 
Immune-Modified RECIST 
Measurable new lesions 
Always represent progression 
Incorporated into the total tumor 
burden a and followed 
Non-measurable new 
lesions 
Always represent progression 
Do not represent progression, but 
preclude CR 
Non-target lesions 
Contribute to defining CR, PR, 
SD, and PD 
Contribute to defining CR only 
CR 
Disappearance of all lesions 
Disappearance of all lesions 
PR 
≥30% decrease in sum of 
diameters of target lesions, in 
the absence of CR, new 
lesions, and unequivocal 
progression in non-target 
lesions 
≥30% decrease in tumor burden, a 
in the absence of CR 
PD 
≥20% increase in sum of 
diameters of target lesions, 
unequivocal progression in 
non-target lesions, and/or 
appearance of new lesions 
≥20% increase in tumor burden a 
SD 
Neither sufficient shrinkage to 
qualify for CR or PR nor 
sufficient increase to qualify 
for PD 
Neither sufficient shrinkage to 
qualify for CR or PR nor sufficient 
increase to qualify for PD 
CR = complete response; PD = progressive disease; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease. 
a Tumor burden is the sum of diameters of target lesions and measurable new lesions. 
 


 
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Tumor Measurability 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below.  All measurable and non-measurable lesions should be assessed at screening 
and at subsequent protocol-specified tumor assessment timepoints.  Additional assessments may 
be performed as clinically indicated for suspicion of progression.   
Definition of Measurable Lesions 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows:  
40. 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ≤5 mm) 
41. 10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
42. 20 mm by chest X-ray 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in the 
short axis when assessed by CT scan (CT scan slice thickness recommended to be ≤5 mm).  
At baseline and follow-up, only the short axis will be measured and followed.  Additional 
information on lymph node measurement is provided below (see "Identification of Target and 
Non-Target Lesions," "New Lesions," and "Calculation of Sum of Diameters"). 
Definition of Non-Measurable Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with short axis ≥10 mm but <15 mm) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by physical 
examination that is not measurable by reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below. 
Bone Lesions: 
43. Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
44. Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT 


 
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or MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
45. Blastic bone lesions are non-measurable. 
Cystic Lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with Prior Local Treatment: 
• Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.   
Methods for Assessing Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during the study.  Imaging-based evaluation should 
always be the preferred option. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10 mm in 
diameter as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
suggested. 
Chest X-Ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT and MRI Scans 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment.  In this guideline, the definition of measurability of lesions on CT scan is 
based on the assumption that CT slice thickness is ≤5 mm.  When CT scans have slice thickness 


 
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of >5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 
study should be guided by the tumor type under investigation and the anatomic location of the 
disease.  For patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be 
performed should also be based on the tumor type and the anatomic location of the disease, and 
should be optimized to allow for comparison with the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new lesions on 
a different modality, since the same lesion may appear to have a different size using a new 
modality. 
Endoscopy, Laparoscopy, Ultrasound, Tumor Markers, Cytology, Histology 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be utilized 
for objective tumor evaluation. 
Assessment of Tumor Burden 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
Identification of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.  This means 
that, for instances in which patients have only one or two organ sites involved, a maximum of 
two lesions (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions 
(albeit measurable) in those organs will be considered non-target lesions.   
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
be representative of all involved organs, but in addition should lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Lymph node size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT, this is almost always the axial plane; for MRI, the 


 
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plane of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node that is reported as being 20 mm × 30 mm has a short 
axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis of <10 mm 
are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or non-measurable), 
including pathological lymph nodes, should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements are not required.  It is possible to record multiple non-target 
lesions involving the same organ as a single item on the Case Report Form (CRF) (e.g., "multiple 
enlarged pelvic lymph nodes" or "multiple liver metastases"). 
New Lesions 
New lesions identified after baseline will be evaluated for measurability with use of the same 
criteria applied to prospective target lesions at baseline per RECIST (e.g., non-lymph node 
lesions must be ≥10 mm on the longest diameter; new lymph nodes must be ≥15 mm on the short 
axis [see note below]).  All new lesions (measurable or non-measurable) must be assessed and 
recorded at the time of identification and at all subsequent tumor assessment timepoints.  
Up to a maximum of five measurable new lesions total (and a maximum of two lesions per 
organ) can be included in the calculation of tumor burden that is performed as part of the tumor 
response evaluation.  New lesion types that would not qualify as target lesions per RECIST 
cannot be included in the calculation of tumor burden and thus will not affect overall tumor 
response evaluation.  New lesions that are not measurable at first appearance but meet 
measurability criteria at a subsequent timepoint can be included in the tumor response evaluation 
from that point on, if the maximum number of measurable new lesions has not been reached. 
Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph node 
lesion is ≥15 mm, it will be considered a measurable new lesion.  If at first appearance the short 
axis of a lymph node lesion is ≥10 mm and <15 mm, the lymph node will not be considered 
measurable but will still be considered a new lesion and should be identified as a non-measurable 
new lesion.  If at first appearance the short axis of a lymph node is <10 mm, the lymph node 
should not be considered pathological and should not be considered a new lesion.  A lymph node 
can subsequently become measurable, when the short axis is ≥15 mm. 
Calculation of Sum of Diameters 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for lymph node 
lesions) will be calculated for all target lesions at baseline as a measure of tumor burden.  At 
each subsequent tumor assessment, a sum of the diameters (longest diameter for non-lymph node 
lesions, short axis for lymph node lesions) will be calculated for all target lesions plus 
measurable new lesions (up to five new lesions, with a maximum of two new lesions per organ) 
that have emerged after baseline.  Hence, each net percentage change in tumor burden per 
assessment accounts for the size and growth kinetics of both old lesions and new lesions as they 
appear. 


 
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Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is ≥15 mm, it will be considered 
a measurable new lesion and may be included in the sum of the diameters.  If the new lymph 
node lesion is included in the sum of diameters, it will continue to be measured and included in 
the sum of diameters at subsequent timepoints, even if the short axis decreases to <15 mm (or 
even <10 mm).  However, if it subsequently decreases to <10 mm and all other lesions are no 
longer detectable or have also decreased to a short axis of <10 mm (if lymph nodes), a response 
assessment of complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded (measured in the 
same anatomical plane as the baseline examination), even if the node regresses to <10 mm 
during the study.  Thus, when lymph nodes are included in the sum of diameters, the sum may 
not be zero even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of <10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph node and 
non−lymph node) should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph nodes 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measurement and may report them as being too small to measure.  When this occurs, it is 
important that a value be recorded on the CRF, as follows: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be ticked.  
(Note:  It is less likely that this rule will be used for lymph nodes since they usually have 
a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well and "too small to measure" should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, that should be 
recorded, even if it is <5 mm, and in that case "too small to measure" should not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the sum of diameters.  Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion.  If the lesions have truly coalesced such that they are no 
longer separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion. 


 
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Evaluation of Non-Target Lesions and Non-Measurable New Lesions 
Measurements are not required for non-target lesions or non-measurable new lesions.  Non-target 
lesions should be noted at baseline, and non-measurable new lesions should be noted at the time 
of identification.  At subsequent evaluations, non-target lesions and non-measurable new lesions 
will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or measurable new 
lesions in excess of five total or two per organ) will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete disappearance 
of all tumor lesions, including non-target lesions and non-measurable new lesions) and will not 
be used to assess progressive disease. 
Response Criteria 
Definitions of the criteria used to determine objective tumor response are provided below: 
• Complete response (CR):  Disappearance of all lesions 
• Any pathological lymph nodes must have reduction in short axis to <10 mm. 
• Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per organ), 
taking as reference the baseline sum of diameters, in the absence of CR 
• Progressive disease (PD):  At least a 20% increase in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per organ), 
taking as reference the smallest sum of diameters on study (including baseline) 
- 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥5 mm. 
- 
New lesions alone do not qualify as progressive disease.  However, their contribution 
to total tumor burden is factored into the sum of the diameters, which is used to 
determine the overall immune-modified RECIST tumor response. 
• Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor sufficient 
increase to qualify for PD 
Criteria for Overall Response at a Single Timepoint 
The table below provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 


 
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Criteria for Overall Response at a Single Timepoint:  Patients with Target Lesions (with or 
without Non-Target Lesions) 
Target Lesions and 
Measurable New Lesionsa 
Non-Target Lesions and 
Non-Measurable New Lesionsb 
Overall Response 
CR 
Absent 
CR 
CR 
Present or not all evaluated 
PR 
PR 
Any 
PR 
SD 
Any 
SD 
Not all evaluated 
Any 
NE 
PD 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a 
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden, in addition to the target lesions 
identified at baseline. 
b 
Also includes measurable new lesions in excess of five total or two per organ. 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target or measurable 
new lesions at a timepoint, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing lesions 
would not change the assigned timepoint response.  This would be most likely to happen in the 
case of PD.  For example, if a patient had a baseline sum of 50 mm with three measured lesions 
and during the study only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion.  
Special Notes on Response Assessment 
Patients with a global deterioration in health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration."  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy.  The objective response status of such patients 
is to be determined by evaluation of target and non-target lesions, as well as new lesions. 


 
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References 
Eisenhauer et al. 2009 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.   
Nishino et al. 2014 
Nishino M, Gargano M, Suda M, et al. Optimizing immune-related tumor response assessment: 
does reducing the number of lesions impact response assessment in melanoma patients treated 
with ipilimumab? J Immunother Can. 2014;2:17. 
Wolchok et al. 2009 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412-20..


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


 
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Appendix F: Management of Tiragolumab/Atezolizumab-Specific Adverse Events 
Toxicities associated or possibly associated with atezolizumab or tiragolumab treatment should 
be managed according to standard medical practice for the management of immune-mediated 
adverse events.  Additional tests, such as autoimmune serology or biopsies, should be used to 
evaluate for a possible immunogenic etiology.  
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab and/or tiragolumab may 
not have an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
The Investigator should consider the benefit-balance of a given patient prior to further 
administration of atezolizumab and/or tiragolumab.  In patients who have met the criteria for 
permanent discontinuation, resumption of atezolizumab and/or tiragolumab may be considered if 
the patient is deriving benefit and has fully recovered from the immune-mediated event.  Patients 
can be rechallenged with atezolizumab and/or tiragolumab only after approval has been 
documented by the Investigator (or an appropriate delegate) and the Medical Monitor.  
Pericardial Events 
Immune-mediated pericardial disorders, including pericarditis, pericardial effusion, and cardiac 
tamponade are an identified risk with atezolizumab. 
Pericardial disorders encompass a range of diseases of the pericardium.  Underlying causes 
include infection (particularly viral), cancer related (metastatic disease or chest radiotherapy), 
cardiac injury related (post myocardial infarction or iatrogenic), and autoimmune disorders.  
Pericardial disorders are also known to be associated with drugs including immune-checkpoint 
inhibitors. 
Pericarditis may be associated with pericardial effusion, which if significant in volume, may 
result in hemodynamic instability and progress to cardiac tamponade.  Cardiac tamponade is a 
life-threatening condition and should be treated as a medical emergency. 
The diagnosis of immune-mediated pericarditis should be considered in all patients presenting 
with chest pain. 
The diagnosis of immune-mediated pericardial effusion and cardiac tamponade should be 
considered in all patients presenting with chest pain associated with dyspnea or hemodynamic 
instability. 
Cardiac tamponade should be treated as a medical emergency and consultation with a 
cardiologist should be sought for further management. 
Caution should be used when considering the use of atezolizumab in a patient who has 
previously experienced a pericardial disorder on prior treatment with other immune-stimulatory 
anticancer agents. 
Management guidelines for pericardial events are presented in Table 5. 


 
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Table 5 
Management Guidelines for Pericardial Events, Including Pericarditis, 
Pericardial Effusion, and Cardiac Tamponade 
Event 
Management 
Immune-mediated 
pericardial disorders, 
including pericarditis, 
pericardial effusion, and 
cardiac tamponade, any 
grade 
• Withhold atezolizumab for any patient with suspected immune-mediated 
pericardial disorders and contact the principal investigator. 
• Permanently discontinue atezolizumab for any grade confirmed immune-
mediated pericardial disorders. 
• Refer patient to cardiologist. 
• 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. 
 
Pulmonary Events  
Immune-mediated pulmonary events are a potential risk with tiragolumab.   
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will also have CT scans of the chest performed at every 
tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  Management 
guidelines for pulmonary events are provided in Table 6. 


 
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Table 6 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event  
Management  
Pulmonary event, Grade 1  
• Continue atezolizumab and tiragolumab, and monitor 
closely.  
• Re-evaluate on serial imaging.  
• Consider patient referral to pulmonary specialist. 
Pulmonary event, Grade 2  
• Withhold atezolizumab and tiragolumab for up to 12 weeks 
after event onset.b  
• Refer patient to pulmonary and infectious disease 
specialists and consider bronchoscopy or BAL.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
• Resume atezolizumab and tiragolumab if event resolves to 
Grade 1 or better within 12 weeks. a, b  
• Permanently discontinue atezolizumab and tiragolumab if 
event does not resolve to Grade 1 or better within 12 
weeks of withholding tiragolumab/atezolizumab.a, b, c  
• For recurrent events, treat as a Grade 3 or 4 event.  
Pulmonary event, Grade 3 or 4  
• Permanently discontinue atezolizumab and tiragolumab, 
and contact Medical Monitor.c  
• Bronchoscopy or BAL is recommended.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.  
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥1 month.  
BAL = bronchoscopic alveolar lavage; IVIG = intravenous immunoglobulin  
a 
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  
b 
Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be 
reduced to ≤10 mg/day oral prednisone or equivalent.   
c 
Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by the Investigator (or an appropriate delegate).  


 
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Hepatic Events 
Immune-mediated hepatic events are a potential risk with tiragolumab. 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases; liver function will be monitored 
throughout study treatment.  Management guidelines for hepatic events are provided in Table 7. 
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. 
Table 7 
Management Guidelines for Hepatic Events 
Event  
Management  
Hepatic event, Grade 1  
• Continue atezolizumab and tiragolumab.  
• Monitor LFTs until values resolve to within normal limits or to baseline 
values.  
Hepatic event, Grade 2  
All events:  
• Monitor LFTs more frequently until return to baseline values.  
Events of >5 days’ duration:  
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. b  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent.  
• Resume atezolizumab and tiragolumab if event resolves to Grade 1 or 
better within 12 weeks.a, b  
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor if event does not resolve to Grade 1 or better within 
12 weeks of withholding tiragolumab/atezolizumab.a, b, c  
Hepatic event, Grade 3 or 
4  
• Permanently discontinue atezolizumab and tiragolumab, and contact 
Medical Monitor.c  
• Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent.  
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.  
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month.  


 
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LFT = liver function tests.  
a 
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab and tiragolumab can be resumed.  
b 
Atezolizumab and tiragolumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the Investigator and the Medical Monitor.  
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 rechallenged with atezolizumab and 
tiragolumab only after approval has been documented by the Investigator (or an appropriate delegate) and 
the Medical Monitor.  


 
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Gastrointestinal Events 
Immune-mediated gastrointestinal events are a potential risk with tiragolumab. 
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 8.  
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased CRP, platelet count, or bandemia):  
Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five 
specimens for standard paraffin block to check for inflammation and lymphocytic infiltrates to 
confirm colitis diagnosis. 
Table 8 
Management Guidelines for Gastrointestinal 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.  
• Initiate symptomatic treatment.  
• Patient referral to GI specialist is recommended.  
• For recurrent events or events that persist >5 days, initiate treatment 
with 1−2 mg/kg/day oral prednisone or equivalent.  
• Resume atezolizumab and tiragolumab if event resolves to Grade 1 or 
better within 12 weeks.a,b  
• Permanently discontinue atezolizumab and tiragolumab if event does 
not resolve to Grade 1 or better within 12 weeks of withholding 
tiragolumab/atezolizumab.a,b,c  
Diarrhea or colitis, Grade 
3  
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. b  
• Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy.  
• Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement.  
• Resume atezolizumab and tiragolumab if event resolves to Grade 1 or 
better within 12 weeks.a, b  
• Permanently discontinue atezolizumab and tiragolumab if event does 
not resolve to Grade 1 or better within 12 weeks of withholding 
tiragolumab/atezolizumab and contact Medical Monitor.a, b, c  


 
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Event  
Management  
Diarrhea or colitis, Grade 4 
• Permanently discontinue atezolizumab and tiragolumab, and contact 
Medical Monitor.c  
• Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy.  
• Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone 
or equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement.  
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.  
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month. 
GI=Gastrointestinal 
a 
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab and tiragolumab can be resumed.  
b 
Atezolizumab and tiragolumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent.  The acceptable length of the 
extended period of time must be agreed upon by the Investigator and Medical Monitor.  
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 rechallenged with atezolizumab and 
tiragolumab only after approval has been documented by the Investigator (or an appropriate delegate) and 
the Medical Monitor.  
Endocrine Events 
Immune-mediated endocrine events are a potential risk with tiragolumab. 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine 
events are provided in Table 9.  
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, mental 
status changes, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathies.  Patients should be referred to an endocrinologist if an endocrinopathy 
is suspected.  Thyroid-stimulating hormone (TSH) and free triiodothyronine (T3) and thyroxine 
(T4) levels should be measured to determine whether thyroid abnormalities are present.  Pituitary 
hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-
stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and 
ACTH stimulation) and magnetic resonance imaging (MRI) of the brain (with detailed pituitary 
sections) may help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency.


 
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Table 9 
Management Guidelines for Endocrine Events 
Event  
Management  
Asymptomatic 
hypothyroidism  
• Continue atezolizumab and tiragolumab.  
• Initiate treatment with thyroid replacement hormone.  
• Monitor TSH weekly.  
Symptomatic 
hypothyroidism  
• Withhold atezolizumab and tiragolumab.  
• Initiate treatment with thyroid replacement hormone.  
• Monitor TSH weekly.  
• Consider patient referral to endocrinologist.  
• Resume atezolizumab and tiragolumab when symptoms are controlled and 
thyroid function is improving.  
Asymptomatic 
hyperthyroidism  
• TSH ≥0.1 mU/L and <0.5 mU/L:  
• Continue atezolizumab and tiragolumab.  
• Monitor TSH every 4 weeks.  
• TSH <0.1 mU/L:  
• • Follow guidelines for symptomatic hyperthyroidism.  
Symptomatic 
hyperthyroidism  
• Withhold 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.  
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor for life-threatening immune-mediated hyperthyroidism.c  
Symptomatic adrenal 
insufficiency, Grades 
2−4  
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a,b  
• Refer patient to endocrinologist.  
• Perform appropriate imaging.  
• Initiate treatment with 1−2 mg/kg/day intravenous methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement.  
• Resume atezolizumab and tiragolumab if event resolves to Grade 1 or 
better and patient is stable on replacement therapy (if required) within 12 
weeks.a, b  
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor if event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy within 12 weeks of withholding 
tiragolumab/atezolizumab.a, b, c  


 
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Hyperglycemia, Grade 
1 or 2  
• Continue atezolizumab and tiragolumab.  
• Investigate for diabetes.  If patient has Type 1 diabetes, treat as a Grade 3 
event.  If patient does not have Type 1 diabetes, treat as per institutional 
guidelines..  
• Monitor for glucose control.  
Hyperglycemia, Grade 
3 or 4 
• Withhold atezolizumab and tiragolumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Resume atezolizumab and tiragolumab when symptoms resolve and 
glucose levels are stable. 
Hypophysitis 
(panhypopituitarism), 
Grade 2 or 3  
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. b 
• 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. a 
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor if event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy within 12 weeks of withholding 
tiragolumab/atezolizumab. 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 
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab and tiragolumab can be resumed. 
b 
Atezolizumab and tiragolumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent. The acceptable length of the 
extended period of time must be agreed upon by the Investigator and the Medical Monitor. 
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 rechallenged with atezolizumab and 
tiragolumab only after approval has been documented by the Investigator (or an appropriate delegate). 
 


 
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Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 10. 
Table 10 
Management Guidelines for Ocular Events 
Event  
Management  
Ocular event, Grade 1  
• Continue atezolizumab and tiragolumab.  
• Patient referral to ophthalmologist is strongly 
recommended.  
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy.  
• If symptoms persist, treat as a Grade 2 event.  
Ocular event, Grade 2  
• Withhold atezolizumab and tiragolumab for up to 12 
weeks after event onset. b  
• Patient referral to ophthalmologist is strongly 
recommended.  
• Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy.  
• Resume atezolizumab and tiragolumab if event resolves to 
Grade 1 or better within 12 weeks.a, b  
• Permanently discontinue atezolizumab and tiragolumab 
and contact if event does not resolve to Grade 1 or better 
within 12 weeks of withholding 
tiragolumab/atezolizumab.a, b, c  
Ocular event, Grade 3 or 4  
• Permanently discontinue atezolizumab and tiragolumab 
and contact Medical Monitor.c  
• Refer patient to ophthalmologist.  
• Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.  
• If event resolves to Grade 1 or better, taper corticosteroids 
over ≥1 month. 
a 
If corticosteroids have been initiated, they must be tapered over ≥1 month to ≤10 mg/day oral prednisone or 
equivalent before atezolizumab and tiragolumab can be resumed.  
b 
Atezolizumab and tiragolumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to ≤10 mg/day oral prednisone or equivalent.  
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 both the Investigator (or an appropriate delegate) 
and the Medical Monitor. 


 
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Immune-Mediated Myocarditis 
Immune-mediated myocarditis is a potential risk with tiragolumab and has been associated with 
the administration of atezolizumab.  Immune-mediated myocarditis should be suspected in any 
patient presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, laboratory (e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest 
pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection (commonly 
viral, e.g., in a patient who reports a recent history of gastrointestinal illness), ischemic events, 
underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 11. 
Table 11 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-4 
 
Immune-mediated 
pericardial disorders  
Grade 2-4 
• Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 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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Infusion-Related Reaction and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab or tiragolumab.  
However, patients who experience an infusion-related reaction (IRR) or cytokine-release 
syndrome (CRS) with atezolizumab may receive premedication with antihistamines, anti-
pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential for 
causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab.  These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells.  Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019).  CRS has 
been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies that target PD-L1 
or PD-1 (Rotz et al. 2017; Adashek and Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for the 
medical management of IRRs and CRS are provided in Table 12.  For subsequent cycles, IRRs 
should be managed according to institutional guidelines. 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin, 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, which 
should be confirmed or refuted through assessment of exposure history, appropriate laboratory 
testing, and clinical or radiologic evaluations per investigator judgment.  If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or institutional guidelines. 
Table 12 
Management Guidelines for Infusion – Related Reactions and Cytokine-
Release Syndrome 
Event 
Management 
Grade 1 a 
fever b with or 
without 
constitutional 
symptoms  
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the 
infusion rate may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including maintenance of IV 
fluids for hydration. 


 
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• In case of rapid decline or prolonged CRS (>2 days) or in patients 
with significant symptoms and/or comorbidities, consider 
managing as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS. 
Grade 2 a 
fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
hypoxia requiring 
low-flow oxygen d 
by nasal cannula 
or blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart 
infusion at half the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the 
ICU, if appropriate).  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS 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, and contact Medical 
Monitor. 
• If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab and tiragolumab may be administered.  
For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or analgesics 
and monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive 
days, contact Medical Monitor. 
Grade 3 a 
fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
• Permanently discontinue atezolizumab and 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. 


 
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hypoxia requiring 
high-flow oxygen 
d by nasal 
cannula, face 
mask, non-
rebreather mask, 
or Venturi mask 
• 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 Medical Monitor. 
Grade 4 a 
fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. e 
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as 
needed.  Monitor other organ function closely.  Manage 
constitutional symptoms and organ toxicities as per institutional 
practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup 
and assess for signs and symptoms of HLH or MAS 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 
Medical Monitor. 
• Hospitalize patient until complete resolution of symptoms. 


 
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ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway pressure; 
CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; CRS = cytokine-release syndrome; 
CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report Form; HLH = hemophagocytic 
lymphohistiocytosis; ICU = intensive care unit; IRR = infusion-related reaction; MAS = macrophage activation syndrome; 
NCCN = National Cancer Comprehensive Network; NCI = National Cancer Institute. 
Note:  These management guidelines have been adapted from the NCCN guidelines for the management of CAR T-cell-related 
toxicities (Version 2.2019). 
a Grading system for these management guidelines is based on ASTCT consensus grading for CRS.  NCI CTCAE v4.03 should 
be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF.  Organ 
toxicities associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature≥38°C not attributable to any other cause.  In patients who develop CRS and who then receive 
anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when subsequently determining event severity 
(grade).  In this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or oxygen.  For 
bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at ≤6 L/min, and high flow is defined as oxygen delivered at > 6 L/min. 
 
e Resumption of atezolizumab and tiragolumab may be considered in patients who are deriving benefit and have fully recovered 
from the event.  Patients can be re-challenged with atezolizumab and tiragolumab only after approval has been documented by 
both the Investigator (or an appropriate delegate) and the Medical Monitor.  For subsequent infusions, administer oral 
premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication 
with corticosteroids and extending the infusion time may also be considered after consulting the Medical Monitor and 
considering the benefit/risk ratio. 
f Refer to Riegler et al. (2019) .


 
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Pancreatic Events 
Immune-mediated pancreatic events are a potential risk with tiragolumab.   
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 13. 
Table 13 
Management Guidelines for Pancreatic Events 
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 Grade 3. 
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 Medical Monitor. c 
• For recurrent events, permanently discontinue atezolizumab and 
tiragolumab, and contact Medical Monitor. c 
Immune-mediated 
pancreatitis, 
Grade 2 or 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue 
atezolizumab/tiragolumab and contact Medical Monitor. c 


 
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Event 
Management 
• For recurrent events, permanently discontinue atezolizumab and 
tiragolumab, and contact Medical Monitor. c  
Immune-mediated 
pancreatitis, 
Grade 4 
• Permanently discontinue atezolizumab and tiragolumab, and contact 
Medical Monitor. c 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month. 
GI = gastrointestinal. 
a Atezolizumab 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 agreed upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone 
before atezolizumab 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 both the Investigator (or an appropriate delegate) and the Medical Monitor. 
Dermatologic Events 
Immune-mediated dermatologic events are a potential risk with tiragolumab. 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
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 Table 14. 
Table 14 
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. 
• 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 


 
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• Refer patient to dermatologist. 
• Initiate treatment with corticosteroids equivalent to 10 
mg/day oral prednisone, increasing dose to 1−2 mg/kg/day if 
event does not improve within 48−72 hours. 
• If event resolves to Grade 1 or better, resume atezolizumab 
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 
Dermatologic event, 
Grade 4 
• Permanently discontinue atezolizumab and tiragolumab, and 
contact Medical Monitor. c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• Withhold atezolizumab and tiragolumab 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 atezolizumab and tiragolumab. 
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 agreed upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone 
before atezolizumab 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 both the Investigator (or an appropriate delegate) and the Medical Monitor.  
Neurologic Disorders 
Immune-mediated neurologic events are a potential risk with tiragolumab.   
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic workup is essential for an accurate characterization to differentiate 
between alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table 15.  
 
 


 
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Table 15 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, Grade 
1 
• Continue atezolizumab and tiragolumab. 
• Investigate etiology. 
Immune-mediated 
neuropathy, Grade 
2  
• Withhold atezolizumab and tiragolumab for up to 12 weeks after 
event onset. a 
• Investigate etiology. 
• Initiate treatment as per institutional guidelines. 
• If event resolves to Grade 1 or better, resume atezolizumab 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 
Immune-mediated 
neuropathy, Grade 
3 or 4 
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. c  
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Atezolizumab 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 agreed upon by the Investigator and the Medical 
Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral 
prednisone before atezolizumab 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 both the Investigator (or an appropriate delegate) and 
the Medical Monitor.  
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis is a potential risk with tiragolumab. 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy or secondary to a paraneoplastic process.   


 
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All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 16. 
Table 16 
Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
• Permanently discontinue atezolizumab and tiragolumab, and 
contact Medical Monitor. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
a 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 both the Investigator (or an appropriate delegate) and the Medical Monitor. 
Renal Events 
Immune-mediated nephritis is a potential risk with tiragolumab and has been associated with the 
administration of atezolizumab.  Eligible patients must have adequate renal function.  Renal 
function, including serum creatinine, should be monitored throughout study treatment.  Patients 
with abnormal renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-steroidal 
anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically indicated.  A renal 
biopsy may be required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 17. 
 
 
 


 
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Table 17 
Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab and tiragolumab. 
• Monitor kidney function closely, including creatinine, until values 
resolve to within normal limits or to baseline values.  
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 Medical Monitor. c 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab and tiragolumab and contact 
Medical Monitor.  
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month. 
a Atezolizumab 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 agreed upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone 
before atezolizumab 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 both the Investigator (or an appropriate delegate) and the Medical Monitor.  
Immune-Mediated Myositis 
Immune-mediated myositis is a potential risk with tiragolumab and has been associated with the 
administration of atezolizumab.  Myositis or inflammatory myopathies are a group of disorders 
sharing the common feature of inflammatory muscle injury; dermatomyositis and polymyositis 
are among the most common disorders.  Initial diagnosis is based on clinical (muscle weakness, 
muscle pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 18. 


 
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Table 18 
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. 
Immune-
mediated 
myositis, 
Grade 2 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset a and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab 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 
Immune-
mediated 
myositis, 
Grade 3 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset a and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
• For recurrent events, treat as a Grade 4 event. 


 
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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 agreed upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone 
before atezolizumab 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 both the Investigator (or an appropriate delegate) and the Medical Monitor.  
Table 18 
Management Guidelines for Immune-Mediated Myositis (cont.) 
Event 
Management 
Immune-
mediated 
myositis, Grade 
4 
• Permanently discontinue atezolizumab and tiragolumab, and contact 
Medical Monitor. c 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1-2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
a Atezolizumab 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 agreed upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 mg/day oral prednisone 
before atezolizumab 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 both the Investigator (or an appropriate delegate) and the Medical Monitor.  
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 et 
al. 2014.  A patient should be classified as having HLH if five of the following eight criteria are 
met: 


 
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● 
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 NK cell activity 
● 
Ferritin > 500 mg/L (500 ng/mL) 
● 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. 2016.  A febrile patient should be classified as 
having MAS if the following criteria are met: 
● 
Ferritin >684 mg/L (684 ng/mL) 
● 
At least two of the following: 
– 
Platelet count ≤181 × 109/L (181,000/L) 
– 
AST ≥48 U/L 
– 
Triglycerides >1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 19.  


 
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Table 19 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis 
or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH or 
MAS 
• Permanently discontinue atezolizumab and tiragolumab and 
contact Medical Monitor. 
• Consider patient referral to hematologist. 
• Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
• Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
• If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according 
to published guidelines (La Rosée et al. 2015; Schram et al. 
2015; La Rosée et al. 2019). 
• If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. a 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
a 
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. 
Immune-Mediated Myelitis 
Immune-mediated myelitis is an identified risk with atezolizumab. 
• Patients should be monitored for clinical signs and symptoms that are suggestive of 
myelitis.  Diagnostic workup is essential for an accurate characterization to differentiate 
between alternative etiologies. 
• Refer patients to neurologist. 
• For Grade 1 myelitis, continue immunotherapy unless symptoms worsen or do not 
improve.  
• Initiate treatment as per institutional guidelines.  
• Atezolizumab should be permanently withdrawn for ≥Grade 2 immune-mediated 
myelitis. 
Immune-Mediated Facial Paresis 
Immune-mediated facial paresis is an identified risk with atezolizumab. 
• Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  
• Refer patient to neurologist.  
• Initiate treatment as per institutional guidelines.  
• Atezolizumab should be withheld for patients with Grade 1 or 2 immune-mediated facial 
paresis and permanently withdrawn for ≥Grade 3 immune-mediated facial paresis. 


 
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Adashek ML et al. 2019 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti-programmed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 2019;15:502-4. 
La Rosée et al. 2015 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc 
Hematol Educ Protram 2015;1:190-6. 
La Rosée et al. 2019 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic 
lymphohistiocytosis in adults. Blood 2019;133:2465−77. 
McClain et al. 2014 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 October 2018; 
cited: 17 May 2019]. Available from: https://www.uptodate.com/contents/clinical-features-and-
diagnosis-of-hemophagocytic-lymphohistiocytosis. 
Ravelli et al. 2016 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League Against 
Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials 
Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:481−9. 
Riegler et al. 2019 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine 
release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag 
2019;15:323−35. 
Rotz et al. 2017 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient receiving PD-1-
directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram et al. 2015 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 
Blood 2015;125:2908−14. 


 
CONFIDENTIAL 
STUDY DRUG(S):  ATEZOLIZUMAB AND TIRAGOLUMAB   
DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
FINAL PROTOCOL DATE:  19 DECEMBER 2022  
 
VERSION 6 
Page 139 of 141 
 
Appendix G: Anaphylaxis Precautions 
Equipment Needed 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, and 
thermometer 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and endotracheal administration in accordance 
with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
Procedures 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
1. Stop the study treatment infusion. 
2. Call for additional medical assistance. 
3. Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible. 
4. Administer antihistamines, epinephrine, or other medications as required by participant status 
and as directed by the physician in charge. 
5. Continue to observe the participant and document observations. 
6. Draw serum/plasma samples for immunogenicity testing. 
Ask participant to return for washout immunogenicity sample if appropriate.


 
CONFIDENTIAL 
STUDY DRUG(S):  ATEZOLIZUMAB AND TIRAGOLUMAB   
DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
FINAL PROTOCOL DATE:  19 DECEMBER 2022  
 
VERSION 6 
Page 140 of 141 
 
Appendix H: Biological Sample Laboratory Testing Information 
Patients with paired pre-PD1 and pre-Atezolizumab tissue sample or paired 
pre-Atezolizumab and post-Atezolizumab tissue sample *:  
1. PD-L1/CD8 IHC (central testing, Genentech-defined laboratory). 
2. Gene expression analysis using RNA sequencing or whole transcriptome sequencing (WTS) 
(via Genentech at a third party lab) 
3. Whole exome sequencing (via Genentech at a third party lab) 
B. Patients with only a pre-Atezolizumab tissue sample*: 
1.  PD-L1/CD8 IHC (central testing, Genentech-defined laboratory) 
2. Gene expression analysis using RT-PCR, RNA sequencing or WTS (via Genentech at a third 
party laboratory). 
*Note: Whenever possible a post-atezolizumab tissue sample will be obtained. 
C. Plasma, serum, and PBMC samples:  
Banking for future analysis, which may include but are not limited to cfDNA (plasma) analysis 
using NGS or RT-PCR, proteomic/cytokine analysis (serum), immune profiling (PBMC).


 
CONFIDENTIAL 
STUDY DRUG(S):  ATEZOLIZUMAB AND TIRAGOLUMAB   
DEVELOPMENT INNOVATIONS STUDY ID: MULTI 29 
FINAL PROTOCOL DATE:  19 DECEMBER 2022  
 
VERSION 6 
Page 141 of 141 
 
Appendix I: Safety Reporting Fax Cover Sheet 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[  ] - [  ] - [  ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET