Clinical trial NCT05116202
Conditions: Melanoma
Sponsor: Hoffmann-La Roche
Start date: 2022-02-02; Completion date: 2024-05-28
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and modify the participant population.

Detailed description:

Arms: arm 1: Cohort 1 participants in the nivolumab plus ipilimumab arm will receive treatment for 2 cycles (6 weeks) on Day 1 of each cycle (cycle length 21 days) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. arm 2: Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. arm 3: Cohort 1 participants in the atezolizumab plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. arm 4: Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. arm 5: Cohort 2 participants in RO7247669 plus tiragolumab arm will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. arm 6: Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. arm 7: Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: RO7247669 2100 mg intervention 4: Atezolizumab intervention 5: Tiragolumab intervention 6: RO7247669 600 mg
Intervention descriptions: intervention 1: Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle. intervention 2: Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle. intervention 3: RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle. intervention 4: Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle. intervention 5: Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle. intervention 6: RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study 
Evaluating the Efficacy and Safety of Multiple Treatment 
Combinations in Patients With Melanoma (Morpheus-Melanoma) 
NCT Number: 
NCT05116202 
Document Date: 
Protocol Version 4: 8-May-2023 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
Protocol BO43328, Version 4 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
TREATMENT COMBINATIONS IN PATIENTS WITH 
MELANOMA (MORPHEUS-MELANOMA) 
PROTOCOL NUMBER: BO43328 
VERSION NUMBER: 
4 
TEST COMPOUNDS: 
Atezolizumab (RO5541267), tiragolumab (RO7092284), 
RO7247669 
STUDY PHASE: 
Phase Ib/II 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  155538 
EudraCT Number:  2021-002147-29 
EU CT No.:  2022-502939-19-00 
Clinical Investigation Identification Number (CIV ID): 
Not applicable  
NCT Number:  NCT05116202 
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 


 
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2/Protocol BO43328, Version 4 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
4 
See electronic date 
stamp on final page 
of this document. 



3 
13 December 2022 
 


2 
24 February 2022 
 
 
 
1 
19 July 2021 
France 
1 
22 September 2021 
 
 
 
 


 
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3/Protocol BO43328, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol BO43328 has been amended primarily to add two new treatment arms to 
Cohort 1.  Changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
The RO7247669 600 mg treatment arm has been added for Cohort 1 to evaluate 
the efficacy, safety, and pharmacokinetics of a lower dose of RO7247669 based on 
emerging data (new Appendix 15).  The following sections of the protocol have been 
updated to reflect the addition of this new treatment arm:  Sections 1.3, 3.1.2, 3.1.3, 
3.1.5, 4.1.2, 4.4, 4.5, 4.5.1, 4.5.2, 4.5.3, 4.5.4, 4.5.5, 4.5.6, 4.5.7.2, 4.5.8, 4.5.9.1, 
4.5.9.2, 4.5.11, 4.6.1, Appendix 9, Figure 2, and Tables 4 and 5.   
 
The RO7247669 600 mg  tiragolumab treatment arm has been added for Cohort 1 
to evaluate the efficacy, safety, and pharmacokinetics of a lower dose of 
RO7247669 in combination with tiragolumab based on emerging data (new 
Appendix 16).  The following sections of the protocol have been updated to reflect 
the addition of this new treatment arm:  Sections 1.3, 3.1.2, 3.1.3, 3.1.5, 4.1.2, 4.4, 
4.5, 4.5.1, 4.5.2, 4.5.3, 4.5.4, 4.5.5, 4.5.6, 4.5.7.2, 4.5.8, 4.5.9.1, 4.5.9.2, 4.5.11, 
4.6.1, Appendix 9, Figure 2, and Tables 4 and 5. 
 
Figure 3 was updated to clarify that collection of archival tissue may take place 
during screening (Section 3.1.2). 
 
The sample sizes have been updated to 195290 patients in Cohort 1 and 
846 patients in Cohort 2 to reflect the number of patients currently enrolled (as of 
20 March 2023) in the trial and the addition of the two new treatment arms 
(Section 3.1.2, Section 6.1, Figure 2, and Table 4). 
 
Text has been added to clarify that for most arms, approximately 20 patients will be 
enrolled during the preliminary phase.  Approximately 40 patients will be enrolled in 
the RO7247669 600 mg and RO7247669 600 mg  tiragolumab arms during the 
preliminary phase to ensure a more precise benefitrisk assessment in arms with 
the lower dose of RO7247669 (Section 3.1.2 and Figure 2). 
 
Text was added to indicate that pausing enrollment while conducting the safety 
evaluation phase after 6 patients will not be needed for a lower dose of a study drug 
that has already completed a safety evaluation for a higher dose (Section 3.1.3), but 
a formal safety evaluation will be still conducted and the same stopping criteria will 
apply as for higher dose arms. 
 
Text has been updated to indicate that tumor assessments performed as standard 
of care prior to obtaining informed consent and within 28 days prior to 
randomization/enrollment do not have to be repeated at screening.  The previous 
timeframe was 14 days; the extension will reduce patient burden (Section 4.5.7.1 
and Appendix 10). 
 
It has been clarified that in Cohort 1, tumor assessments performed outside the 
protocol mandated time window do not have to be repeated (Section 4.5.7.2). 


 
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4/Protocol BO43328, Version 4 
 
Text has been clarified to indicate that fresh tumor tissue will be processed as 
described in the laboratory manual (Section 4.5.9.2) 
 
Table 6 has been updated to clarify that archival tissue collection during screening 
for Cohorts 1 and 2 is mandatory, if tissue is available (Section 4.5.9.2). 
 
Text has been added to indicate that after the end of the reporting period for 
non-serious adverse events (defined as 30 days after the final dose of study 
treatment), all treatment-related non-serious adverse events that lead to surgery 
delay will continue to be reported until 135 days after the final dose of study 
treatment.  This will allow reporting of these adverse events, which are outside of 
the allowed 30 day reporting period, in the event of delay in surgery (Section 5.6 
and footnotes in schedule of activities for all appendices).  
 
Text has been modified to clarify that patients who do not proceed to complete 
lymph node dissection will be classified as non-responders (Section 6.4.1). 
 
Text has been added to specify that weight, limited physical examination, 12-lead 
ECG, and Eastern Cooperative Oncology Group assessments may be performed 
within 24 hours prior to dosing during the treatment period in order to provide 
additional flexibility for patients and study sites (schedule of activities for 
Appendices 1116). 
 
Language has been added to indicate the approval of  relatlimab  by the U.S. Food 
and Drug Administration for the treatment of unresectable or metastatic melanoma 
(Section 1.1.1.2 and Appendices 12, 14, 15, and 16). 
 
Text has been updated describing Study NP41300 to align with the RO7247669 
Investigator’s Brochure Version 4 (Appendices 12, 14, 15, and 16). 
 
Throughout the protocol, the dose of RO7247669 has been updated to indicate the 
use of either 2100 or 600 mg. 
  
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 
 




 
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3.4.5 
Rationale for Pathologic Response Rate as Primary 
Endpoint in Cohort 1 ................................................................ 49 
3.4.6 
Rationale for Using Nivo  Ipi as Comparator in Cohort 1 ....... 49 
3.4.7 
Rationale for Biomarker Assessments ..................................... 50 
4. 
MATERIALS AND METHODS ...................................................... 51 
4.1 
Patients .................................................................................... 51 
4.1.1 
Inclusion Criteria ...................................................................... 51 
4.1.1.1 
Shared Inclusion Criteria for Cohort 1 and Cohort 2 ................ 51 
4.1.1.2 
Inclusion Criteria for Cohort 1 .................................................. 53 
4.1.1.3 
Inclusion Criteria for Cohort 2 .................................................. 53 
4.1.2 
Exclusion Criteria ..................................................................... 54 
4.1.2.1 
Exclusion Criteria for Cohort 1 and Cohort 2 ........................... 54 
4.1.2.2 
Exclusion Criteria for Cohort 1 ................................................. 56 
4.1.2.3 
Exclusion Criteria for Cohort 2 ................................................. 57 
4.1.2.4 
Exclusion Criteria for RO7247669-Containing Arms 
(Cohort 1 and Cohort 2) ........................................................... 58 
4.1.2.5 
Exclusion Criteria for Tiragolumab-Containing Arms 
(Cohort 1 and Cohort 2) ........................................................... 58 
4.2 
Method of Treatment Assignment ............................................ 59 
4.3 
Study Treatment ...................................................................... 59 
4.3.1 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 59 
4.3.2 
Post-Trial Access to Study Treatment ..................................... 60 
4.4 
Concomitant Therapy and Prohibited Food ............................. 61 
4.5 
Study Assessments ................................................................. 61 
4.5.1 
Informed Consent Forms and Screening Log .......................... 61 
4.5.2 
Medical History, Molecular Profile, Concomitant 
Medication, and Demographic Data ......................................... 62 
4.5.3 
Physical Examinations ............................................................. 62 
4.5.4 
Vital Signs ................................................................................ 63 
4.5.5 
Electrocardiograms .................................................................. 63 
4.5.6 
Evaluation of Left Ventricular Function .................................... 63 
4.5.7 
Tumor and Response Evaluations ........................................... 64 
4.5.7.1 
Radiographic Procedures for Screening (Cohorts 1 and 2) ..... 64 


 
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4.5.7.2 
Cohort 1 Tumor, Response, and Disease Status 
Evaluations .............................................................................. 64 
4.5.7.3 
Cohort 2 Tumor and Response Evaluations ............................ 66 
4.5.8 
Classification of Surgical Complications .................................. 67 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples ............ 67 
4.5.9.1 
Local Laboratory Assessments ................................................ 67 
4.5.9.2 
Central Laboratory Assessments ............................................. 69 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 72 
4.5.11 
Optional Tumor Biopsies ......................................................... 73 
4.5.12 
Optional Samples for Research Biosample Repository ........... 74 
4.5.12.1 
Overview of the Research Biosample Repository .................... 74 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 74 
4.5.12.3 
Sample Collection .................................................................... 75 
4.5.12.4 
Confidentiality .......................................................................... 75 
4.5.12.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 76 
4.5.12.6 
Withdrawal from the Research Biosample Repository ............. 76 
4.5.12.7 
Monitoring and Oversight ......................................................... 77 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 77 
4.6.1 
Study Treatment Discontinuation ............................................. 77 
4.6.2 
Patient Discontinuation from Study .......................................... 78 
4.6.3 
Study Discontinuation .............................................................. 79 
4.6.4 
Site Discontinuation ................................................................. 79 
5. 
ASSESSMENT OF SAFETY ......................................................... 79 
5.1 
Safety Plan .............................................................................. 79 
5.2 
Safety Parameters and Definitions .......................................... 80 
5.2.1 
Adverse Events ........................................................................ 80 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 80 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 81 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 81 


 
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5.3.1 
Adverse Events Reporting Period ............................................ 81 
5.3.2 
Eliciting Adverse Event Information ......................................... 82 
5.3.3 
Assessment of Severity of Adverse Events ............................. 82 
5.3.4 
Assessment of Causality of Adverse Events............................ 84 
5.3.5 
Procedures for Recording Adverse Events .............................. 85 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release 
Syndrome ................................................................................ 85 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 86 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 86 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 87 
5.3.5.5 
Abnormal Laboratory Values ................................................... 87 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 88 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 88 
5.3.5.8 
Deaths ..................................................................................... 89 
5.3.5.9 
Preexisting Medical Conditions ................................................ 89 
5.3.5.10 
Lack of Efficacy or Worsening of Melanoma ............................ 89 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 90 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 90 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 92 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 93 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 93 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 93 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 93 
5.5 
Follow-Up of Patients after Adverse Events............................. 94 
5.5.1 
Investigator Follow-Up ............................................................. 94 
5.5.2 
Sponsor Follow-Up .................................................................. 94 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 94 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 95 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 95 


 
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6.1 
Determination of Sample Size ................................................. 96 
6.2 
Summaries of Conduct of Study .............................................. 96 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 96 
6.4 
Efficacy Analyses ..................................................................... 96 
6.4.1 
Primary Efficacy Endpoint in Cohort 1 ..................................... 96 
6.4.2 
Secondary Efficacy Endpoints in Cohort 1 ............................... 97 
6.4.3 
Exploratory Efficacy Endpoints in Cohort 1 .............................. 98 
6.4.4 
Primary Efficacy Endpoint in Cohort 2 ..................................... 98 
6.4.5 
Secondary Efficacy Endpoints in Cohort 2 ............................... 98 
6.4.6 
Exploratory Efficacy Endpoints in Cohort 2 .............................. 98 
6.5 
Safety Analyses ....................................................................... 99 
6.6 
Pharmacokinetic Analyses ....................................................... 99 
6.7 
Immunogenicity Analyses ...................................................... 100 
6.8 
Biomarker Analyses ............................................................... 101 
6.9 
Interim Analyses .................................................................... 101 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 102 
7.1 
Data Quality Assurance ......................................................... 102 
7.2 
Electronic Case Report Forms ............................................... 102 
7.3 
Source Data Documentation .................................................. 102 
7.4 
Use of Computerized Systems .............................................. 103 
7.5 
Retention of Records ............................................................. 103 
8. 
ETHICAL CONSIDERATIONS .................................................... 104 
8.1 
Compliance with Laws and Regulations ................................ 104 
8.2 
Informed Consent .................................................................. 104 
8.3 
Institutional Review Board or Ethics Committee .................... 105 
8.4 
Confidentiality ........................................................................ 106 
8.5 
Financial Disclosure ............................................................... 106 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 107 
9.1 
Study Documentation ............................................................ 107 
9.2 
Protocol Deviations ................................................................ 107 
9.3 
Site Inspections ..................................................................... 107 


 
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9.4 
Administrative Structure ......................................................... 107 
9.5 
Dissemination of Data and Protection of Trade Secrets ........ 108 
9.6 
Protocol Amendments ........................................................... 109 
10. 
REFERENCES............................................................................ 110 
 
 
LIST OF TABLES 
Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products ........................ 27 
Table 2 
Objectives and Corresponding Endpoints for Cohort 1 ............... 29 
Table 3 
Objectives and Corresponding Endpoints for Cohort 2 ............... 32 
Table 4 
Treatment Regimens .................................................................. 37 
Table 5 
Arm-Specific Exclusion Criteria ................................................... 54 
Table 6 
Overview of Mandatory Tissue Samples ..................................... 70 
Table 7 
Overview of Optional Tissue Samples ........................................ 73 
Table 8 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 83 
Table 9 
ASTCT CRS Consensus Grading Scale ..................................... 84 
Table 10 
Causal Attribution Guidance ....................................................... 85 
 
 
LIST OF FIGURES 
Figure 1 
Study Design ............................................................................... 35 
Figure 2 
Study Schema ............................................................................. 38 
Figure 3 
Detailed Study Schema (Cohort 1) ............................................. 41 
 
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 115 
Appendix 2 
Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST).................................................................................. 125 
Appendix 3 
Pathologic Assessment of Resection Specimens After 
Neoadjuvant Therapy for Metastatic Melanoma........................ 130 
Appendix 4 
Criteria for Adequate Surgical Procedures for  Therapeutic 
Lymph Node Dissection ............................................................ 132 
Appendix 5 
Classification of Surgical Complications ................................... 135 
Appendix 6 
ECOG Performance Status Scale ............................................. 136 
Appendix 7 
Preexisting Autoimmune Diseases and Immune Deficiencies .. 137 
Appendix 8 
Anaphylaxis Precautions ........................................................... 138 


 
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Appendix 9 
Guidelines for Management of Atezolizumab-, Tiragolumab-, 
and/or RO7247669-Specific Adverse Events ............................ 139 
Appendix 10 
Study Details Specific to Screening .......................................... 177 
Appendix 11 
Study Details Specific to Nivo  Ipi Arm (Control) ..................... 179 
Appendix 12 
Study Details Specific to RO7247669 2100 mg Arm ................. 195 
Appendix 13 
Study Details Specific to AtezoTira Arm.................................. 223 
Appendix 14 
Study Details Specific to RO7247669 2100 mg  Tira Arm 
(Cohorts 1 and 2) ...................................................................... 258 
Appendix 15 Study Details Specific to RO7247669 600 mg Arm ................. 305 
Appendix 16 Study Details Specific to RO7247669 600 mg  Tira Arm ....... 333 
Appendix 17 
Investigational, Auxiliary, and Non-investigational Medicinal 
Product Designations (for Use in the European Economic 
Area) ......................................................................................... 372 
 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
TREATMENT COMBINATIONS IN PATIENTS WITH 
MELANOMA (MORPHEUS-MELANOMA) 
PROTOCOL NUMBER: BO43328 
VERSION NUMBER: 
4 
TEST COMPOUNDS: 
Atezolizumab (RO5541267), tiragolumab (RO7092284), 
RO7247669 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a signed 
copy as instructed by Covance. 


 
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13/Protocol BO43328, Version 4 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED 
UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY 
OF MULTIPLE TREATMENT COMBINATIONS IN PATIENTS 
WITH MELANOMA (MORPHEUS-MELANOMA) 
REGULATORY AGENCY 
IDENTIFIER NUMBERS: 
IND Number:  155538  
EudraCT Number:  2021-002147-29  
EU CT No.:  2022-502939-19-00 
Clinical Investigation Identification Number (CIV ID):  Not applicable 
NCT Number:  NCT05116202  
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of treatment 
combinations in cancer immunotherapy (CIT)-naive patients with resectable Stage III melanoma 
(Cohort 1) and in patients with Stage IV melanoma (Cohort 2). Four checkpoint inhibitors, 
namely ipilimumab, pembrolizumab, nivolumab, and relatlimab are now approved by the U.S. 
Food and Drug Administration for the treatment of unresectable or advanced disease.  For 
patients with macroscopic Stage III melanoma, surgery followed by adjuvant immunotherapy 
within 1 year of either nivolumab or pembrolizumab treatment is generally indicated.  Patients 
with clinically detectable Stage III melanoma are ideal candidates for neoadjuvant therapy 
because they represent a high-risk patient population with poor outcomes when treated with 
upfront surgery alone.  Neoadjuvant therapy also has the advantage of providing information on 
pathologic response, which is valuable to estimate prognosis and to guide the choice of 
adjuvant therapy and follow-up.  This study protocol was developed in accordance with 
International Neoadjuvant Melanoma Consortium guidelines to create the needed consistency 
amongst neoadjuvant trials in order to facilitate optimal data organization for future regulatory 
review.  Its exploratory analysis plan will strengthen translational research across the melanoma 
disease continuum. 
OBJECTIVES AND ENDPOINTS 
Table 1 
Objectives and Corresponding Endpoints for Cohort 1 
Primary Efficacy Objective 
Corresponding Endpoint  
 To evaluate the efficacy of treatment 
 pRR (defined as the proportion of patients with pCR, 
pnCR, and pPR) at time of surgery, as determined 
by independent pathologic review 
Secondary Efficacy Objectives 
Corresponding Endpoints  
 To evaluate the efficacy of treatment 
 pRR (defined as the proportion of patients with pCR, 
pnCR, and pPR) at time of surgery, as determined 
by local pathologic assessment 
 EFS, defined as the time from randomization to any 
of the following events (whichever occurs first):  
Disease progression that precludes surgery, as 
assessed by the investigator according to 
RECIST v1.1; local, regional or distant disease 
recurrence; or death from any cause 
 RFS, defined as the time from surgery to the first 
documented recurrence of disease or death from 
any cause 
 OS, defined as the time from randomization to death 
from any cause 


 
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Table  1 
Objectives and Corresponding Endpoints for Cohort 1 (cont.) 
Secondary Efficacy Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
 ORR, defined as the proportion of patients with a CR 
or PR as determined by the investigator according to 
RECIST v1.1, prior to surgery 
Responses will be assessed and determined 
according to RECIST v1.1 but are not required to 
be confirmed by later imaging. 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of treatment 
 Incidence, , nature, and severity of adverse events 
and laboratory abnormalities, with severity 
determined according to NCI CTCAE v5.0 
CRS severity will also be determined according to 
the ASTCT CRS Consensus Grading Scale. 
 Incidence and nature of immune-related adverse 
events Grade  3 during the first 12 weeks 
 Rate and duration of delayed surgery due to 
treatment-related adverse events 
 Surgical complication rates according to 
ClavienDindo- surgical classification after CLND 
ASTCT  American Society for Transplantation and Cellular Therapy; CLND  completion lymph 
node dissection; CR  complete response; CRS  cytokine-release syndrome; EFS  event-free 
survival; NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0; ORR  objective response rate; OS  overall survival; pCR  pathologic 
complete response; pnCR  pathologic near complete response; pPR  pathologic partial response; 
PR  partial response; pRR  pathologic response rate; RECIST v1.1  Response Evaluation 
Criteria in Solid Tumors, Version 1.1; RFS  relapse-free survival. 
  
Table 2 
Objectives and Corresponding Endpoints for Cohort 2 
Primary Efficacy Objective 
Corresponding Endpoint  
 To evaluate the efficacy of treatment 
 ORR, defined as the proportion of patients with a CR 
or PR on two consecutive occasions  4 weeks 
apart, as determined by the investigator according to 
RECIST v1.1 
Secondary Objectives 
Corresponding Endpoints  
 To evaluate the efficacy of treatment 
 PFS after randomization/enrollment, defined as the 
time from randomization/enrollment to the first 
occurrence of disease progression or death from any 
cause (whichever occurs first), as determined by the 
investigator according to RECIST v1.1 
 OS after randomization/enrollment, defined as the 
time from randomization/enrollment to death from any 
cause 
 OS at specific timepoints (e.g., 6 months) 
 


 
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Table 2 
Objectives and Corresponding Endpoints for Cohort 2 (cont.) 
Secondary Objectives 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
 DOR, defined as the time from the first occurrence of 
a documented objective response to disease 
progression or death from any cause (whichever 
occurs first), as determined by the investigator 
according to RECIST v1.1 
 Disease control, defined as stable disease 
for  12 weeks or a CR or PR, as determined by the 
investigator according to RECIST v1.1 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of treatment 
 Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined 
according to NCI CTCAE v5.0 
CRS severity will also be determined according to 
the ASTCT CRS Consensus Grading Scale. 
ASTCT  American Society for Transplantation and Cellular Therapy; CR  complete response; 
CRS  cytokine-release syndrome; DOR  duration of response; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PR  partial response; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
   
OVERALL DESIGN AND STUDY POPULATION 
This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in patients with 
resectable Stage III (Cohort 1) or Stage IV (Cohort 2) melanoma.  The study is designed with 
the flexibility to open new treatment arms as new treatments become available, close existing 
treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, modify the 
patient population (e.g., with regard to prior anti-cancer treatment or biomarker status), or 
introduce additional cohorts of patients with other types of melanoma. 
Two cohorts will be enrolled in parallel in this study.  Cohort 1 will consist of patients with 
resectable Stage III melanoma with measurable lymph node metastases according to Response 
Evaluation Criteria in Solid Tumors, Version 1.1 that can be biopsied, who have no history of 
in-transit metastases within the last 6 months, and who have not received systemic CIT for their 
disease, for example, PD-1/PD-L1 and/or CTLA-4 blocking agents or other agents.  Cohort 2 
will consist of patients with Stage IV melanoma who experienced disease progression during or 
after at least one but not more than two lines of treatment for metastatic disease.  Up to two 
lines of checkpoint inhibition therapy (monotherapy or combination therapy) are allowed.  
Patients with BRAF-mutant disease may have received an additional line of targeted therapy 
(either before, intermittent with, or after the checkpoint inhibition therapy) or may have received 
targeted therapy and checkpoint inhibition therapy concurrently as one combination treatment.  
Patients with BRAF-mutant melanoma with rapidly progressive disease who have not been 
previously treated with approved targeted therapies are not eligible. 
In each cohort, eligible patients will initially be randomly assigned to one of several treatment 
arms (see below).  Currently, there are no arms open for enrollment in Cohort 2. 
 
 
 
 
 
 


 
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Several key aspects of the study design and study population are summarized below. 
 
Phase: 
Phase Ib/II 
Population Type: 
Adult patients 
Control Method: 
Active comparator 
Population Diagnosis 
or Condition: 
Cohort 1: resectable 
Stage III melanoma 
Cohort 2: Stage IV 
(metastatic) cutaneous 
melanoma 
Interventional 
Model: 
Parallel 
Population Age: 
 18 years 
Test Compound{s}: Atezolizumab 
(RO5541267),   
tiragolumab 
(RO7092284), 
RO7247669 
Site Distribution: 
Multi-site and 
multi-region 
Active Comparator: Nivolumab, 
ipilimumab 
Study Intervention 
Assignment Method: 
Randomization 
Number of Arms: 
6 
Number of Participants 
to Be Enrolled: 
Cohort 1: 
Approximately 
195290 patients 
Cohort 2: 
Approximately 
846 patients 
 


 
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STUDY TREATMENT 
Table 3 
Study Treatments for Cohorts 1 and 2 
Study Treatments for Cohort 1 
Treatment Group 
Administration Method and Schedule 
Nivolumab plus ipilimumab (Nivo  Ipi) 
(Control Arm) 
(21-day cycles) 
 Nivolumab 3 mg/kg IV on Day 1 of each cycle 
 Ipilimumab 1 mg/kg IV on Day 1 of each cycle 
RO7247669 2100 mg 
(21-day cycles) 
 RO7247669 2100 mg by IV infusion on Day 1 of each 
cycle 
 RO7247669 2100 mg plus 
tiragolumab (CIT combination) 
(21-day cycles) 
 RO7247669 2100 mg by IV infusion on Day 1 of each 
cycle 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
Atezolizumab plus tiragolumab 
(CIT combination) 
(21-day cycles) 
 Atezolizumab 1200 mg IV on Day 1 of each cycle 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
RO7247669 600 mg 
(21-day cycles) 
 RO7247669 600 mg by IV infusion on Day 1 of each 
cycle 
RO7247669 600 mg plus tiragolumab 
(CIT combination) 
(21-day cycles) 
 RO7247669 600 mg by IV infusion on Day 1 of each 
cycle 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
Study Treatment for Cohorts 1 and 2 a 
RO7247669 2100 mg plus tiragolumab 
(CIT combination) 
(21-day cycles) 
 RO7247669 2100 mg IV on Day 1 of each cycle b 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
CIT  cancer immunotherapy; Ipi  ipilimumab; Nivo  nivolumab. 
a There are currently no arms open for enrollment in Cohort 2. 
b After the safety run-in has been completed, the Sponsor may explore lower doses  
     (e.g., 1200 mg and 600 mg). 
  
There will be no dose modifications for atezolizumab, tiragolumab, or RO7247669 in this study.  
Treatment with atezolizumab, tiragolumab, or RO7247669 may be temporarily suspended in 
patients experiencing toxicity considered to be related to study treatment.  Guidelines for the 
management of atezolizumab-, tiragolumab-, and RO7247669-specific adverse events are 
described in Appendix 9 of the protocol. 
DURATION OF PARTICIPATION 
In Cohort 1, the total duration of study participation for each individual from screening until the 
treatment completion visit and start of adjuvant treatment is expected to be approximately 
17 weeks (not including long-term follow-up).  After the treatment period, participants may 
continue onto long-term follow-up, where information will be collected by telephone, patient 
medical records, and/or clinic visits approximately every 3 months until death.   
In Cohort 2, the total duration of study participation for each individual is expected to be up to 
5 years (including long-term follow-up). 
 


 
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COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee; Scientific Oversight Committee 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody  
ASTCT 
American Society for Transplantation and Cellular Therapy 
Atezo 
atezolizumab 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
CIT 
cancer immunotherapy 
CLND 
complete lymph node dissection 
CMV 
cytomegalovirus 
COVID-19 
coronavirus disease 2019 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRS 
cytokine-release syndrome 
CSR 
Clinical Study Report 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CTLA-4 
cytotoxic T lymphocyteassociated protein 4 
DOR 
duration of response 
EBNA 
Epstein-Barr nuclear antigen 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
event-free survival 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HLH 
hemophagocytic lymphohistiocytosis 
ICH 
International Council for Harmonisation 


 
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Abbreviation 
Definition 
IFN 
interferon 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INMC 
International Neoadjuvant Melanoma Consortium 
Ipi 
ipilimumab 
IPRF 
Independent Pathology Review Facility 
IRB 
Institutional Review Board 
iRECIST 
modified RECIST v1.1 for immune-based therapeutics 
IRR 
infusion-related reaction 
IxRS 
interactive web-based response system 
LAG-3 
lymphocyte activation gene-3 
LVEF 
left ventricular ejection fraction 
MEK 
mitogen-activated protein kinase kinase 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0 
NGS 
next-generation sequencing 
Nivo 
nivolumab 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
pCR 
pathologic complete response 
PD-1 
programmed death-1 
PD-1LAG-3 
programmed death-1 lymphocyte activation gene-3 
PD-L1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
pnCR 
pathologic near complete response 
pPR 
pathologic partial response 
PR 
partial response 


 
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Abbreviation 
Definition 
pRR 
pathologic response rate 
PS 
performance status 
QTcF 
QT interval corrected through use of Fridericia’s formula 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RFS 
relapse-free survival 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SITC 
Society for Immunotherapy of Cancer 
SmPC 
Summary of Product Characteristics 
SOC 
Scientific Oversight Committee 
T3 
triiodothyronine 
T4 
thyroxine 
TB 
tuberculosis 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
Tira 
tiragolumab 
TnI 
troponin I 
TnT 
troponin T 
TSH 
thyroid-stimulating hormone 
TTE 
transthoracic echocardiogram 
ULN 
upper limit of normal 
VCA 
viral capsid antigen 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON MELANOMA 
Melanoma is a malignant tumor of melanocytes.  This potentially deadly form of skin 
cancer is one of the fastest growing malignancies (Algazi et al. 2010; Finn et al. 2012).  
More than 300,000 people worldwide are currently diagnosed with melanoma each year, 
and 57,000 people die of the disease (Ferlay et al. 2018).  The clinical outcomes of 
patients with melanoma are highly dependent on the stage at presentation.  
When melanoma is diagnosed early (Stage I and II), it is generally curable with surgery 
as the treatment of choice, with a long-term survival rate of around 90% for Stage I 
melanoma (Balch et al. 2009).  However, most people with more advanced melanoma 
have a poor prognosis (Finn et al. 2012).  Patients with lymph-node involvement 
(Stage III) have a high risk of local and distant relapse after surgery, and the 5-year 
survival rate is 32%93% in this patient group (Gershenwald et al. 2017).  Few patients 
have metastatic disease (Stage IV) at presentation, but some develop metastases after 
their initial definitive treatment.  Immunotherapy and targeted therapies have improved 
the outcomes of those patients, and the 5-year survival rate is around 50% (Larkin et al. 
2015; Wolchok et al. 2017; Larkin et al. 2019; Robert et al. 2019; Long et al. 2020).  
Despite recent therapeutic advances, melanoma continues to be a serious health issue, 
with a high medical need and a steadily increasing incidence over the past 30 years 
(Bataille 2009). 
1.1.1 
Treatment for Melanoma 
Remarkable progress has been made in melanoma research over the last decade.  
The U.S. Food and Drug Administration (FDA) has approved 13 new melanoma 
therapies since 2011, including both targeted and immune-based therapies (Luke et al. 
2017).  Current standard of care includes treatment with immune checkpoint inhibitors 
(CPIs), either alone or in combination, as well as targeted therapies, including BRAF and 
MEK inhibitors.  Interleukin (IL)-2, oncolytic viral, and interferon (IFN) therapies are also 
viable treatment options for a subset of patients. 
1.1.1.1 
Targeted Therapies 
Targeted therapies have demonstrated efficacy in improving overall survival (OS) and 
have been approved by the FDA for the BRAF-mutant subtype of metastatic 
melanoma.  Combination therapies with BRAF and MEK inhibitors show improved 
outcomes over treatment with a single-agent inhibitor alone.  However, most patients 
acquire resistance to therapy and relapse.  Therefore, treatment with dabrafenib 
(a selective BRAF inhibitor) in combination with trametinib (a selective MEK inhibitor) 
was tested in the adjuvant setting in the COMBI-AD trial in patients with BRAFV600E or 
BRAFV600K mutation-positive melanoma.  This combination improves relapse-free 
survival (RFS) and OS, and has been approved by the FDA for adjuvant use (Long et 
al. 2017).  In addition, there is further improvement in progression-free survival (PFS) 
when a PD-L1 inhibitor (atezolizumab) is added to the combination of BRAF plus MEK 
inhibitors (vemurafenib plus cobimetinib).  The Phase III IMspire150 study of patients 


 
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with previously untreated BRAFV600 mutation-positive advanced melanoma 
demonstrated that the triple combination helped reduce the risk of disease worsening or 
death compared to placebo plus vemurafenib and cobimetinib (Gutzmer et al. 2020).  
The IMspire150 study was the first Phase III study to combine targeted therapy and 
immunotherapy to show a benefit for patients with BRAFV600 mutation-positive advanced 
melanoma, and this triplet therapy has been approved by the FDA. 
1.1.1.2 
Immunotherapies 
A variety of immunotherapies have been approved for the treatment of melanoma, and 
immunotherapy has shown benefit regardless of PD-L1 expression or BRAF mutations. 
Four CPIs, namely ipilimumab, pembrolizumab, nivolumab, and relatlimab are now 
approved by the FDA for the treatment of unresectable or advanced disease.  Each has 
shown improved OS against different comparators.  Treatments shown to be effective in 
the unresectable or metastatic disease setting have also proven to be effective adjuvant 
therapies for patients with resectable Stage III melanomas.  The current standard of care 
is surgery followed by adjuvant antiPD-1 or targeted therapy. 
Ipilimumab, a monoclonal antibody targeting CTLA-4, demonstrated significant 
improvement in OS in two randomized trials (Hodi et al. 2010; Robert et al. 2011), and 
was the first CPI approved for use in unresectable or metastatic melanoma.  It was also 
the first CPI to be approved by the FDA as adjuvant therapy, and it has demonstrated 
improved OS at a dose of 10 mg/kg when compared with placebo in the European 
Organisation for Research and Treatment of Cancer 18071 study (Eggermont et al. 
2016).  The subsequent Intergroup E1609 trial demonstrated better outcomes with 
low-dose (3 mg/kg) ipilimumab; this dose has been approved for metastatic disease 
(Tarhini et al. 2020).  Anti–PD-1 monotherapy (pembrolizumab or nivolumab) shows 
improved efficacy outcomes with better safety profiles compared with treatment using 
single-agent antiCTLA-4 (ipilimumab) or the investigator’s choice of chemotherapy. 
Pembrolizumab was initially approved for the treatment of patients with advanced or 
unresectable melanoma who progressed after ipilimumab and/or BRAF therapy 
(Ribas et al. 2015a; Robert et al. 2015b).  It is now approved for the treatment of patients 
with unresectable or metastatic melanoma, as well as for the adjuvant treatment of 
patients with melanoma with lymph node involvement following complete resection. 
Nivolumab was originally approved in advanced melanoma patients without BRAF 
mutation (Robert et al. 2015a).  It is now approved for patients with unresectable or 
metastatic melanoma, and for patients with melanoma with lymph node involvement or 
metastatic disease who have undergone complete resection in the adjuvant setting. 
The combination of anti–PD-1 and anti–CTLA-4 immunotherapies (nivolumab plus 
ipilimumab) further prolonged PFS and OS compared with ipilimumab or nivolumab 
alone, and this combination has been approved for previously untreated patients with 


 
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unresectable or metastatic melanoma (Larkin et al. 2015).  The CheckMate 238 study 
compared nivolumab with ipilimumab.  At a median follow-up of 51 months, nivolumab 
improved RFS and distant metastasis-free survival while reducing toxicity.  The OS was 
similar in the two groups (Ascierto et al. 2020). 
Relatlimab is now approved with nivolumab for patients with unresectable or 
metastatic melanoma.  The combination of relatlimab and nivolumab improved PFS 
compared to nivolumab alone in patients with untreated advanced melanoma 
(Tawbi et al. 2022).  
1.1.2 
Treatment for Stage III Melanoma 
For patients with macroscopic Stage III melanoma, surgery followed by adjuvant 
immunotherapy with one year of either nivolumab or pembrolizumab is generally 
indicated (Weber et al. 2017; Eggermont et al. 2018).  These agents are PD-1 inhibitors.  
For patients with a tumor that contains a BRAFV600 mutation, targeted therapy with BRAF 
and MEK inhibitors represents an alternative therapy, especially for patients with 
Stage III disease who are unable to receive adjuvant immunotherapy due to active 
autoimmune disease or due to the need for immunosuppressive therapy. 
Clinical trial data suggest that 40% of patients with macroscopic Stage III melanoma 
relapse within 3 years after surgery (Bloemendal et al. 2019).  Moreover, a substantial 
subset of patients (15%–25%) relapse soon after surgery and before starting adjuvant 
therapy (Weber et al. 2017), resulting in a 3-year RFS of the intent-to-treat population of 
less than 50%.  Patients with clinical or palpable lymph node involvement have a 5-year 
survival rate of 20% to 59%, with certain subgroups of patients (based on number of 
involved nodes, extracapsular extension, or iliac involvement in groin metastases) 
showing even worse survival rates of around 5% at 5 years (Hauschild et al. 2018; 
Ascierto et al. 2020; Eggermont et al. 2020). 
1.1.2.1 
Neoadjuvant Immunotherapy Treatment in Stage III Melanoma 
Nonclinical studies demonstrated improved survival and increased anti-tumor immunity 
when immune CPI therapy was given before surgery as compared with adjuvant 
application (Liu et al. 2016; Brockwell et al. 2017; Bourgeois-Daigneault et al. 2018; 
Brooks et al. 2018; O’Donnell et al. 2019).  Patients with clinically detectable Stage III 
melanoma are ideal candidates for neoadjuvant therapy because they represent a 
high-risk patient population with poor outcomes when treated with upfront surgery alone.  
Neoadjuvant therapy also has the advantage of providing information on pathologic 
response, which is valuable to estimate prognosis and to guide the choice of adjuvant 
therapy and follow-up (Tetzlaff et al. 2018).  Moreover, the availability of tumor tissue 
before and following therapy enables efficient exploration of possible mechanisms of 
resistance and response as well as identification of baseline biomarkers.  Neoadjuvant 
therapy for melanoma is now an active area of research, with numerous completed and 
ongoing trials that have disparate designs, endpoints, and analyses (Menzies et al. 
2021).  The International Neoadjuvant Melanoma Consortium (INMC) was created by 


 
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experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, 
and translational research who developed recommendations for investigating 
neoadjuvant therapy in melanoma to align future trial designs and correlative analyses 
(Amaria et al. 2019). 
Six melanoma neoadjuvant trials were conducted recently with BRAF/MEK-targeted 
therapy or PD-1-based immunotherapy (reviewed by Amaria et al. 2019).  These trials 
demonstrated that neoadjuvant therapies can achieve high pathologic complete 
response (pCR) rates and impressive RFS in Stage III melanoma (Menzies et al. 2021; 
Rozeman et al. 2021).  The initial data are particularly promising for the neoadjuvant 
combination of nivolumab plus ipilimumab.  Treatment with nivolumab plus ipilimumab 
results in pathologic response rates (pRRs) between 70%80%, is well tolerated, and 
may reduce surgical morbidity (Rozeman et al. 2019; Blank et al. 2020). 
This study protocol was developed in accordance with INMC guidelines to create the 
needed consistency amongst neoadjuvant trials in order to facilitate optimal data 
organization for future regulatory review.  Its exploratory analysis plan will strengthen 
translational research across the melanoma disease continuum. 
1.1.2.2 
Treatment for Metastatic Melanoma 
Current standard of care includes treatment with immune CPIs, either alone or in 
combination, as well as treatment with targeted BRAF and MEK inhibitor therapies.  IL-2, 
oncolytic viral, and IFN therapy remain options for a subset of patients.  Radiation 
therapy may have a palliative role for symptomatic localized areas of disease.  Cytotoxic 
chemotherapy (single agent or combination) has not been shown to improve OS in 
patients with advanced melanoma.  Response rates are typically less than 20%, and 
median response durations are 4 to 6 months.  Consequently, the role of chemotherapy 
(e.g., dacarbazine, temozolomide, carboplatin/paclitaxel, and fotemustine) is limited to 
patients who have progressed after optimal treatment with other systemic therapy 
options. 
1.2 
STUDY RATIONALE 
This randomized Phase Ib/II umbrella study is designed to accelerate the development 
of treatments or treatment combinations by identifying early signals and establishing 
proof-of-concept clinical data in patients with resectable melanoma.  Single-agent 
immune CPIs or targeted therapies, dual CPI combinations, and CPIs in combination 
with targeted therapies have shown promising objective response rates (ORRs) and OS 
and are approved for use in patients with melanoma. 
The currently prevailing cancer immunotherapy (CIT) approach is to circumvent immune 
evasion mechanisms and reinvigorate anti-tumor responses by targeting T-cell inhibitory 
factors such as PD-1/PD-L1.  Other approaches build on the removal or inhibition of 
tumor-promoting cell types or employ immune stimulation via cytokines, engagement of 
costimulatory receptors, or antibody-directed T-cell activation. 


 
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CIT has demonstrated clear clinical efficacy, with significant survival benefit observed 
across multiple advanced malignancies, and there is evidence that PD-1/PD-L1 
checkpoint blockade can generate pCR and durable responses in patients with 
melanoma (Rozeman et al. 2019; Blank et al. 2020).  Although these targets have 
resulted in remarkable clinical therapeutic success for various cancer indications, 
ongoing research indicates that a series of stepwise events is necessary for the 
generation of an effective anti-tumor immune response (Chen and Mellman 2013).  Each 
event is critical for an effective response, and each is also susceptible to several tumor 
immune-evasion mechanisms.  Thus, the need to identify and circumvent the various 
factors that account for the absence of, or escape from, an effective anti-cancer immune 
response will be critical for propagating cancer immunity and advancing the field of CIT.  
The combination of PD-1/PD-L1 blocking with agents targeting different immune-evasion 
mechanisms may further increase response rates and decrease rates of disease 
recurrence in this population. 
The potential risks for patients will be immune-related adverse events associated with 
the study treatments.  Adverse events could potentially impact the timely conduct of 
surgery.  Further, although post-surgery recovery could be altered when applying 
neoadjuvant CIT, these theoretical concerns have not been borne out by data from 
recent studies in the neoadjuvant setting (Blank et al. 2018; Rozeman et al. 2019).  
The current study is designed with the flexibility to open new treatment arms as novel 
treatment combinations become available and to close existing treatment arms that 
demonstrate minimal clinical activity or unacceptable toxicity.  Enrollment of multiple 
experimental arms within a single study, rather than one or two experimental arms within 
multiple studies, will result in an overall reduction in the number of patients receiving 
control arm treatment.  More importantly, this study will assess the importance of 
simultaneously targeting multiple mechanisms of immune escape through immune cell 
priming and activation, tumor infiltration, and/or recognition of tumor cells for elimination.  
To improve the confidence of clinical signal detection in the experimental arms, this 
study will include a control arm (currently available in Cohort 1). 
The target and proposed mechanism-of-action classification for each experimental 
investigational medicinal product (IMP) is summarized in Table 1.  The control and 
experimental treatment regimens are described in Section 3.1 (see also Table 1).  
Background information and a rationale for each treatment combination, including a 
benefitrisk assessment for experimental IMPs, are provided in the respective appendix 
for that treatment arm, as outlined in Appendix 11 through Appendix 16. 


 
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Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products 
Experimental 
IMP 
Target(s) 
Proposed Mechanism-of-Action Classification 
Atezolizumab 
PD-L1 
Immune checkpoint inhibitor 
RO7247669 
PD-1, LAG-3 
Bispecific, dual immune checkpoint inhibitor a 
Tiragolumab 
TIGIT 
TIGIT antagonist, improves the activation and 
effectiveness of T-cell and NK-cell tumor-killing activity b 
IMP  investigational medicinal product; LAG-3  lymphocyte activation gene-3; NK  natural 
killer; PD-1  programmed death-1; PD-L1  programmed death-ligand 1; TIGIT  T-cell 
immunoreceptor with Ig and ITIM domains. 
a Codarri et al. 2019. 
b Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014. 
  
1.3 
COVID-19 BENEFITRISK ASSESSMENT 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of SARS-CoV-2. 
A possible consequence of immune checkpoint inhibition may be the modulation of the 
host immune response to acute infection, which may result in immunopathology or 
dysregulated immune defenses.  In nonclinical models, PD-1/PD-L1 blockade appears to 
be associated with serious exacerbation of inflammation in the setting of acute 
(as opposed to chronic) viral infection with lymphocytic choriomeningitis virus (Clone 13) 
(Frebel et al. 2012).  However, there are insufficient and inconsistent clinical data to 
assess if outcome from SARS-CoV-2 is altered by CIT. 
Severe SARS-CoV-2 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines IL-6, IL-10, IL-2, and IFN- (Merad and 
Martin 2020).  While it is not known, there may be a potential for an increased risk of an 
enhanced inflammatory response if a patient develops acute SARS-CoV-2 infection 
while receiving immune CPI therapies (e.g., atezolizumab, tiragolumab, and 
RO7247669).  At this time, there is insufficient evidence for causal association between 
immune CPI therapies and an increased risk of severe outcomes from SARS-CoV-2. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with immune CPI therapies and clinical and 
radiologic features for SARS-CoV-2related interstitial pneumonia.  Thus, investigators 
should use their clinical judgment when evaluating and managing patients with 
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There is a paucity of data concerning the possible interactions between CIT treatment 
and COVID-19 vaccination, and it is recognized that human immune responses are 
highly regulated and that immune-modifying therapies could positively or negatively 
impact COVID-19 vaccination efficacy and safety (Society for Immunotherapy of Cancer 
[SITC] 2020). 
Per the recommendations of the National Comprehensive Cancer Network (NCCN) 
COVID-19 Vaccination Advisory Committee, COVID-19 vaccination is recommended for 
all patients with cancer receiving active therapy (including immune CPIs) with the 
understanding that there are limited safety and efficacy data in these patients 
(NCCN COVID-19 vaccination and cancer patients).  Given the lack of clinical data, 
currently no recommendations can be made regarding the optimal sequence of 
COVID-19 vaccine and treatment with CIT (SITC 2020). 
For patients enrolling in this study with atezolizumab, tiragolumab, and RO7247669, the 
decision to administer the vaccine should be individualized by the physicians in 
consultation with the patient, based on the risk of SARS-CoV-2 infection/complications 
and potential benefit from the vaccine, the general condition of the patient, underlying 
disease, and the severity of COVID-19 outbreak in a given area/region.  For further 
details on permitted and prohibited therapies, see Sections A11–4.2 
(nivolumab  ipilimumab [Nivo  Ipi]), A12–4.2 (RO7247669 2100 mg), A13–4.2 
(atezolizumab  tiragolumab [Atezo  Tira]), A14–4.2 (RO7247669 2100 mg  Tira 
Cohorts 1 and 2), A15–4.2 (RO7247669 600 mg), and A16–4.2 
(RO7247669 600 mg  Tira).  The SITC and NCCN recommendations referenced above 
and institutional guidelines should be considered by the investigator in decision making.  
When administered, SARS-CoV-2 vaccines must be given in accordance with the 
approved or authorized vaccine label.  Receipt of the SARS-CoV-2 vaccine is 
considered a concomitant medication and should be documented as such (Section 4.4). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of treatment 
combinations in CIT-naive patients with resectable Stage III melanoma (Cohort 1) and in 
patients with Stage IV melanoma (Cohort 2). 
Specific objectives and corresponding endpoints for the study are outlined below for 
Cohort 1 (see Table 2) and Cohort 2 (see Table 3). 


 
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Table 2 
Objectives and Corresponding Endpoints for Cohort 1 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of treatment 
 pRR (defined as the proportion of patients with pCR, 
pnCR, and pPR) at time of surgery, as determined by 
independent pathologic review 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
 pRR (defined as the proportion of patients with pCR, 
pnCR, and pPR) at time of surgery, as determined by 
local pathologic assessment 
 EFS, defined as the time from randomization to any of 
the following events (whichever occurs first):  Disease 
progression that precludes surgery, as assessed by 
the investigator according to RECIST v1.1; local, 
regional or distant disease recurrence; or death from 
any cause 
 RFS, defined as the time from surgery to the first 
documented recurrence of disease or death from any 
cause 
 OS, defined as the time from randomization to death 
from any cause 
 ORR, defined as the proportion of patients with a CR 
or PR as determined by the investigator according to 
RECIST v1.1, prior to surgery 
Responses will be assessed and determined 
according to RECIST v1.1 but are not required to be 
confirmed by later imaging. 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
 Landmark EFS, defined as the time from 
randomization to any of the following events 
(whichever occurs first):  Disease progression that 
precludes surgery, as assessed by the investigator 
according to RECIST v1.1; local, regional or distant 
disease recurrence; or death from any cause at 
specific timepoints (1, 2, 3, and 5 years) 
 Landmark RFS, defined as the time from surgery to the 
first documented recurrence of disease or death from 
any cause at specific timepoints (1, 2, 3, and 5 years) 
 Landmark OS, defined as the time from randomization 
to death from any cause at specific timepoints (1, 2, 3, 
and 5 years) 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CLND  completion lymph node dissection; CR  complete response; CRS  cytokine-release 
syndrome; EFS  event-free survival; NCI CTCAE v5.0  National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0; ORR  objective response rate; OS  overall 
survival; pCR  pathologic complete response; PK  pharmacokinetic; pnCR  pathologic near 
complete response; pPR  pathologic partial response; PR  partial response; pRR  pathologic 
response rate; RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1; 
RFS  relapse-free survival. 


 
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Table 2 
Objectives and Corresponding Endpoints for Cohort 1 (cont.) 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of treatment 
 Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined 
according to NCI CTCAE v5.0 
CRS severity will also be determined according to 
the ASTCT CRS Consensus Grading Scale. 
 Incidence and nature of immune-related adverse 
events Grade  3 during the first 12 weeks 
 Rate and duration of delayed surgery due to 
treatment-related adverse events 
 Surgical complication rates according to 
Clavien-Dindo surgical classification after CLND 
Exploratory Pharmacokinetic 
Objectives 
Corresponding Endpoints 
 To characterize the PK profile of 
drugs that are administered as part of 
treatment  
 Plasma or serum concentration of each drug (as 
appropriate) at specified timepoints 
 To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of treatment 
 Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate, on 
the basis of available data) and efficacy endpoints 
 Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate, on 
the basis of available data) and safety endpoints 
Exploratory Immunogenicity 
Objectives 
Corresponding Endpoints 
 To evaluate the immune response to 
drugs that are administered  
 For drugs for which ADA formation is measured:  
Presence of ADAs during the study relative to the 
presence of ADAs at baseline 
 To evaluate potential effects of ADAs   For drugs for which ADA formation is measured:  
Relationship between ADA status and efficacy, 
safety, or PK endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CLND  completion lymph node dissection; CR  complete response; CRS  cytokine-release 
syndrome; EFS  event-free survival; NCI CTCAE v5.0  National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0; ORR  objective response rate; 
OS  overall survival; pCR  pathologic complete response; PK  pharmacokinetic; 
pnCR  pathologic near complete response; pPR  pathologic partial response; PR  partial 
response; pRR  pathologic response rate; RECIST v1.1  Response Evaluation Criteria in Solid 
Tumors, Version 1.1; RFS  relapse-free survival. 


 
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Table 2 
Objectives and Corresponding Endpoints for Cohort 1 (cont.) 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive 
biomarkers), are associated with 
progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated with 
resistance to study treatment, are 
associated with susceptibility to 
developing adverse events (i.e., 
safety biomarkers), can provide 
evidence of study treatment activity 
(i.e., pharmacodynamic biomarkers), 
or can increase the knowledge and 
understanding of disease biology 
 Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.9) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CLND  completion lymph node dissection; CR  complete response; CRS  cytokine-release 
syndrome; EFS  event-free survival; NCI CTCAE v5.0  National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0; ORR  objective response rate; 
OS  overall survival; pCR  pathologic complete response; PK  pharmacokinetic; 
pnCR  pathologic near complete response; pPR  pathologic partial response; PR  partial 
response; pRR  pathologic response rate; RECIST v1.1  Response Evaluation Criteria in Solid 
Tumors, Version 1.1; RFS  relapse-free survival. 
 


 
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Table 3 
Objectives and Corresponding Endpoints for Cohort 2  
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of treatment  ORR, defined as the proportion of patients with a CR or 
PR on two consecutive occasions  4 weeks apart, as 
determined by the investigator according to RECIST v1.1 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment  PFS after randomization/enrollment, defined as the time 
from randomization/enrollment to the first occurrence of 
disease progression or death from any cause (whichever 
occurs first), as determined by the investigator according 
to RECIST v1.1 
 OS after randomization/enrollment, defined as the time 
from randomization/enrollment to death from any cause 
 OS at specific timepoints (e.g., 6 months) 
 DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression 
or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1 
 Disease control, defined as stable disease for  12 weeks 
or a CR or PR, as determined by the investigator 
according to RECIST v1.1 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment  ORR, PFS, DOR, and disease control as determined by 
the investigator according to iRECIST 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of treatment 
 Incidence, nature, and severity of adverse events and 
laboratory abnormalities, with severity determined 
according to NCI CTCAE v5.0 
CRS severity will also be determined according to 
the ASTCT CRS Consensus Grading Scale. 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CR  complete response; CRS  cytokine-release syndrome; DOR  duration of response; 
eCRF  electronic Case Report Form; iRECIST  modified RECIST v1.1 for immune-based 
therapeutics; NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0; ORR  objective response rate; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; PR  partial response; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Overall response per iRECIST (see Appendix 2) will not be 
captured in the eCRF, but will instead be calculated programmatically by the Sponsor on the 
basis of investigator-assessed individual lesion data recorded in the eCRF. 
 


 
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Table 3 
Objectives and Corresponding Endpoints for Cohort 2 (cont.) 
Exploratory 
Pharmacokinetic Objectives 
Corresponding Endpoints 
 To characterize the PK profile of 
drugs that are administered as part of 
treatment  
 Plasma or serum concentration of each drug (as 
appropriate) at specified timepoints  
 To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of treatment 
 Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate on 
the basis of available data) and efficacy endpoints 
 Relationship between plasma or serum concentration 
or PK parameters for each drug (as appropriate on 
the basis of available data) and safety endpoints 
Exploratory 
Immunogenicity Objectives 
Corresponding Endpoint 
 To evaluate the immune response to 
drugs that are administered  
 For drugs for which ADA formation is measured:  
Presence of ADAs during the study relative to the 
presence of ADAs at baseline 
 To evaluate potential effects of ADAs   For drugs for which ADA formation is measured:  
Relationship between ADA status and efficacy, 
safety, or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 To identify biomarkers that are 
predictive of response to study 
treatment (i.e., predictive 
biomarkers), are associated with 
progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated with 
resistance to study treatment, are 
associated with susceptibility to 
developing adverse events (i.e., 
safety biomarkers), can provide 
evidence of study treatment activity 
(i.e., pharmacodynamic biomarkers), 
or can increase the knowledge and 
understanding of disease biology 
 Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.9) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CR  complete response; CRS  cytokine-release syndrome; DOR  duration of response; 
eCRF  electronic Case Report Form; iRECIST  modified RECIST v1.1 for immune-based 
therapeutics; NCI CTCAE v5.0  National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0; ORR  objective response rate; OS  overall survival; 
PFS  progression-free survival; PK  pharmacokinetic; PR  partial response; 
RECIST v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Overall response per iRECIST (see Appendix 2) will not be 
captured in the eCRF, but will instead be calculated programmatically by the Sponsor on the 
basis of investigator-assessed individual lesion data recorded in the eCRF. 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in patients with 
resectable Stage III (Cohort 1) or Stage IV (Cohort 2) melanoma.  The study is designed 
with the flexibility to open new treatment arms as new treatments become available, 
close existing treatment arms that demonstrate minimal clinical activity or unacceptable 
toxicity, modify the patient population (e.g., with regard to prior anti-cancer treatment or 
biomarker status), or introduce additional cohorts of patients with other types of 
melanoma. 
When additional treatment options become available, patients may be eligible to receive 
treatment with a different treatment combination in an additional study stage (Stage 2).  
When a Stage 2 treatment is available, this will be introduced by amending the protocol. 
Two cohorts will be enrolled in parallel in this study.  Cohort 1 will enroll patients with 
resectable Stage III melanoma with measurable lymph node metastases according to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) that can be 
biopsied, who have no history of in-transit metastases within the last 6 months, and who 
have not received systemic CIT for their disease, e.g., PD-1/PD-L1 and/or CTLA-4 
blocking agents or other agents.  Cohort 2 will enroll patients with Stage IV melanoma 
who experienced disease progression during or after at least one but not more than two 
lines of treatment for metastatic disease.  Up to two lines of checkpoint inhibition therapy 
(monotherapy or combination therapy) are allowed.  Patients with BRAF-mutant disease 
may have received an additional line of targeted therapy (either before, intermittent with, 
or after the checkpoint inhibition therapy) or may have received targeted therapy and 
checkpoint inhibition therapy concurrently as one combination treatment.  Patients with 
BRAF-mutant melanoma with rapidly progressive disease who have not been previously 
treated with approved targeted therapies are not eligible. 
In each cohort, eligible patients will be assigned to one of several treatment arms 
(see Section 3.1.2).  For the study design, see Figure 1.


 
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Figure 1 Study Design 
 
 
CIT  cancer immunotherapy; CLND  complete lymph node dissection; R  randomization. 
Note: All treatment arms (except the safety run-in) will include a mandatory on-treatment biopsy (see Section 4.5.9 for details). 
a Refer to Table 4 for a summary of available treatment regimens. 
b Patients with BRAF-mutant disease may have received an additional line of targeted therapy. 
c Enrollment will begin with a 6-patient safety run-in phase.  Biopsies are optional for patients enrolled in the safety run-in. 


 
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3.1.2 
Treatment Assignment 
In Cohort 1, patients will be randomly assigned to a control arm (nivolumab plus 
ipilimumab [Nivo  Ipi]) or an experimental arm consisting of RO7247669 2100 mg, 
atezolizumab in combination with tiragolumab (Atezo  Tira), RO7247669 2100 mg in 
combination with tiragolumab (RO7247669 2100 mg  Tira), RO7247669 600 mg, or 
RO7247669 600 mg in combination with tiragolumab (RO7247669 600 mg   Tira).  
Patients will be stratified by geographic region (Australia vs. Rest of the World) and 
baseline LDH ( the upper limit of normal [ULN] vs.  ULN).  Details on the treatment 
regimens are provided in the respective appendices, Appendix 11 through Appendix 16, 
as specified in Table 4 and Figure 2. 
In Cohort 2, patients will be enrolled into an experimental arm consisting of 
RO7247669 2100 mg in combination with tiragolumab (RO7247669 2100 mg  Tira).  
Enrollment will begin with a 6-patient safety run-in phase.  Patients from French 
investigational sites are excluded from the safety run-in phase and may only be enrolled 
into the preliminary phase, which succeeds the safety-run-in.  Details on the treatment 
regimens are provided in Appendix 14 as specified in Table 4 and Figure 2. 
Approximately 203336 patients will be enrolled during the study, including 
approximately 6 patients who will be enrolled in the safety run-in phase of Cohort 2.  
Enrollment within the experimental arms will take place in two phases:  a preliminary 
phase, followed by an expansion phase.  For most arms, approximately 20 patients will 
be enrolled during the preliminary phase.  Approximately 40 patients will be enrolled 
in the RO7247669 600 mg and RO7247669 600 mg  Tira arms during the preliminary 
phase to ensure a more precise benefitrisk assessment in arms with the lower dose of 
RO7247669.  If clinical activity (pathologic response in Cohort 1) is observed in an 
experimental arm during the preliminary phase, approximately 20 additional patients 
may be enrolled in that arm during the expansion phase. 
The Sponsor may decide to delay or suspend enrollment within a given treatment arm.  
Experimental arms with insufficient clinical activity or unacceptable toxicity will not be 
expanded.  Additional patients may be enrolled to ensure balance among treatment 
arms with respect to demographic and baseline characteristics, including potential 
predictive biomarkers, in order to enable further subgroup analyses.  New experimental 
arms may be added during the study by amending the protocol. 
The randomization ratio will depend on the number of experimental arms that are 
available (e.g., if an arm is added or enrollment in an arm is suspended, pending 
analysis of results from the preliminary phase), with the stipulation that the likelihood of 
being allocated to the control arm is no more than 35%.  Randomization will take into 
account arm-specific exclusion criteria.  Patients will be ineligible for a specific arm if 
they meet any of the exclusion criteria outlined for that arm (see Section 4.1.2).  Details 
on treatment assignment and randomization are provided in Section 4.2. 


 
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Table 4 
Treatment Regimens 
Cohort 
Study Treatment a 
Number of Patients 
(Sponsor Assignment) b 
Number of Patients  
(Random Assignment) c 
Appendix 
Safety Run-in Phase 
Preliminary Phase 
Expansion Phase d 
1 
Control arm:  Nivo  Ipi 
N/A 
Variable c 
Appendix 11  
1 
RO7247669 2100 mg 
N/A 
20 e 
20 
Appendix 12  
1 
Atezo  Tira 
N/A 
20 e 
20 
Appendix 13  
1 
RO7247669 2100 mg  Tira f 
N/A 
20 e 
20 
Appendix 14  
1 
RO7247669 600 mg 
N/A 
40   
20 
Appendix 15  
1 
RO7247669 600 mg  Tira 
N/A 
40  
20 
Appendix 16  
2 
RO7247669 2100 mg  Tira 
~6 
20 
20 
Appendix 14  
Atezo  atezolizumab; Ipi  ipilimumab; Nivo  nivolumab; Tira  tiragolumab. 
a The Sponsor may decide to delay or suspend enrollment within a given treatment arm.  Thus, all experimental arms may not be open for 
enrollment at the same time. 
b During the safety run-in phase, patients will be assigned to available treatment arms.  The treatment assignment ratio will depend on the 
number of experimental arms that are open for enrollment (see Section 4.2 for more information). 
c The randomization ratio will depend on the number of experimental arms that are open for randomization (e.g., if an arm is added or 
randomization into an arm is suspended pending analysis of results from the preliminary phase), with the stipulation that the likelihood of being 
allocated to the control arm is no more than 35%.  See Section 4.2 for more information. 
d If clinical activity is observed in an experimental arm during the preliminary phase, approximately 20 additional patients will be enrolled in that 
arm during the expansion phase.  Experimental arms with minimal clinical activity or unacceptable toxicity will not undergo expansion. 
e Enrollment will be suspended in the Cohort 1 RO7247669 2100 mg, Atezo  Tira, and RO7247669 2100 mg  Tira arms to allow for a safety 
evaluation in a minimum of 6 patients (see Section 3.1.3). 
f Enrollment in the RO7247669 2100 mg  Tira arm will open in Cohort 1 after safety assessment of the treatment combination in Cohort 2. 


 
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Figure 2 Study Schema 
 
 
Atezo  atezolizumab; CIT  cancer immunotherapy; CLND  completion lymph node dissection; Ipi  ipilimumab; Nivo  nivolumab; 
R  randomization; Tira  tiragolumab. 
Note:  All treatment arms (except the safety run-in) will include a mandatory on-treatment biopsy (see Section 4.5.9 for details). 
a Enrollment in the RO7247669 2100 mg  Tira arm will open in Cohort 1 if the stopping criteria are not met during the safety run-in phase in 
Cohort 2. 
b Patients with BRAF-mutant disease may have received an additional line of targeted therapy. 
c Enrollment in the RO7247669 2100 mg  Tira arm will begin with a 6-patient safety run-in phase in Cohort 2.  Biopsies are optional for patients 
enrolled in the safety run-in.


 
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In Cohort 1, patients in the control arm and the experimental arms will receive 
neoadjuvant treatment during a 6-week period.  After completion of neoadjuvant 
treatment, or in case of discontinuation due to toxicity and in absence of disease 
progression, patients will undergo surgery (completion lymph node dissection [CLND]) in 
Week 7.  After the treatment completion/discontinuation visit and at the discretion of the 
investigator, patients will start either adjuvant therapy or observation (see Figure 3).  
Because of the possibility of an initial increase in the size of metastatic lymph nodes 
caused by immune-cell infiltration in the context of a T-cell response (termed 
pseudoprogression) with CITs, suspected clinical or radiographic progression per 
RECIST v1.1 may not be indicative of true disease progression.  In the absence of 
unacceptable toxicity, patients who meet the criteria for disease progression per 
RECIST v1.1 while receiving treatment with a CIT drug will be permitted to continue 
study treatment until surgery.  Before discontinuation of study treatment and/or 
cancellation of surgery, progression should be confirmed by biopsy or repeated 
radiographic assessment by an additional expert reviewer.  All patients are expected to 
proceed with surgery, provided that there are no distant metastases and the surgeon 
considers the disease to be completely resectable. 
In Cohort 2, patients will continue to receive treatment until unacceptable toxicity or loss 
of clinical benefit as determined by the investigator after an integrated assessment of 
radiographic and biochemical data, local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease).  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 other 
CITs, radiographic progression per RECIST v1.1 may not be indicative of true disease 
progression.  In the absence of unacceptable toxicity, patients who meet criteria for 
disease progression per RECIST v1.1 while receiving treatment with a CIT combination 
will be permitted to continue treatment 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 Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients eligible for treatment beyond progression will be informed by the investigator 
that they may be foregoing other treatment options known to confer clinical benefit while 
continuing to receive the study treatment.  Patients have the right to voluntarily withdraw 
from the study at any time for any reason.  In addition, the investigator has the right to 


 
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withdraw a patient from the study for medical conditions that the investigator or Sponsor 
determines may jeopardize the patient’s safety if he/she continues in the study. 
If at a subsequent tumor assessment, pseudoprogression is ruled out and progression of 
the disease is confirmed, the patient will be discontinued from study treatment. 


 
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Figure 3 Detailed Study Schema (Cohort 1) 
 
 
CLND  completion lymph node dissection; Comp.  completion; CT  computed tomography; Discon.  discontinuation; FU  follow-up; 
LT  long-term; M  month; R  randomization; Q3M  every 3 months; Tx  treatment; W  week. 
a At the discretion of the investigator, patients will start either adjuvant therapy or observation commencing in Week 13.  
b  The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration.


 
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3.1.3 
Safety Evaluation Phase (Cohort 1) 
To evaluate the toxicities of the experimental treatments in the neoadjuvant setting, 
enrollment will be suspended after approximately 6 patients have been enrolled to allow 
for a safety evaluation.   
The safety evaluation will be based on safety data from a minimum of 6 patients who 
have received at least one dose of treatment (i.e., one dose of each agent for a given 
combination) and who have completed safety follow-up assessments until surgery.  
Notably, timely conduct of surgery (CLND) is an indicator of treatment tolerability.  
During the 6-patient safety evaluation, or following safety evaluations, if  30% of 
patients experience one or more of the following events that is considered to be at least 
possibly related to study treatment, enrollment for that combination will be put on hold 
while the Sponsor evaluates the benefitrisk profile of that treatment: 
 
A treatment-related Grade  3 adverse event that does not improve (with or without 
treatment) to Grade 2 or better within 2 weeks 
 
A treatment-related adverse event causing  2-week delay in surgery 
 
A treatment-related serious adverse event 
 
A treatment-related adverse event that requires permanent discontinuation of study 
drug 
 
Death, except those that are incontrovertibly related to disease progression or 
extraneous causes such as accidents 
 
If no new safety signals are detected, enrollment will be resumed in that arm. 
For the same study drug or study drug combination, if a higher dose arm has passed the 
safety evaluation for a minimum of 6 patients, enrollment will be not suspended after 
6 patients are enrolled in the lower dose arms pending the outcome of the safety 
evaluation.  However, the Sponsor will still conduct a formal safety evaluation from a 
minimum of 6 patients who have received at least one dose of treatment (i.e., one dose of 
each agent for a given combination) and who have completed safety follow-up 
assessments until surgery.  The stopping rules outlined above will also apply to the 
lower dose arms at this safety evaluation.   
3.1.4 
Safety Run-In Phase (Cohort 2) 
To assess the safety and tolerability of novel combinations that are tested clinically for 
the first time, an initial safety run-in phase will be implemented in Cohort 2.  
Approximately 6 patients with metastatic disease will be treated with the novel 
combination and assessed for safety and tolerability for a minimum of 28 days. 
A minimum of 6 patients in Cohort 2 must complete the initial safety run-in phase.  If the 
combination is determined to be tolerable, enrollment for the preliminary phase may be 
opened, and the same arm in Cohort 1 can be opened for enrollment (refer to 
Section 3.1.2 for details).  Patients in the safety run-in phase will be enrolled and treated 


 
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in a sequential manner, with at least one week between the first patient and the 
remaining patients. 
The assessment will be based on safety data from a minimum of 6 patients who have 
received at least one dose of treatment (i.e., one dose of each agent) and who have 
completed safety follow-up assessments for at least 28 days.  During the 6-patient safety 
run-in phase, or following safety evaluations, if  30% of patients experience one or more 
of the following events that is considered to be at least possibly related to study 
treatment, enrollment for that combination will be put on hold while the Sponsor 
evaluates the benefitrisk profile of that treatment: 
 
A treatment-related Grade  3 adverse event that does not improve (with or without 
treatment) to Grade 2 or better within 2 weeks 
 
A treatment-related serious adverse event 
 
A treatment-related adverse event that requires permanent discontinuation of study 
drug 
 
Death, except those that are incontrovertibly related to disease progression or 
extraneous causes such as accidents 
 
If no new safety signals are detected, the combination will also be initiated in Cohort 1. 
3.1.5 
Assessments and Monitoring 
All patients will be closely monitored for adverse events throughout the study.  Adverse 
events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).  CRS severity will also be 
graded according to the American Society for Transplantation and Cellular Therapy 
(ASTCT) CRS Consensus Grading Scale. 
Patients in Cohort 1 will receive neoadjuvant treatment for 2 cycles (6 weeks) and will 
undergo surgery (CLND) in Week 7.  All patients are expected to proceed with surgery, 
provided that there are no distant metastases and the surgeon considers the disease to 
be completely resectable.  Pathologic response will be assessed locally and by 
independent pathologic review. 
Patients who discontinue treatment due to unacceptable toxicity and continue to have no 
evidence of metastatic disease will still be eligible for surgery and proceed with CLND 
after the adverse event has resolved and re-staging confirms Stage III disease.  
If patients have confirmed disease progression, patient management and treatment 
selection will be at the discretion of the treating physician.  These patients will remain in 
the study for follow-up. 
Patients will undergo radiological tumor assessments in Week 6 (from Day 1 of Cycle 1) 
prior to surgery (CLND) (see Section 4.5.7 for details).  Response will be assessed and 


 
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determined by the investigator in accordance with RECIST v1.1, but confirmation by 
later imaging studies is not required (see Appendix 1). 
Patients in Cohort 2 will undergo tumor assessments every 9 weeks (from Day 1 of 
Cycle 1) for the first 54 weeks and then every 12 weeks thereafter (see Section 4.5.7).  
Response will be assessed by the investigator using RECIST v1.1 (see Appendix 1).  
Response per modified RECIST v1.1 for immune-based therapeutics (iRECIST) (see 
Appendix 2) will be determined programmatically by the Sponsor on the basis of 
investigator-assessed individual lesion data. 
For Cohort 1 and Cohort 2, if clinical activity is demonstrated in an experimental arm, the 
Sponsor may request that tumor assessment scans for that arm and the corresponding 
control arm be submitted for evaluation by an independent review facility. 
For all patients, blood samples will be collected at baseline and during the study for 
biomarker research, including blood-based next-generation sequencing (NGS) and 
circulating tumor DNA (ctDNA) testing. 
Tumor and blood samples will be collected at baseline and during the study for 
biomarker assessments.  Baseline tumor tissue samples will be collected from all 
patients (except patients in the Cohort 2 safety run-in phase) by biopsy of a metastatic 
lymph node (Cohort 1) or other metastatic lesion (Cohort 2) at screening.  In addition, 
archival primary tumor tissue will be submitted from all patients if available.  For patients 
in Cohort 1, on-treatment tissue samples will be collected by biopsy on Day 1 of Cycle 2 
(up to 72 hours prior to drug administration), and at surgery (CLND).  For patients 
enrolled in Cohort 2, on-treatment tissue samples will be collected by biopsy on Day 8 of 
Cycle 2.  These samples will be utilized for biomarker research (see rationale for 
biomarker assessments in Section 3.4.7 and details on tissue sample collection in 
Section 4.5.9).  If possible, baseline screening samples should be collected after all 
other screening assessments have been evaluated for eligibility. 
To characterize the pharmacokinetic (PK) properties and/or immunogenicity of 
atezolizumab and the other therapeutic agents, blood samples will be taken at various 
timepoints before and during study treatment administration. 
On the basis of a review of real-time safety data and available PK data, treatment 
regimens may be modified by the Sponsor as deemed appropriate. 
The schedule of activities for each treatment arm is presented in Sections A11–6 
(Nivo  Ipi), A12–6 (RO7247669 2100 mg), A13–6 (Atezo  Tira), A14–6 
(RO7247669 2100 mg  Tira Cohort 1), A14–8 (RO7247669 2100 mg  Tira Cohort 2), 
A15–6 (RO7247669 600 mg), and A16–6 (RO7247669 600 mg  Tira). 


 
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3.1.6 
Internal Monitoring Committee 
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  
The IMC will include representatives from clinical science, safety science, and 
biostatistics.  In addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events, serious adverse events, deaths, and laboratory abnormalities 
performed by the investigator and the Medical Monitor, the IMC will review all necessary 
cumulative data at regular intervals during the study.  At the time of each review, the 
IMC will make appropriate recommendations (e.g., the study should continue as 
planned, enrollment in a specific arm should be discontinued, a treatment regimen 
should be modified, the protocol should be amended, or enrollment should be held 
pending further safety evaluations).  Decisions will be made in consideration of the 
totality of the available data.  Ad-hoc meetings may be called in addition to scheduled 
meetings, as necessary, to provide recommendations on management of any new safety 
issues.  Specific operational details such as the committee's composition, frequency and 
timing of meetings, and members' roles and responsibilities will be detailed in an IMC 
Charter. 
3.1.7 
Scientific Oversight Committee 
A Scientific Oversight Committee (SOC) will act as a consultative body to the Sponsor, 
providing external expert opinions on the safety data collected during the study.  This 
committee will consist of an external group of at least three oncology experts in CIT who 
will advise the Sponsor on the interpretation of study data.  For this purpose, the SOC 
will evaluate aggregate safety data on a periodic basis, approximately every 6 months 
from the time the first patient is enrolled in the study.  Members will follow a charter that 
outlines their roles and responsibilities.  Data being evaluated by the SOC will include 
demographic, adverse event, serious adverse event, and relevant laboratory data.  The 
SOC may review efficacy data if safety concerns necessitate benefitrisk assessments.  
The Sponsor will retain all decision-making authority for this study. 
3.1.8 
Independent Pathology Review 
An Independent Pathology Review Facility (or facilities) (IPRF[s]) will perform an 
independent review of resection tissue, and other clinical data as needed, for the primary 
efficacy analyses.  Review will be performed according to the guidelines of Pathologic 
Assessment of Resection Specimens After Neoadjuvant Therapy for Metastatic 
Melanoma (Appendix 3) IPRF membership and procedures will be detailed in an IPRF 
charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient completes the last visit, 
including long-term follow-up visits conducted by telephone or in the clinic. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years. 


 
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3.3 
DURATION OF PARTICIPATION 
In Cohort 1, the total duration of study participation for each individual from screening 
until the treatment completion visit and start of adjuvant treatment is expected to be 
approximately 17 weeks (not including long-term follow-up): 
 
Screening: Up to 4 weeks; Days 28 to 1 
 
Treatment period: 13 weeks; participants will receive neoadjuvant treatment during 
a 6-week period and will undergo surgery at Week 7.  After surgery and prior to 
commencing adjuvant treatment, treatment completion will be performed in 
Week 13. 
  
After the treatment period, participants may continue onto long-term follow-up: 
 
Information on long-term follow-up and new anti-cancer therapy (including targeted 
therapy and immunotherapy) will be collected by telephone, patient medical records, 
and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study). 
 
In Cohort 2, the total duration of study participation for each individual is expected to be 
up to 5 years: 
 
Screening: Up to 4 weeks; Days 28 to 1 
 
Treatment period: participants will continue to receive treatment until unacceptable 
toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results 
(if available), and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease).  
 
Safety follow-up: 28 days after the last dose of treatment 
 
Long-term follow-up: Information on long-term follow-up and new anti-cancer 
therapy (including targeted therapy and immunotherapy) will be collected by 
telephone, patient medical records, and/or clinic visits approximately every 3 months 
until death (unless the patient withdraws consent or the Sponsor terminates the 
study). 
   
3.4 
RATIONALE FOR STUDY DESIGN 
3.4.1 
Rationale for Patient Population 
Cohort 1 will enroll patients with resectable Stage III melanoma with measurable lymph 
node metastases (according to RECIST v1.1) that can be biopsied, and who have no 
history of in-transit metastases within the last 6 months.  Enrolled patients must not have 
received prior immunotherapy for their disease. 
This same patient population was enrolled in the OpACIN and OpACIN-neo studies, 
including the PRADO extension cohort.  These studies evaluated the neoadjuvant (and 
adjuvant) combination of nivolumab and ipilimumab in patients with resectable 
melanoma.  Neoadjuvant therapy was found to have a statistically significant and 


 
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clinically meaningful benefit as compared with adjuvant therapy (Rozeman et al. 2019; 
Blank et al. 2020; Rozeman et al. 2021).  In addition, the safety profile of the treatment 
was found to be tolerable in an optimized treatment schedule. 
Despite the recently demonstrated benefit of checkpoint inhibition therapy, there is a 
continuing need for treatment regimens that are more efficacious (i.e., broader and 
deeper pathologic response in the surgical specimen) and better tolerated for patients 
with resectable melanoma.  The multiple treatment options in this study are expected to 
stimulate the immune system through a variety of mechanisms (see Appendix 11 
through Appendix 16 for more details).  The aim is to extend the benefit of CIT beyond 
that of current checkpoint inhibition to a larger population with resectable melanoma. 
Cohort 2 will enroll patients with Stage IV melanoma who experienced disease 
progression during or after at least one but not more than two lines of treatment for 
metastatic disease.  Up to two lines of checkpoint inhibition therapy (monotherapy or 
combination therapy) are allowed.  Patients with BRAF-mutant disease may have 
received an additional line of targeted therapy (either before, intermittent with, or after 
the checkpoint inhibition therapy) or may have received targeted therapy and checkpoint 
inhibition therapy concurrently as one combination treatment.  Patients with 
BRAF-mutant melanoma with rapidly progressive disease who have not been previously 
treated with approved targeted therapies are not eligible. 
Novel combinations of compounds with a clinical and/or biological rationale for 
anti-melanoma activity that have not yet been tested clinically will be investigated in 
Cohort 2.  Importantly, for individual compounds considered for novel combinations, 
safety and tolerability have been already established in other studies and a safe dose 
and schedule are available.  The Cohort 2 safety run-in phase will assess the safety of 
the novel combination with regards to potential overlapping toxicities (see Section 3.1.4 
for details). 
3.4.2 
Rationale for Immunotherapy-Based Treatment beyond Initial 
Radiographic Progression 
In studies of immunotherapeutic agents, complete response (CR), partial response (PR), 
and stable disease (SD) have each been shown to occur after radiographic evidence of 
an apparent increase in tumor burden.  This initial increase in tumor burden caused by 
immune-cell infiltration in the setting of a T-cell response has been termed 
pseudoprogression (Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types.  In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells. 
In Cohort 1, because of the possibility of an initial increase in the size of metastatic 
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T-cell response in the absence of unacceptable toxicity, patients who meet the criteria 
for disease progression in the target lymph node metastases per RECIST v1.1 while 
receiving treatment with a CIT drug will be permitted to continue study treatment until 
surgery.  However, the appearance of novel, previously undetected non-lymph node 
lesions may indicate that the patient has in fact been understaged and rather presents 
with more advanced or Stage IV disease.  Because of the potential for a response after 
pseudoprogression, this study will allow patients randomly allocated to immunotherapy-
based treatment arms to continue combination treatment after apparent radiographic 
progression per RECIST v1.1, provided the benefitrisk ratio is judged to be favorable by 
the investigator (see criteria in Section 3.1.2).  Patients should be discontinued for 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (see Section 3.1.2 for details). 
3.4.3 
Rationale for the Use of Modified RECIST for Immune-Based 
Therapeutics 
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 
disease progression does not necessarily reflect 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 iRECIST (Seymour et al. 2017; see Appendix 2), 
tumor response criteria that have been modified for unconventional tumor change 
patterns associated with CIT. 
iRECIST was developed by the RECIST working group in an effort to create a common 
set of criteria that the CIT field could apply to clinical trials (Seymour et al. 2017).  
iRECIST accounts for responses that may occur following transient radiographic 
progression caused by immune-cell infiltration in tumors (leading to a transient increase 
in the size of existing lesions, including those that were previously undetectable and 
consequently appear as new lesions).  iRECIST relies on collection of tumor assessment 
data after initial disease progression per RECIST v1.1. 
Given the proposed immunomodulatory mechanism-of-action of atezolizumab and other 
CPIs and the possibility of observing delayed responses, exploratory efficacy endpoints 
will include analyses based on iRECIST.  These analyses will allow for evaluation of 
iRECIST as an improved measure of the efficacy of immunotherapies relative to 
standard RECIST v1.1. 
3.4.4 
Rationale for Neoadjuvant Treatment in Melanoma in Cohort 1 
Neoadjuvant therapy has several potential advantages over adjuvant therapy, and could 
even be superior to adjuvant therapy in this patient population.  In particular, using 
neoadjuvant therapy could allow investigators to determine therapy efficacy in individual 
patients, which could guide the use of additional adjuvant therapy, if needed.  


 
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Neoadjuvant therapy could also reduce tumor burden before surgery, and the pathologic 
response data could be used as surrogate outcome markers for RFS and OS.  In the 
case of T-cell checkpoint blockade, neoadjuvant therapies could have a potentially 
significant advantage.  T-cell checkpoint-blocking antibodies enhance T-cell activation 
when an antigen is encountered.  Drug exposure during the time the major tumor mass 
is still present may therefore potentially induce a stronger and broader tumor-specific 
T-cell response (Blank et al. 2018).  Indeed, preclinical data provided support for the 
superior activity of T-cell checkpoint blockade when given before surgery (Liu et al. 
2016). 
Data from the recent OpACIN and OpACIN-neo studies show that two cycles of 
neoadjuvant ipilimumab plus nivolumab without additional adjuvant therapy induces 
durable RFS in more than 80% of patients, and further endorse pathologic response as 
a strong surrogate outcome marker for RFS (Rozeman et al. 2021). 
3.4.5 
Rationale for Pathologic Response Rate as Primary Endpoint 
in Cohort 1 
The pathologic response to neoadjuvant therapy is a surrogate endpoint of improved 
patient outcomes in the treatment of several cancer types.  The majority of neoadjuvant 
studies that are ongoing in melanoma are testing immunotherapy and use pathologic 
response as an endpoint (Mueller et al. 2021). 
Several studies, including OpACIN and OpACIN-neo, have shown that pathologic 
response appears to be a strong surrogate marker for long-term benefit.  A pooled 
analysis of the INMC confirmed that pathologic response strongly correlates with RFS 
and OS with neoadjuvant therapy in Stage III melanoma.  It is further reported that 
particularly with combination immunotherapy, any degree of pathologic response with 
immunotherapy is sufficient to confer excellent survival. 
Six neoadjuvant melanoma studies were conducted recently with BRAF/MEK-targeted 
therapy or PD-1-based immunotherapy, and demonstrated that neoadjuvant therapies 
achieve high pCR rates and RFS in Stage III melanoma.  In the pooled analysis, pCR 
occurred in 40% of patients:  47% with targeted therapy and 33% with immunotherapy 
(43% combination and 20% monotherapy).  pCR correlated with improved RFS (pCR 
2-year 89% vs. no pCR 50%, p  0.001) and OS (pCR 2-year OS 95% vs. no pCR 83%, 
p  0.027).  In patients achieving a pathologic response with immunotherapy, very few 
relapses were seen (2-year RFS 96%), and no patient had died from melanoma at time 
of the report.  With pCR from targeted therapy, the 2-year RFS was only 79%, and OS 
was only 91% (Menzies et al. 2021). 
3.4.6 
Rationale for Using Nivo  Ipi as Comparator in Cohort 1 
No standard of care exists for neoadjuvant treatment of resectable melanoma.  The 
highest pathologic response rates have been observed in Stage IV disease and in 
Stage III disease in the neoadjuvant setting with the combination of nivolumab and 


 
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ipilimumab (Menzies et al. 2021).  As pathologic response (especially pCR, but also 
near pCR) emerges as a potential surrogate endpoint for RFS benefit, the combination 
of nivolumab and ipilimumab was chosen as the active comparator for this study.  
In addition, given the positive data in several studies and the approval of the 
combination of nivolumab and ipilimumab for patients with advanced melanoma, this 
combination was considered to be the best comparator for the anticipated patient 
population in this study (Wolchok et al. 2013; Sznol et al. 2014).  Furthermore, a Phase 
III study with the objective of establishing nivolumab combined with ipilimumab as a 
standard of care option for neoadjuvant therapy is planned (NADINA Trial). 
The recommended dose for advanced melanoma is 1 mg/kg nivolumab and 3 mg/kg 
ipilimumab.  This study will use alternative dosing of 3 mg/kg nivolumab and 1 mg/kg 
ipilimumab because this dosing schedule induced a lower rate of immune-mediated 
toxicity in the OpACIN-neo study, and thus was identified as the optimal dosing regimen 
in the neoadjuvant setting (Rozeman et al. 2019). 
Randomized studies evaluating immunotherapy combinations will allow us to identify 
safe and effective neoadjuvant treatments for patients with resectable melanoma while 
also significantly increasing our understanding of cancer biology. 
3.4.7 
Rationale for Biomarker Assessments 
Blood samples for biomarker assessments will be collected at baseline and during the 
study.  Changes in biomarkers in blood may provide evidence of biologic activity of the 
specific treatments and treatment combinations.  Correlations between surrogate 
biomarkers in blood (such as tumor burden markers, cytokines, chemokines, immune 
cell subpopulations, gene expression, and ctDNA) and drug dose and efficacy and 
safety endpoints may allow for the development of a blood-based biomarker to help 
define future treatments and predict which patients are more likely to benefit from 
specific treatment combinations. 
Baseline tumor tissue samples will be collected from all patients (except patients in the 
Cohort 2 safety run-in phase) by biopsy at screening.  In addition, on-treatment tissue 
samples will be collected up to 72 hours prior to drug administration. If available, archival 
primary tumor tissue will be submitted from all patients. 
Tumor samples will be evaluated for biomarkers such as tumor-infiltrating immune cells, 
PD-L1, CD8, and expression of targets specific to each drug combination.  Evaluation of 
the tumor microenvironment in response to treatment within each arm, including 
changes in the number, locations, densities and functional status of tumor-infiltrating 
immune cells, could provide validation of the postulated mechanism-of-action, 
confirmation that an appropriate dose and exposure for the specific treatment 
combination have been achieved, and/or response prediction capacity.  Differences in 
biomarkers and lymphocyte infiltration in baseline primary tumor compared to metastasis 
may be assessed. 


 
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Tumor tissue and blood samples may be analyzed through use of NGS methods such as 
whole exome sequencing (WES) to identify somatic mutations that are predictive of 
response to study drug, are associated with progression to a more severe disease state, 
are associated with acquired resistance to study drug, are associated with susceptibility 
to developing adverse events, or can increase the knowledge and understanding of 
disease biology. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet all of the criteria outlined in Section 4.1.1.1 and Section 4.1.1.2 to 
qualify for Cohort 1.  Patients must meet all of the criteria outlined in Section 4.1.1.1 and 
Section 4.1.1.3 to qualify for Cohort 2. 
4.1.1.1 
Shared Inclusion Criteria for Cohort 1 and Cohort 2 
Patients must meet all of the following criteria to qualify for Cohort 1 and Cohort 2: 
 
Signed Informed Consent Form 
 
Age  18 years at the time of signing Informed Consent Form 
 
ECOG performance status (PS) of 0 or 1 
 
Ability to comply with the protocol, in the investigator’s judgment 
 
Availability of a representative tumor specimen that is suitable for biomarker testing 
via central laboratory 
Baseline tumor tissue samples will be collected from all patients (except 
patients in the Cohort 2 safety run-in phase) by biopsy of a metastatic lymph 
node (Cohort 1) or other metastatic lesion (Cohort 2) at screening. 
In addition, archival primary tumor tissue will be submitted from all patients.  
In exceptional cases where no archival primary tissue is available (e.g., for 
patients with unknown primary tumor), enrollment is permitted.  For archival 
tissue, a formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a 
paraffin block (preferred) with sufficient size and tumor content representation, 
preferably including the invasive margin, or, if available, at least 16 slides 
containing unstained, freshly cut, serial sections must be submitted along with 
an associated pathology report. 
Refer to Section 4.5.9 and to the laboratory manual for additional information on 
tumor specimens collected at screening. 


 
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 
Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 14 days prior to initiation of study treatment: 
– 
ANC  1.5  109/L (1500/L) 
– 
Lymphocyte count  0.5  109 cells/L (500/L) 
Borderline machine lymphocyte counts may be confirmed by a manual 
count. 
– 
Platelet count  100  109/L (100,000/L) 
– 
Hemoglobin  90 g/L (9 g/dL) 
– 
AST, ALT, and ALP  2.5   ULN with the following exceptions: 
For Cohort 2, patients with documented liver metastases: AST and ALT 
 5  ULN. 
For Cohort 2, patients with documented liver or bone metastasis: 
ALP  5  ULN. 
– 
Total bilirubin  1.5  ULN, with the following exception: 
Patients with known Gilbert disease:  bilirubin level  3  ULN 
– 
Creatinine 1.5  ULN or creatinine clearance  30 mL/min (calculated using the 
Cockcroft-Gault formula) 
– 
Serum albumin  25 g/L (2.5 g/dL) 
– 
For patients not receiving therapeutic anticoagulation:  INR and 
aPTT  1.5  ULN 
 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen (i.e., 
no new thrombosis, thromboembolic event, or bleeding episode within 3 months prior 
to study treatment start) 
 
Negative HIV test at screening, with the following exception:  Patients with a 
positive HIV test at screening are eligible provided they are stable on anti-retroviral 
therapy, have a CD4 count   200/L, and have an undetectable viral load. 
Patients without a prior positive HIV test result will undergo an HIV test at 
screening, unless not permitted per local regulations. 
 
Negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core 
antibody (HBcAb) test at screening.  If a patient has a negative hepatitis B surface 
antigen (HBsAg) test and a positive total HBcAb test at screening, an hepatitis B 
virus (HBV) DNA test must also be performed to rule out active HBV. 
 
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody 
test followed by a negative HCV RNA test at screening 
The HCV RNA test will be performed only for patients who have a positive 
HCV antibody test. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, as outlined for each 
specific treatment arm in Appendix 11 through Appendix 16. 


 
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 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
outlined for each specific treatment arm in Appendix 11 through Appendix 16. 
 
4.1.1.2 
Inclusion Criteria for Cohort 1 
Patients must meet all of the following criteria to qualify for Cohort 1: 
 
Histologically confirmed resectable Stage III melanoma (T:  T0, Tx or T14;  
N: cN13, pN1b/2b/3b; M: M0 according to AJCC-8 [Gershenwald et al. 2017]) and 
no history of in-transit metastases within the last 6 months 
Patients may present with primary melanoma with concurrent regional nodal 
metastasis, or a history of primary melanoma or unknown primary melanoma 
with clinically detected regional nodal recurrence, and may belong to any of the 
following groups: 
– 
Primary cutaneous melanoma with concurrent clinically/radiologically 
apparent regional lymph node metastases 
– 
Clinically/radiologically detected recurrent melanoma at the proximal 
regional lymph node(s) basin 
– 
Clinically/radiologically detected nodal melanoma (if single site) arising 
from an unknown primary 
 
Fit and planned for CLND (as assessed by surgeon prior to randomization 
according to local guidelines) 
 
Measurable disease (at least one target lesion) according to RECIST v1.1 
At least one macroscopic lymph node metastasis (measurable according to 
RECIST v1.1) to be biopsied. 
 
4.1.1.3 
Inclusion Criteria for Cohort 2 
Patients must meet all of the following criteria to qualify for Cohort 2: 
 
Life expectancy  3 months, as determined by the investigator 
 
Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to 
AJCC-8 (Gershenwald et al. 2017) 
 
Disease progression during or following at least one but no more than two lines of 
treatment for metastatic disease 
Up to two lines of CPI therapy (monotherapy or combination therapy) are 
allowed.  Patients with BRAF-mutant disease may have received an additional 
line of targeted therapy (either before, intermittent with, or after the CPI therapy), 
or may have received targeted therapy and CPI therapy concurrently as one 
combination treatment.  Patients with BRAF-mutant melanoma with rapidly 
progressive disease who have not been previously treated with approved 
targeted therapies are not eligible.  Patients who received adjuvant treatment 
with CPI therapy for localized melanoma require an additional line of CPI 
therapy in the metastatic setting.  Patients who relapse or systemically progress 


 
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during or within 6 months of completion of adjuvant therapy are eligible and do 
not require an additional line of CPI therapy. 
 
Measurable disease (at least one target lesion) according to RECIST v1.1 
At least one metastasis (measurable according to RECIST v1.1). 
 
4.1.2 
Exclusion Criteria 
Patients will be excluded from enrollment in specific arms if they meet any of the 
applicable criteria outlined in subsequent sections, as summarized by treatment arm in 
Table 5. 
Table 5 
Arm-Specific Exclusion Criteria 
Cohort 
Treatment Arm 
Applicable Exclusion Criteria 
1 
Nivo  Ipi (control) 
Sections 4.1.2.1 and 4.1.2.2 
 
RO7247669 2100 mg 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.4 
 
Atezo  Tira 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.5 
 
RO7247669 2100 mg  Tira 
Sections 4.1.2.1, 4.1.2.2, 4.1.2.4, and 4.1.2.5  
 
RO7247669 600 mg 
Sections 4.1.2.1, 4.1.2.2, and 4.1.2.4 
 
RO7247669 600 mg  Tira 
Sections 4.1.2.1, 4.1.2.2, 4.1.2.4, and 4.1.2.5 
2 
RO7247669 2100 mg  Tira 
Sections 4.1.2.1, 4.1.2.3, 4.1.2.4, and 4.1.2.5 
Atezo  atezolizumab; Ipi  ipilimumab; Nivo  nivolumab; Tira  tiragolumab. 
  
4.1.2.1 
Exclusion Criteria for Cohort 1 and Cohort 2 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Mucosal and uveal melanoma 
Acral lentiginous melanoma is excluded for Cohort 1. 
For Cohort 2, acral lentiginous melanoma is permitted; however, the proportion 
of patients should not exceed 20% of response-evaluable patients. 
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Treatment with systemic immunostimulatory agents (including, but not limited to, IFN 
and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to 
initiation of study treatment 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Known immunodeficiency or conditions requiring treatment with systemic 
immunosuppressive medication (including, but not limited to, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), or 
anticipation of need for systemic immunosuppressant medication during study 
treatment, with the following exceptions: 
Patients on replacement doses of corticosteroids to manage hypopituitary or 
adrenal insufficiency are eligible for the study. 


 
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Patients who received acute, low-dose, systemic immunosuppressant 
medications, 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 requiring chronic low-dose systemic corticosteroid 
treatment (i.e., a maximal dose of corticosteroids  10mg/day equivalent 
prednisone) are eligible. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during study treatment or within 
5 months after the final dose of study treatment 
 
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 7) 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 a stable 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. 
– 
There is 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. 
 
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.  Patients 
with a history of CIT-related pneumonitis Grade  2 are eligible. 
 
History of malignancy other than malignant melanoma within 2 years prior to 
screening, with the exception of malignancies with a negligible risk of metastasis or 
death (e.g., 5-year OS rate  90%), such as adequately treated carcinoma in situ of 
the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal 
carcinoma in situ, or Stage I uterine cancer 


 
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 
Active tuberculosis (TB) 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that, in the opinion of the investigator, could 
impact patient safety 
 
Treatment with therapeutic or prophylactic oral or IV antibiotics within 2 weeks prior 
to initiation of study treatment 
 
Significant cardiovascular disease such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction or cerebrovascular accident within 
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable 
angina 
 
Uncontrolled hypertension (defined as resting systolic blood pressure  150 mmHg 
and/or diastolic blood pressure  100 mmHg in two or more serial measurements) 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure other than 
CLND, during the study 
Placement of central venous access catheter (e.g., port or similar) is not 
considered a major surgical procedure and is therefore permitted. 
 
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, impair the ability of the patient to participate in the 
study, or may render the patient at high risk from treatment complications 
 
History of severe allergic reactions to chimeric or humanized antibodies or fusion 
proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies 
 
Known allergy or hypersensitivity to any of the study drugs or their excipients 
 
Known intolerance to any of the drugs required for premedication (acetaminophen, 
ranitidine, diphenhydramine, and methylprednisolone) 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 
Eligible only for the control arm 
 
4.1.2.2 
Exclusion Criteria for Cohort 1 
Patients who meet any of the following criteria will be excluded from Cohort 1: 
 
Distantly metastasized melanoma 
 
History of in-transit metastases within the last 6 months 
 
Prior radiotherapy 


 
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 
Prior immunotherapy, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic 
antibodies, and other systemic therapy for melanoma 
 
4.1.2.3 
Exclusion Criteria for Cohort 2 
Patients who meet any of the following criteria will be excluded from Cohort 2: 
 
Symptomatic, untreated, or progressing CNS metastases 
Asymptomatic patients with treated 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. 
– 
CNS metastases are stable for  4 weeks prior to initiation of study, or 
neurosurgical resection occurred   28 days prior to initiation of study 
treatment. 
– 
The patient has no requirement for corticosteroids as therapy for CNS 
disease for at least 14 days prior to initiation of study treatment. 
– 
Anti-convulsant therapy at a stable dose is permitted. 
 
Active or history of carcinomatous meningitis/leptomeningeal disease 
 
Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at screening. 
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. 
 
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. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium  ULN) 
 
Any history of an immune-mediated Grade 4 adverse event attributed to prior CIT 
(other than endocrinopathy managed with replacement therapy or asymptomatic 
elevation of serum amylase or lipase) that resulted in permanent discontinuation of 
the prior immunotherapeutic agent 


 
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 
All immune-mediated adverse events related to prior immunomodulatory therapy 
(other than endocrinopathy managed with replacement therapy or stable vitiligo) that 
have not resolved completely to baseline.  Patients treated with corticosteroids for 
immune-mediated adverse events, except for corticosteroids replacement therapy 
for adrenal insufficiency (provided that the patient receives   10 mg prednisone/day 
or equivalent), must not have related symptoms or signs for   4 weeks following 
discontinuation of corticosteroids 
 
Adverse events related to any prior radiotherapy, chemotherapy, targeted therapy, 
CPI therapy or surgical procedure must have resolved to Grade 1 or better, except 
alopecia (any grade), Grade 2 peripheral neuropathy, and hypothyroidism and/or 
hypopituitarism on a stable dosage of hormone replacement therapy (e.g., 
thyroxine, hydrocortisone, prednisolone, others) 
 
4.1.2.4 
Exclusion Criteria for RO7247669-Containing Arms 
(Cohort 1 and Cohort 2) 
Patients who meet any of the following criteria will be excluded from the 
RO7247669-containing arms: 
 
Prior treatment with an antiLAG-3 agent 
 
History of myocarditis (regardless of etiology) 
 
Left ventricular ejection fraction (LVEF)  50% assessed by either transthoracic 
echocardiogram (TTE) or multiple-gated acquisition (MUGA) scan (TTE preferred 
test) within 6 months prior to initiation of study treatment 
 
Troponin T (TnT) or troponin I (TnI)  institutional ULN 
Patients with TnT or TnI levels between  1 and  2  ULN are eligible if repeat 
levels within 24 hours are  1  ULN.  If repeat levels within 24 hours are 
between  1 and  2  ULN, patients need to undergo a cardiac evaluation and 
may be considered for treatment if there are no clinically significant findings. 
 
4.1.2.5 
Exclusion Criteria for Tiragolumab-Containing Arms (Cohort 1 
and Cohort 2) 
Patients who meet any of the following criteria will be excluded from the 
tiragolumab-containing arms: 
 
Prior treatment with an anti-TIGIT agent 
 
Acute Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV 
infection at screening 
Patients with a positive EBV viral capsid antigen (VCA) IgM test at screening are 
excluded from this arm.  An EBV PCR test should be performed as clinically 
indicated to screen for active infection or suspected chronic active infection.  
Patients with a positive EBV PCR test are excluded from this arm. 
 


 
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4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a randomized, open-label study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient’s 
identification number and treatment assignment from the interactive web-based 
response system (IxRS). 
For Cohort 1, this study will employ a permuted-block randomization method with 
dynamically changing randomization ratios to account for fluctuation in the number of 
treatment arms that are open for enrollment over the course of the study.  
The randomization ratio will depend on the number of experimental arms that are open 
for enrollment (e.g., if an arm is added or enrollment in an arm is suspended pending 
analysis of results from the preliminary phase), with the stipulation that the likelihood of 
being allocated to the control arm will be no more than 35%.  The randomization ratios 
may be altered to increase enrollment in a particular arm. 
Randomization will be stratified according to the following criteria: 
 
Geographic region:  Australia vs. Rest of the World 
 
Baseline LDH:   ULN vs.  ULN 
 
Randomization will take into account general exclusion criteria and arm-specific 
exclusion criteria as outlined in Section 4.1.2.  For example, the Atezo  Tira arm will be 
removed as an option for patients who are ineligible for that arm.  If a patient is only 
eligible for the control arm, that patient will not be enrolled in the study. 
For Cohort 2, patients will be assigned to receive treatment with 
RO7247669 2100 mg  Tira.  If additional treatment arms are opened at a later time, a 
permuted-block randomization method will be employed from this point forward. 
Patients who do not receive at least one dose of each drug for their assigned treatment 
regimen will not be included in the efficacy analyses.  Additional patients may be 
enrolled to reach the target number of treated patients planned for analysis. 
4.3 
STUDY TREATMENT 
Details on the therapeutic agents for each treatment arm are provided in the respective 
appendix for that treatment arm, as outlined in Table 4. 
4.3.1 
Investigational Medicinal Product Handling and Accountability 
The IMPs for this study are atezolizumab, tiragolumab, RO7247669, nivolumab, and 
ipilimumab.  Appendix 17 identifies all IMPs, non-investigational medicinal products, and 
auxiliary medicinal products for this study. 


 
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All IMPs required for completion of this study will be provided by the Sponsor where 
required by local regulations.  The study site (i.e., investigator or other authorized 
personnel [e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the 
site, IMP inventory at the site, IMP use by each patient, and disposition or return of 
unused IMP, thus enabling reconciliation of all IMP received, and for ensuring that 
patients are provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS 
to confirm the shipment condition and content.  Any damaged shipments will be 
replaced.  The investigator or designee must confirm that appropriate temperature 
conditions have been maintained during transit for all IMPs received and that any 
discrepancies have been reported and resolved before use of the IMPs.  All IMPs must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions, with access limited to the 
investigator and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor (if supplied by the 
Sponsor) with the appropriate documentation.  The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on a drug accountability log. 
Refer to the pharmacy manual and/or the applicable Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 
4.3.2 
Post-Trial Access to Study Treatment 
Currently, the Sponsor does not have any plans to provide study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing study treatments in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 


 
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4.4 
CONCOMITANT THERAPY AND PROHIBITED FOOD 
Details on concomitant therapy, prohibited food, and additional restrictions are provided 
in the respective appendix for each treatment arm (see Sections A11–4.2 [Nivo  Ipi], 
A12–4.2 [RO7247669 2100 mg], A13–4.2 [Atezo  Tira], and A14–4.2 
[RO7247669 2100 mg  Tira Cohorts 1 and 2], A15–4.2 [RO7247669 600 mg], and  
A16–4.2 [RO7247669 600 mg  Tira]). 
4.5 
STUDY ASSESSMENTS 
A schedule of activities to be performed during the study is provided for screening in 
Appendix 10 and for each treatment arm in Sections A11–6 (Nivo  Ipi), A12–6 
(RO7247669 2100 mg), A13–6 (Atezo  Tira), A14–6 (RO7247669 2100 mg  Tira 
Cohort 1), and A14–8 (RO7247669 2100 mg  Tira Cohort 2), A15–6 
(RO7247669 600 mg), and A16–6 (RO7247669 600 mg  Tira).  All activities must be 
performed and documented for each patient.  Patients will be closely monitored for 
safety and tolerability throughout the study.  Patients should be assessed for toxicity 
prior to each infusion; dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations) and may be 
obtained more than 28 days before initiation of study treatment.  Informed Consent 
Forms for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
Screening evaluations are to be performed within 28 days prior to initiation of study 
treatment (Day 1).  All screening evaluations must be completed and reviewed to 
confirm that patients meet all eligibility criteria before enrollment. 
Patients who fail their first screening for study eligibility may qualify for two re-screening 
opportunities (for a total of three screenings per patient) at the investigator’s discretion.  
Patients must re-sign the Informed Consent Form prior to re-screening. 
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within a specified time prior to Day 1 may be used as outlined in the 
schedule of activities (see Appendix 10 [screening], Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], A15–6 [RO7247669 600 mg], 
and A16–6 [RO7247669 600 mg  Tira]).  Such tests do not need to be repeated for 
screening or re-screening. 


 
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4.5.2 
Medical History, Molecular Profile, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, and smoking 
history, will be recorded at baseline.  The patient’s molecular profile for melanoma, if 
available, will be recorded at screening and whenever updated information becomes 
available during the study.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within a specified time prior to initiation of study 
treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.  Demographic data will include age, sex, and self-reported 
race/ethnicity. 
Refer to the schedule of activities for information about the timing of medical history, 
molecular profile, concomitant medication, and demographic data collection 
(Appendix 10 [screening], Sections A11–6 [Nivo  Ipi], A12–6 [RO7247669 2100 mg], 
A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira Cohort 1], A14–8 
[RO7247669 2100 mg  Tira Cohort 2], A15–6 [RO7247669 600 mg], and A16–6 
[RO7247669 600 mg  Tira]). 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include evaluations as per clinical practice (e.g., evaluations of the head, eyes, 
ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurologic systems).  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions electronic Case Report Form (eCRF). 
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes. 
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
Height will be recorded at screening.  Weight will be recorded at specified timepoints 
during the study. 
Refer to the schedule of activities for information about the timing of physical 
examinations (Appendix 10 [screening], Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], A15–6 [RO7247669 600 mg], 
and A16–6 [RO7247669 600 mg  Tira]). 


 
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4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, pulse oximetry, and 
temperature. 
Vital signs should be measured within 60 minutes prior to administration of each study 
treatment and, if clinically indicated, during or after treatment administration.  In addition, 
vital signs should be measured at other specified timepoints as outlined in the schedule 
of activities (see Appendix 10 [screening], Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], A15–6 [RO7247669 600 mg], 
and A16–6 [RO7247669 600 mg  Tira]). 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
4.5.5 
Electrocardiograms 
An ECG will be performed at screening, as clinically indicated, and as outlined in the 
schedules of activities (see Appendix 10 [screening], Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], A15–6 [RO7247669 600 mg], 
and A16–6 [RO7247669 600 mg  Tira]).  ECGs for each patient should be obtained 
from the same machine wherever possible.  Lead placement should be as consistent as 
possible.  It is recommended that patients be resting in a supine position for at least 
10 minutes prior to ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.6 
Evaluation of Left Ventricular Function 
Patients will undergo evaluation of LVEF, either by TTE or MUGA scan at screening and 
as outlined in the schedules of activities (see Appendix 10 [screening], Sections A11–6 
[Nivo  Ipi], A12–6 [RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 
[RO7247669 2100 mg  Tira Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], 
A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]).  Evaluation of 
LVEF must be performed using the same method for each patient.  TTE measurements 
should be performed by the same operator whenever possible, following the most recent 
echocardiography society guidelines.  Paper copies of reports will be kept as part of the 
patient’s permanent study file at the site. 


 
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4.5.7 
Tumor and Response Evaluations 
4.5.7.1 
Radiographic Procedures for Screening (Cohorts 1 and 2) 
All measurable and evaluable lesions should be assessed and documented at screening 
as outlined in the schedule of activities (Appendix 10).  Tumor assessments performed 
as standard of care prior to obtaining informed consent and within 28 days prior to 
randomization/enrollment do not have to be repeated at screening. 
Screening assessments must include CT scans (with oral and/or IV contrast) or 
magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis.  A spiral 
CT scan of the chest may be obtained but is not a requirement.  If a CT scan with 
contrast is contraindicated (i.e., in patients with contrast allergy or impaired renal 
clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the 
abdomen and pelvis should be performed.  A CT scan with contrast or MRI scan of the 
head with contrast must be done at screening to evaluate CNS metastasis in all patients 
(MRI scan must be performed if contrast is contraindicated).  Bone scans and CT or MRI 
scans of the neck should also be performed if clinically indicated.  At the investigator’s 
discretion, other methods of assessment of measurable disease may be used as per 
RECIST v1.1. 
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan.  The same radiographic procedures used to assess 
disease sites at screening should be used for subsequent tumor assessments (e.g., the 
same contrast protocol for CT scans). 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at 
subsequent tumor evaluations as outlined in Section 4.5.7.2 (Cohort 1) or 
Section 4.5.7.3 (Cohort 2).  The same radiographic procedures used to assess disease 
sites at screening should be used for subsequent tumor assessments (e.g., the same 
contrast protocol for CT scans). 
4.5.7.2 
Cohort 1 Tumor, Response, and Disease Status Evaluations 
Patients in Cohort 1 will be assessed for pathologic and radiologic response to 
treatment.  Patients will undergo pathological tumor assessments after 6 weeks of 
treatment at surgery (CLND).  The complete resection of Stage III lymph nodes (CLND) 
in Week 7 must be performed in compliance with the criteria for adequate surgical 
procedures for therapeutic lymph node dissection (see Appendix 4).  CLND should be 
performed as planned if the patient is receiving corticosteroids or other anti-inflammatory 
drugs for the management of immune-mediated adverse events, provided these are 
being given at a stable or tapering dose and the severity of adverse events is Grade 2 or 
better.  CLND may be delayed for up to 2 weeks if study treatment-related adverse 
events have not improved sufficiently at the time of planned surgery (see Section 3.1.3).  
Pathological response will be determined by local and independent pathologic review 
according to INMC guidelines (Tetzlaff et al. 2018; Appendix 3). 


 
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Patients will undergo radiographic tumor assessments at baseline and after 6 weeks of 
treatment before surgery (CLND) according to RECIST v1.1, as outlined for each arm in 
the schedules of activities (see Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]).  
At the treatment completion/discontinuation visit (Week 13), the disease status will be 
assessed by radiographic tumor assessments for the absence of recurrent disease.  
Tumor assessments that have been performed outside the protocol-mandated time 
window do not have to be repeated.  However, at the investigator’s discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected. 
Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  Available results must 
be reviewed by the investigator prior to treatment administration. 
Disease Follow-Up and Confirmation of Disease Progression or Recurrence 
During the neoadjuvant treatment, diagnosis of disease progression should be confirmed 
by clinical, laboratory, radiological, and/or histological findings.  After surgery, prior to 
commencing adjuvant treatment or observation, the first planned tumor assessment will 
be performed in Week 13 to conclude the neoadjuvant therapy-surgery intervention 
window and should include a CT scan.  After the treatment phase, during the follow-up 
phase, all patients must be followed to assess disease recurrence and survival as 
outlined for each arm in the schedules of activities (see Sections A11–6 [Nivo  Ipi],  
A12–6 [RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]).  
Tumor assessments that have been performed outside the protocol-mandated time 
window do not have to be repeated.  However, at the investigator’s discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected. 
The designation of disease recurrence, whether local, regional, or distant, can be made 
only when clinical, laboratory, radiological and/or histological findings confirm the 
diagnosis. 
During the post-surgery period, disease status should be clinically evaluated and 
documented every 3 months for the first 2 years; every 6 months in the third year and 
annually thereafter until a diagnosis of a recurrence (defined below).  In addition to 
physical examinations, liver function tests, bone scans, chest X-ray/diagnostic CT scan, 
liver imaging, and/or other radiographic modalities may be considered when clinically 
indicated to exclude metastatic disease within timelines as per current local standard of 
practice. 
The diagnosis of a progression or recurrence should be confirmed histologically 
whenever clinically possible.  The earliest date of diagnosis of disease progression or 


 
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recurrent disease should be used and recorded.  This date should be based on objective 
clinical, radiological, histological, or cytological evidence.  Recurrent disease includes 
local, regional, or distant recurrence:  local recurrence is defined as tumor regrowth 
within 2 cm of the primary lesion’s tumor bed; regional recurrence as any nodal or 
non-nodal tumor lesions that are more than 2 cm from the primary lesion but are not 
beyond the regional nodal basin; distant recurrence as any non-local/non-regional 
recurrence. 
The definitions of and procedures for confirming disease recurrence, death, and other 
noteworthy events on follow-up are provided below.  Documentation of recurrence will 
require specification of all sites involved to establish the pattern of recurrence.  
The following criteria of treatment failure constitute the only acceptable evidence of 
disease recurrence: 
 
Lung:  Positive cytology or biopsy in the presence of a single new lesion or the 
appearance of multiple lesions consistent with metastatic disease 
 
Liver:  Positive cytology or biopsy in the presence of a single new lesion or the 
appearance of multiple lesions consistent with metastatic disease 
 
Central nervous system:  A positive brain CT or MRI scan or CSF cytology 
 
Cutaneous, subcutaneous, and lymph node recurrence:  Positive cytology or biopsy 
in the presence of a single new lesion or the appearance of multiple lesions 
consistent with metastatic disease 
 
Bone and other organs:  Positive cytology or biopsy in the presence of a single new 
lesion or the appearance of multiple lesions consistent with metastatic disease 
identified on two different radiologic studies (i.e., positive nuclear bone scan or PET 
scan and contrast GI series or ultrasound, X-ray or CT of abdomen for abdominal 
disease) 
 
4.5.7.3 
Cohort 2 Tumor and Response Evaluations 
Patients in Cohort 2 will undergo tumor assessments every 9 ( 1) weeks (from Day 1 of 
Cycle 1) for the first 54 weeks and then every 12 ( 2) weeks thereafter, regardless of 
dose delays, as outlined in the schedule of activities (see Section A14–8 
[RO7247669 2100 mg  Tira Cohort 2]).  The exception is patients who continue 
treatment after radiographic disease progression.  Such patients will undergo tumor 
assessments every 9 weeks until loss of clinical benefit as determined by the 
investigator (see Section 3.1.2 for details).  Thus, tumor assessments are to continue 
according to schedule in patients who discontinue treatment for reasons other than loss 
of clinical benefit, even if they start new, nonprotocol-specified anti-cancer therapy.  
Tumor assessments that have been performed outside the protocol-mandated time 
window do not have to be repeated.  However, at the investigator’s discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected. 
Brain metastases treated with radiotherapy or surgery will not be considered measurable 
or evaluable but will be documented at screening as a site of metastatic disease.  Brain 


 
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metastases identified at baseline that have been treated with radiotherapy or surgery will 
not be considered measurable or evaluable unless there is suspected disease 
progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent 
head scans are not required unless clinically indicated. 
To facilitate evaluation of response per iRECIST in Cohort 2, tumor assessments must 
be continued after disease progression per RECIST v1.1 for patients who receive 
treatment beyond progression.  This includes continued measurement of target lesions, 
evaluation of non-target lesions (including monitoring for further worsening of any 
non-target lesions that have shown unequivocal progression), and evaluation of any 
newly identified lesions (including measurements, if lesions are measurable; see 
Appendix 1) at all subsequent assessments. 
Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  Available results must 
be reviewed by the investigator prior to treatment administration. 
Overall response per iRECIST (see Appendix 2) will not be captured in the eCRF, but 
will instead be calculated programmatically by the Sponsor on the basis of 
investigator-assessed individual lesion data recorded in the eCRF. 
4.5.8 
Classification of Surgical Complications 
Surgical complications will be scored according to Clavien-Dindo classification 
(Appendix 5).  Complication rates for every grade will be reported and scored for 
patients that underwent CLND, as outlined for each arm in the schedules of activities 
(see Sections A11–6 [Nivo  Ipi], A12–6 [RO7247669 2100 mg], A13–6 [Atezo  Tira],  
A14–6 [RO7247669 2100 mg  Tira Cohort 1], A15–6 [RO7247669 600 mg], and A16–6 
[RO7247669 600 mg  Tira]). 
4.5.9 
Laboratory, Biomarker, and Other Biological Samples 
4.5.9.1 
Local Laboratory Assessments 
For information about the timing of local laboratory assessments, please refer to the 
schedule of activities for screening (Appendix 10) or the appropriate treatment arm 
(Sections A11–6 [Nivo  Ipi], A12–6 [RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 
[RO7247669 2100 mg  Tira Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], 
A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]). 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
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 
Chemistry panel (serum or plasma):  includes sodium, potassium, magnesium, 
chloride, bicarbonate or total carbon dioxide (if considered standard of care in the 
region), glucose, BUN or urea, creatinine, total protein, ferritin, albumin, phosphate, 
calcium, total bilirubin, ALP, ALT, AST, amylase, lipase, and LDH.  In addition, 
adrenocorticotropic hormone (ACTH), cortisol, S100, and erythrocyte sedimentation 
rate (ESR) will be assessed at screening and pre-surgery visits for patients enrolled 
in Cohort 1. 
 
Lipid panel:  includes triglycerides, HDL, and LDL 
 
Coagulation:  INR and aPTT 
 
Thyroid function testing:  TSH, free T3 (or total T3 for sites where free T3 is not 
performed), and free T4 
 
Cardiac enzymes:  troponin I or T 
 
C-reactive protein 
 
HIV serology, unless not permitted per local regulations 
 
HBV serology:  hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), total hepatitis B core antibody (HBcAb), and (if HBsAg test is negative and 
total HBcAb test is positive) HBV DNA 
If a patient has a negative HBsAg test and a positive total HBcAb test at 
screening, an HBV DNA test must also be performed to determine if the patient 
has an HBV infection. 
 
HCV serology:  HCV antibody and (if HCV antibody test is positive) HCV RNA 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
 
EBV serology: 
– 
EBV VCA IgM 
– 
EBV VCA IgG or Epstein-Barr nuclear antigen (EBNA) IgG 
– 
EBV PCR (only if clinically indicated) 
 
Cytomegalovirus (CMV) serology: CMV IgM and IgG 
If a patient has a positive CMV IgM test or  4  ULN increase in CMV IgG, 
quantitative PCR should used to determine if the patient has a CMV infection. 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.  Pregnancy tests will also be performed at treatment 
completion/discontinuation at Week 13 and during follow-up at 6 months in 
Cohort 1, and at 3 and 6 months in Cohort 2. 


 
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A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted 
4.5.9.2 
Central Laboratory Assessments 
For information about the timing of central laboratory assessments, please refer to the 
schedule of activities for screening (Appendix 10) or the appropriate treatment arm 
(Sections A11–6 [Nivo  Ipi], A12–6 [RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 
[RO7247669 2100 mg  Tira Cohort 1], A14–8 [RO7247669 2100 mg  Tira Cohort 2], 
A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]). 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum sample for analysis of autoantibodies:  antinuclear antibody, 
antidouble-stranded DNA, circulating antineutrophil cytoplasmic antibody, and 
perinuclear antineutrophil cytoplasmic antibody 
 
Serum samples for PK analysis through use of validated assays 
 
Serum samples for immunogenicity analysis through use of validated assays 
 
Plasma and blood for exploratory research on biomarkers including blood-based 
NGS/WES ctDNA assay to determine tumor-specific alterations 
 
Archival tumor tissue sample for exploratory research on biomarkers 
An archival primary tumor tissue sample, preferably as a FFPE tumor tissue 
block with representation and sufficient tumor content, including the invasive 
margin (preferred), or, if available, at least 16 slides containing unstained, 
freshly cut, serial sections, must be submitted along with an associated 
pathology report.  For the Cohort 2 safety run-in phase, submission of an 
archival sample is preferred, but patients are eligible for the study if no archival 
sample is available.  Remaining archival tumor tissue blocks will be returned to 
the site upon request or 18 months after final closure of the study database, 
whichever occurs first. 
 
Fresh baseline and on-treatment tumor tissue for exploratory research on 
biomarkers 
Baseline tumor tissue samples will be collected from all patients (except 
patients in the Cohort 2 safety run-in phase) by biopsy of a metastatic lymph 
node (Cohort 1) or other metastatic lesion (Cohort 2) at screening.  For patients 
in Cohort 1, on-treatment tissue samples will be collected by biopsy on Day 1 of 
Cycle 2 (up to 72 hours prior to drug administration), and at surgery (CLND).  
For patients enrolled in Cohort 2, on-treatment tissue samples will be collected 




 
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lavage samples are not acceptable.  Tumor tissue from bone metastases that have been 
decalcified is not acceptable. 
Exploratory biomarker research may include, but will not be limited to, analysis of genes 
or gene signatures associated with tumor immunobiology, PD-L1, lymphocyte 
subpopulations and their functional and/or activation status, T-cell receptor repertoire, 
or cytokines associated with T-cell activation.  Research may involve extraction of DNA, 
cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, and 
other genomic variants; and genomic profiling through use of NGS of a comprehensive 
panel of genes.  DNA extracted from blood may be compared with DNA extracted from 
tissue to identify somatic variants by distinguishing germline variants from somatic 
variants.  NGS methods may include whole genome sequencing (WGS) or WES of 
tissue and blood samples, but WGS or WES of blood samples will be performed only at 
participating sites (see Section 4.5.10). 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biologic samples will be destroyed no 
later than the time of completion of the final Clinical Study Report (CSR), with the 
following exceptions: 
 
Serum and plasma samples collected for PK analysis or immunogenicity analysis 
may be needed for additional immunogenicity characterization and PK and 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final CSR has been completed. 
 
Blood, plasma, peripheral blood mononuclear cell (PBMC), and tumor tissue 
collected for biomarker research will be destroyed no later than 5 years after the final 
CSR has been completed, with the exception of the samples that undergo WES, 
which will be stored until they are no longer needed or until they are exhausted.  
However, the storage period for the WES samples will be in accordance with the 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements). 
 
For enrolled patients, remaining archival tissue blocks will be returned to the site 
upon request or no later than the time of final closure of the study database, 
whichever occurs first.  For patients who are not enrolled, remaining archival tissue 
blocks will be returned to the site no later than 6 weeks after eligibility determination. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 


 
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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
Given the complexity and exploratory nature of biomarker analyses, data derived from 
these analyses will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with acquired 
resistance to study drug, are associated with susceptibility to develop adverse events, 
can lead to improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  DNA extracted from 
blood may be compared with DNA extracted from tissue to identify somatic variants by 
distinguishing germline variants from somatic variants.  The samples may be sent to one 
or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.10) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
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The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to provide optional biopsies. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Optional Biopsy 
Sample Informed Consent eCRF. 
Samples may be used for exploratory biomarker research as described in Section 4.5.9.  
Refer to Section 4.5.9 for details on sample storage, use of samples after patient 
withdrawal, confidentiality standards for data, and availability of data derived from 
biomarker analyses. 
4.5.12 
Optional Samples for Research Biosample Repository 
4.5.12.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of biomarker assays, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker assays and establish the performance characteristics of these 
assays 
 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.12) 
will not be applicable at that site. 


 
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4.5.12.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to CIT, diseases, or drug 
safety: 
 
Leftover blood, serum, plasma, PBMC, and tumor tissue samples (with the exception 
of leftover tissue from archival FFPE blocks, which will be returned to sites) and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides) collected during the study, 
including leftover tissue samples from additional tumor biopsies or medically 
indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, 
colonoscopy) performed at the investigator's discretion 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.12.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 


 
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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. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent from the RBR at any time for any reason.  After withdrawal of consent, any 
remaining samples will be destroyed or will no longer be linked to the patient.  However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her samples, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the site, the investigator must 
inform the Sponsor by emailing the study number and patient number to the following 
email address: 
global.rcr-withdrawal@roche.com  


 
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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from this study. 
4.5.12.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Use of another nonprotocol-specified anti-cancer therapy 
 
Pregnancy 
 
Cohort 1:  Confirmed disease progression or dissemination prior to surgery.  Patients 
who discontinue study treatment early because of an unacceptable toxicity should 
continue to be followed for both resolution of toxicity and disease recurrence as 
outlined in the schedule of activities (Sections A11–6 [Nivo  Ipi], A12–6 
[RO7247669 2100 mg], A13–6 [Atezo  Tira], A14–6 [RO7247669 2100 mg  Tira 
Cohort 1], A15–6 [RO7247669 600 mg], and A16–6 [RO7247669 600 mg  Tira]). 
 
Cohort 2:  Loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results 
(if available), and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease) (see Section 3.1.2 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 


 
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For Cohort 1, regardless of whether they complete the study drug treatment period or 
discontinue study drug prematurely, patients who proceed to surgery  will return to the 
clinic for a treatment completion/discontinuation visit 6 weeks after surgery and patients 
who do not proceed to surgery will return to the clinic for a treatment 
completion/discontinuation visit not more than 30 days after the final dose of study 
treatment.  For patients who progress or have loss of clinical benefit, the visit at which 
response assessment shows progressive disease or loss of clinical benefit may be used 
as the treatment discontinuation visit.  
For Cohort 2, patients who discontinue study treatment for any reason other than 
progressive disease or loss of clinical benefit will continue to undergo tumor response 
assessments as outlined in the schedule of activities (see A14–8). 
Information on long-term follow-up and new anti-cancer therapy (including targeted 
therapy and immunotherapy) will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months until death (unless the patient 
withdraws consent or the Sponsor terminates the study).  If a patient requests to be 
withdrawn from follow-up, this request must be documented in the source documents 
and signed by the investigator.  If the patient withdraws from study, the study staff may 
use a public information source (e.g., country records) to obtain information about 
survival status only. For an experimental arm in which all patients discontinued treatment 
and passed the safety follow-up window, as well as approximately 80% of patients 
discontinued the study, the Sponsor may conclude the arm (the remaining ~20% of 
patients will be discontinued from the study). 
4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  Patients who withdraw from the 
study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., country records) to obtain information about survival status. 


 
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4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
A safety plan for each treatment arm, including a summary of risks and management 
guidelines for patients who experience specific adverse events, is provided in the 
respective appendix for that treatment arm in Appendix 11 through Appendix 16. 
Patients with active infection are excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient 
develops suspected CRS during the study, a differential diagnosis should include 
SARS-CoV-2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
investigator judgment.  If a diagnosis of SARS-CoV-2 infectionis confirmed, the disease 
should be managed as per local or institutional guidelines. 


 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions) 


 
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 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for each 
treatment arm are listed in the respective appendix for that treatment arm 
(see Appendix 11 through Appendix 16). 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.3.5.125.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Events Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 


 
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After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 135 days after the final dose of study treatment 
or until initiation of new systemic anti-cancer therapy, whichever occurs first. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for 
assessing adverse event severity.  Table 8  will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 8 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  
The ASTCT CRS Consensus Grading Scale (see Table 9 ) should be used in addition to 
NCI CTCAE when reporting severity of CRS (see Section 5.3.5.1 for details on CRS 
reporting). 


 
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Table 9 
ASTCT CRS Consensus Grading Scale 
Grade 
Symptom(s) 
1 
 
Fever a, with or without constitutional symptoms 
 
No hypotension 
 
No hypoxia 
2 
 
Fever a combined with at least one of the following: 
 Hypotension not requiring vasopressors 
 Hypoxia requiring low-flow oxygen b by nasal cannula or blow-by 
3 
 
Fever a combined with at least one of the following: 
 Hypotension requiring one vasopressor, with or without vasopressin 
 Hypoxia requiring high-flow oxygen b by nasal cannula, face mask, 
non-rebreather mask, or Venturi mask 
4 
 
Fever a combined with at least one of the following: 
 Hypotension requiring multiple vasopressors (excluding vasopressin) 
 Hypoxia requiring oxygen by positive pressure (e.g., CPAP, BiPAP, 
intubation, and mechanical ventilation) 
5 
 
Death due to CRS for which the cause is not the principal factor leading 
to this outcome 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level positive 
airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine-release 
syndrome. 
a Fever is defined as temperature  38C not attributable to any other cause.  In patients who 
develop CRS and then receive antipyretic, anticytokine, or corticosteroid therapy, fever is no 
longer required when determining CRS severity (grade).  In this case, the CRS grade is 
driven by the presence of hypotension and/or hypoxia. 
b Low flow is defined as oxygen delivered at  6 mL/min, and high flow is defined as  6 L/min. 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 10): 
 
Temporal relationship of event onset to the initiation of study treatment 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment (as 
applicable) 
 
Known association of the event with study treatment or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 


 
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 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
  
Table 10 Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions and Cytokine-Release Syndrome 
There may be significant overlap in signs and symptoms of infusion-related reactions 
(IRRs) and 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, hemophagocytic lymphohistiocytosis (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 


 
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dedicated Infusion-Related Reaction eCRF or Cytokine-Release Syndrome eCRF, as 
appropriate. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF or Cytokine-Release Syndrome eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 9, and guidelines for management of IRRs in the RO7247669 arms are 
provided in Appendix 12 and Appendix 15. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 


 
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5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 


 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  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 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 


 
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5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of disease should be recorded on the Death 
Attributed to Progressive Disease eCRF.  All other deaths that occur during the adverse 
event reporting period, regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Melanoma 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  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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5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug 
 
In some cases, a medication error may be intercepted prior to administration of the 
drug 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 


 
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 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For atezolizumab, tiragolumab, and RO7247669, adverse 
events associated with special situations should be recorded as described below for 
each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with atezolizumab, tiragolumab, and 
RO7247669, regardless of whether they result in an adverse event, should be recorded 
on the Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 


 
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 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 


 
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 
Pregnancies (see arm-specific appendices for details on pregnancy reporting 
requirements for each treatment arm) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will continue to be reported until 135 days after the final dose of study treatment 
or until initiation of new systemic anti-cancer therapy, whichever occurs first.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 


 
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fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 135 days after the final dose of study treatment or until 
initiation of new, systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF. 
After the end of the reporting period for non-serious adverse events (defined as 30 days 
after the final dose of study treatment), all treatment-related non-serious adverse events 
that lead to surgery delay will continue to be reported until 135 days after the final 
dose of study treatment. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 


 
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faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
 
Opdivo EMA Summary of Product Characteristics (SmPC; nivolumab) 
 
Yervoy EMA SmPC (ipilimumab) 
 
RO7247669 Investigator's Brochure 
 
Atezolizumab Investigator's Brochure 
 
Tiragolumab Investigator's Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The final study analysis will be based on patient data collected through study 
discontinuation.  If not otherwise specified, efficacy analyses will be based on the 
efficacy-evaluable population, defined as all patients who receive at least one dose of 
each drug for their assigned treatment regimen, and safety analyses will be based on 
the safety-evaluable population, defined as all patients who receive any amount of study 
treatment. 
The analysis results will be summarized by the treatment that patients actually receive.  
Data will be described and summarized as warranted by sample size.  Continuous 
variables will be summarized through use of means, standard deviations, medians, and 
ranges.  Categorical variables will be summarized through use of counts and 
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6.1 
DETERMINATION OF SAMPLE SIZE 
This study is not designed to make explicit power and type I error considerations for a 
hypothesis test.  Instead, this study is designed to obtain preliminary efficacy, safety, 
and PK data on treatments or treatment combinations when administered to patients 
with melanoma.  Cohort 1 will consist of patients with resectable Stage III melanoma 
who have not received prior systemic therapy for their disease.  Cohort 2 will consist of 
patients with Stage IV melanoma who experienced disease progression during or after 
at least one but not more than two lines of treatment for metastatic disease. 
In Cohort 1, approximately 195290 patients will be randomly allocated to the control 
and experimental arms during the study (3550 patients to the control arm and 
2060 patients to each experimental arm).  In Cohort 2, approximately 846 patients will 
be assigned to an experimental arm.  Please refer to Table 4 for further details. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment will be summarized by region, country, and investigator by treatment arm.  
Patient disposition will be summarized by treatment arm.  Major protocol deviations, 
including major deviations with regard to the inclusion and exclusion criteria, will be 
summarized by treatment arm. 
For safety-evaluable patients, study drug administration data will be tabulated or listed 
by treatment arm, and any dose modifications will be flagged.  Means and standard 
deviations will be used to summarize the total dose and dose intensity for each study 
drug.  Reasons for discontinuation of study drugs will also be tabulated. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND 
BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, weight, 
malignancy duration, metastatic disease site [if applicable], and baseline ECOG PS) will 
be summarized overall and by treatment arm. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint in Cohort 1 
The primary efficacy endpoint in Cohort 1 is pRR at time of surgery.  pRR will be 
assessed after completion of neoadjuvant treatment (Week 7) at time of CLND.  
The pRR is defined as the proportion of patients who achieve pCR (a complete absence 
of viable tumor in the treated tumor bed), pathologic near complete response 
(pnCR;  10% of viable tumor in the treated tumor bed); and pathologic partial response 
(pPR;  50% of the treated tumor bed is occupied by viable tumor cells) as determined 
by independent pathologic review.  Patients with missing or no pathologic response 
assessment, including patients who do not proceed to CLND, will be classified as 
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pRR will be calculated for each arm along with 95% CIs (Clopper-Pearson method).  
The difference in pRR between the experimental arms and the control arm will also be 
calculated, along with 95% CIs using the Wald method with continuity correction. 
6.4.2 
Secondary Efficacy Endpoints in Cohort 1 
The secondary efficacy endpoints in Cohort 1 are pRR at time of surgery as determined 
by local pathologic assessment, event-free survival (EFS), RFS, OS, and ORR prior to 
surgery.  pRR is defined in Section 6.4.1. 
EFS is defined as the time from randomization to any of the following events (whichever 
occurs first):  disease progression that precludes surgery, as assessed by the 
investigator according to RECIST v1.1 (see Section 4.5.7); local, regional, or distant 
disease recurrence; or death from any cause.  Patients who have not experienced such 
events will be censored at the time of their last post-tumor tumor assessment. 
RFS is defined as the time from surgery to the first documented recurrence of disease or 
death from any cause.  For patients who do not have documented recurrence of disease 
or death, RFS will be censored at the day of the last tumor assessment. 
OS is defined as the time from randomization to death from any cause.  Patients who 
are still alive at the time of OS analysis will be censored at the last date they were known 
to be alive. 
The Kaplan-Meier method will be used to estimate the median for RFS, EFS, and OS, 
95% CIs will be constructed using the Brookmeyer and Crowley method.  The RFS, 
EFS, and OS rate at specific timepoints will also be estimated using the Kaplan-Meier 
method, with 95% CIs calculated on the basis of Greenwood’s estimate for the variance. 
The ORR according to RECIST v1.1 will be assessed after completion of neoadjuvant 
treatment (Week 7) and is defined as the proportion of patients with a CR or PR, as 
determined by the investigator according to RECIST v1.1.  Patients with missing or no 
response assessments will be classified as non-responders.  Note that ORR will be 
determined using unconfirmed pre-operative radiologic responses.  Although RECIST 
v1.1 requires confirmatory imaging assessments to be completed at least 4 weeks after 
the initial response, due to the timing of CLND, these responses cannot be confirmed 
with subsequent imaging. 
ORR will be calculated for each arm, along with 95% CIs (ClopperPearson method).  
The difference in ORR between the experimental arms and the control arm will also be 
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6.4.3 
Exploratory Efficacy Endpoints in Cohort 1 
The exploratory efficacy endpoints in Cohort 1 are landmark EFS, landmark RFS, and 
landmark OS at specific timepoints (1, 2, 3, and 5 years).  RFS, EFS, and OS are 
defined in Section 6.4.2. 
Landmark EFS rates, landmark RFS rates, and landmark OS rates will be estimated for 
each study arm using the Kaplan-Meier method, with 95% CIs calculated through use of 
Greenwood’s formula. 
6.4.4 
Primary Efficacy Endpoint in Cohort 2 
The primary efficacy endpoint in Cohort 2 is ORR, as defined in Section 2 (see Table 3).  
ORR is determined by the investigator according to RECIST v1.1.  Patients with missing 
or no response assessments will be classified as non-responders. 
ORR, the proportion of patients with a complete or partial response, will be calculated for 
each arm, along with 95% CIs (ClopperPearson method). 
6.4.5 
Secondary Efficacy Endpoints in Cohort 2 
The secondary efficacy endpoints in Cohort 2 are PFS, OS, OS at specific timepoints 
(e.g., 6 months), duration of response (DOR), and disease control, as defined in 
Section 2 (see Table 3).  PFS, DOR, and disease control are determined by the 
investigator according to RECIST v1.1. 
DOR will be derived for efficacy-evaluable patients with a CR or PR. 
For patients who do not have documented disease progression or death, PFS and DOR 
will be censored at the day of the last tumor assessment. 
Patients who are still alive at the time of OS analysis will be censored at the last date 
they were known to be alive. 
The Kaplan-Meier method will be used to estimate the median for PFS, OS, and DOR, 
with 95% CIs constructed through use of the Brookmeyer and Crowley method.  OS rate 
at specific timepoints will also be estimated using the Kaplan-Meier method, with 
95% CIs calculated on the basis of Greenwood’s estimate for the variance. 
Disease control rate (the proportion of patients with SD for  12 weeks), a PR, or a CR, 
will be calculated for each treatment arm, with 95% CIs estimated through use of 
Clopper-Pearson’s exact method. 
6.4.6 
Exploratory Efficacy Endpoints in Cohort 2 
The exploratory efficacy endpoints are ORR, PFS, DOR, and disease control as 
determined by the investigator according to iRECIST (see Appendix 2). 


 
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ORR, PFS, DOR, and disease control will be analyzed through use of the same methods 
described in Sections 6.4.4 and Section 6.4.5.  DOR will be derived for 
efficacy-evaluable patients with a CR or PR.  
6.5 
SAFETY ANALYSES 
Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to NCI 
CTCAE v5.0 and also according to the ASTCT CRS Consensus Grading Scale for CRS. 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs and ECGs, and exposure to study drugs.  Exposure to 
combination treatment and length of safety follow-up will be summarized by treatment 
arm. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms.  Adverse event severity will be graded according to 
NCI CTCAE v5.0, and severity of CRS will also be graded by the investigator according 
to the ASTCT Consensus Grading (Lee et al. 2019).  All adverse events, serious 
adverse events, adverse events leading to death, adverse events of special interest, and 
adverse events leading to study treatment discontinuation that occur on or after the first 
dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, and severity grade.  For events of varying 
severity, the highest grade will be used in the summaries.  Deaths and causes of death 
will be summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory test results 
will be used to summarize the baseline and maximum postbaseline severity grade.  
Changes in vital signs and ECGs will be summarized. 
Additionally, in Cohort 1, the incidence, nature of immune-related adverse events 
Grade  3 during the first 12 weeks, and the rate and duration of delayed surgery due to 
treatment-related adverse events will be summarized by treatment arm.  CLND may be 
delayed for up to 2 weeks if study treatment-related adverse events have not improved 
sufficiently at the time of planned surgery (see Section 3.1.3). 
Additionally, surgical complications will be scored according to Clavien-Dindo 
classification (Appendix 5).  Complication rates for every grade will be reported and 
scored for patients that underwent CLND. 
6.6 
PHARMACOKINETIC ANALYSES 
Sparse samples will be collected for PK analyses of atezolizumab (patients who receive 
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combination with atezolizumab (patients who receive at least one dose of the drug).  
Serum or plasma concentrations of the various study drugs will be reported as individual 
values and summarized (mean, standard deviation, coefficient of variation, median, 
range, geometric mean, and geometric mean coefficient of variation) by treatment arm 
and by cycle and day when appropriate and as data allow.  Individual and median serum 
or plasma concentrations of the various study drugs will be plotted by treatment arm and 
cycle and day.  PK data for combination drugs may be compared with available historical 
data from internal and published previous studies.  Atezolizumab or other study drug 
concentration data may be pooled with data from other studies using an established 
population PK model to derive PK parameters such as clearance, volume of distribution, 
and area under the curve. 
The relationship between PK parameters and safety, efficacy, PK, and biomarker 
endpoints may be analyzed and reported via descriptive statistics. 
6.7 
IMMUNOGENICITY ANALYSES 
Immunogenicity may be assessed for atezolizumab and other study treatments as 
appropriate (refer to arm-specific appendices for details).  The immunogenicity analyses 
will include all patients with at least one anti-drug antibody (ADA) assessment.  Patients 
will be grouped according to treatment received or, if no treatment is received prior to 
study discontinuation, according to treatment assigned. 
For atezolizumab, the numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after drug administration 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60-titer unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60-titer 
unit greater than the titer of the baseline sample (treatment unaffected). 
For other study treatments where ADA is tested, positivity will be determined according 
to standard methods established in previous studies of that drug. 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported via descriptive statistics. 


 
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6.8 
BIOMARKER ANALYSES 
Exploratory biomarker analyses will be performed in an effort to understand the 
association of these biomarkers with response to study drugs, taking into account 
efficacy and safety endpoints (see Section 4.5.9 for more details). 
6.9 
INTERIM ANALYSES 
Given the exploratory nature of this study, it is anticipated that interim analyses will be 
conducted during the study, with the earliest interim analysis taking place when at least 
one experimental arm has completed enrollment in the preliminary phase, and patients 
have completed their pathologic response assessment (Cohort 1), or when at least one 
experimental arm has completed enrollment in the preliminary phase and patients have 
been followed for a minimum of 9 weeks for the primary endpoint analysis (ORR) 
(Cohort 2).  Further interim analyses may be conducted as deemed appropriate by 
Sponsor.  In Cohort 1, a posterior probability may be used to guide further enrollment 
based on the interim analysis of clinical activity in the experimental arm compared with 
the control arm.  If the interim analysis suggests that the activity in an experimental arm 
is higher than that in the control arm, for example, the posterior probability of having a 
pRR improvement (e.g., 10%) is greater than a threshold (e.g., 70% confidence level), 
there may be further enrollment of 20 additional patients in the experimental arm 
(expansion phase). 
In Cohort 2, a posterior probability may be used to guide further enrollment in a 
treatment arm based on an interim analysis of clinical activity in the experimental arm 
compared with a predefined ORR threshold, defined as an improvement over standard 
of care.  For example, if available data suggest a standard of care ORR of 10%, and an 
ORR improvement of 10% is considered to be a clinical meaningful change, this would 
lead to an ORR threshold of 20% in the calculation of the posterior probability. 
The ORR for standard of care treatment will be based on emerging internal and external 
data for in-class immune-modulating investigational and other compounds for the patient 
population in Cohort 2 who have received at least two lines of prior treatment at the time 
of the analysis. 
The Sponsor may make a decision to expand enrollment in an arm based on the totality 
of available data including, but not limited to, duration of the observed responses, PFS, 
and potentially early OS data.  Safety and biomarker data (available at the time of 
making this decision) will also be taken into consideration from the perspective of an 
adequate benefit-risk assessment. 
The interim analyses will be performed and interpreted by Sponsor study team 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMPs, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 


 
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8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with U.S. FDA regulations 
and applicable local, state, and federal laws.  Studies conducted in the European Union 
or European Economic Area will comply with the E.U. Clinical Trials Directive 
(2001/20/EC) or Clinical Trials Regulation (536/2014) and applicable local, regional, and 
national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 


 
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If the Consent Forms are revised (through an amendment or an addendum) to 
communicate information that might affect a patient's willingness to continue in the 
study, the patient or a legally authorized representative must re-consent by signing the 
most current version of the Consent Forms or the addendum, in accordance with 
applicable laws and IRB/EC policy.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 


 
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8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted clinical study reports and other summary reports will be provided 
upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.  
Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.9.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study.  
An SOC will provide external expert opinions on the safety data collected during the 
study. 


 
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9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details).  
In addition, redacted Clinical Study Reports and/or other summaries of clinical study 
results may be available in health authority databases for public access, as required by 
local regulation, and will be made available upon request.  For more information, refer to 
the Roche Global Policy on Sharing of Clinical Study Information at the following 
website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only. 


 
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10. 
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Appendix 1  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
TABLE OF CONTENTS 
A1–1 
Tumor Measurability ................................................................. 116 
A1–1.1 
Definition of Measurable Lesions .............................................. 116 
A1–1.1.1 
Tumor Lesions .......................................................................... 116 
A1–1.1.2 
Malignant Lymph Nodes ........................................................... 116 
A1–1.2 
Definition of Non-Measurable Lesions ...................................... 117 
A1–1.3 
Special Considerations Regarding Lesion Measurability .......... 117 
A1–2 
Methods for Assessing Lesions ................................................ 118 
A1–2.1 
Clinical Lesions ......................................................................... 118 
A1–2.2 
Chest X-Ray .............................................................................. 118 
A1–2.3 
CT and MRI Scans .................................................................... 118 
A1–2.4 
Endoscopy, Laparoscopy, Ultrasound, Tumor Markers, 
Cytology, Histology ................................................................... 119 
A1–3 
Assessment of Tumor Burden ................................................... 119 
A1–3.1 
Identification of Target and Non-Target Lesions ....................... 119 
A1–3.2 
Calculation of Sum of Diameters ............................................... 120 
A1–3.2.1 
Measuring Lymph Nodes .......................................................... 120 
A1–3.2.2 
Measuring Lesions That Become Too Small to Measure .......... 120 
A1–3.2.3 
Measuring Lesions That Split or Coalesce on Treatment ......... 121 
A1–3.3 
Evaluation of Non-Target Lesions ............................................. 121 
A1–4 
Response Criteria ..................................................................... 121 
A1–4.1 
Criteria for Target Lesions......................................................... 121 
A1–4.2 
Criteria for Non-Target Lesions ................................................. 122 
A1–4.3 
Special Notes on Assessment of Progression of Non-Target 
Lesions ..................................................................................... 122 
A1–4.3.1 
Patients with Measurable and Non-Measurable Disease .......... 122 
A1–4.4 
New Lesions ............................................................................. 122 
A1–4.5 
Criteria for Overall Response at a Single Timepoint ................. 123 
A1–4.6 
Missing Assessments and Not-Evaluable Designation ............. 123 
A1–4.7 
Special Notes on Response Assessment ................................. 123 
A1–5 
References ................................................................................ 124 
 
 
 
 


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1) (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication, and the addition of explanatory text as needed for clarity. 
For Cohort 1, responses will be assessed and determined according to RECIST v1.1, 
but are not required to be confirmed by later imaging studies. 
A1–1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
A1–1.1 
DEFINITION OF MEASURABLE LESIONS 
A1–1.1.1 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows: 
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
A1–1.1.2 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 


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A1–1.2 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathologic 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. 
A1–1.3 
SPECIAL CONSIDERATIONS REGARDING LESION 
MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography (PET) 
scans, and plain films are not considered adequate imaging techniques for 
measuring bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) because 
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. 
 


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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118/Protocol BO43328, Version 4 
A1–2 
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. 
A1–2.1 
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. 
A1–2.2 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, because 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. 
A1–2.3 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a 
noncontrast 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 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 


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lesions on a different modality, because the same lesion may appear to have a different 
size using a new modality. 
A1–2.4 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR 
MARKERS, CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation. 
A1–3 
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. 
A1–3.1 
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 because they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathologic 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathologic nodes (those with short axis  10 mm 


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathologic and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
nonmeasurable), including pathologic 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"). 
A1–3.2 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
A1–3.2.1 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, because a normal lymph node is defined as having 
a short axis of  10 mm. 
A1–3.2.2 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes because 
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.) 


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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. 
A1–3.2.3 
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. 
A1–3.3 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
A1–4 
RESPONSE CRITERIA 
A1–4.1 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathologic lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters on study (including 
baseline) 
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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A1–4.2 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
nontarget lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedules of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathologic in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
A1–4.3 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF 
NON-TARGET LESIONS 
A1–4.3.1 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
A1–4.4 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 


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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
A1–4.5 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE 
TIMEPOINT 
Table A1-1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at baseline. 
Table A1-1 Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial response; 
SD  stable disease. 
 
A1–4.6 
MISSING ASSESSMENTS AND NOT-EVALUABLE 
DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
A1–4.7 
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 


Appendix 1:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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having "symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table A1-1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
A1–5 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 


 
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Appendix 2  
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
TABLE OF CONTENTS 
A2–1 
Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST).................................................................................. 126 
A2–1.1 
Evaluation of Lesions to Support iRECiST Response 
Assessment after Disease Progression per RECIST v1.1 ........ 126 
A2–1.1.1 
Target Lesions .......................................................................... 127 
A2–1.1.2 
Non-Target Lesions .................................................................. 127 
A2–1.1.3 
New Lesions ............................................................................. 127 
A2–1.2 
Summary of Criteria for Overall Response at a Single 
Timepoint .................................................................................. 128 
A2–2 
References ................................................................................ 129 
 
 
 


Appendix 2:  Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
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Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immunotherapy-specific response criteria adaptations to 
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1; Eisenhauer 
et al. 2009) have been developed to allow for unconventional response and progression 
patterns.  This includes modified RECIST v1.1 for immune-based therapeutics 
(iRECIST), which are described below. 
A2–1 
MODIFIED RECIST V1.1 FOR IMMUNE-BASED THERAPEUTICS 
(IRECIST) 
iRECIST (Seymour et al. 2017) was developed by the RECIST working group in an effort 
to create a common set of criteria that the CIT field could apply to clinical 
trials.  Response evaluation through use of iRECIST requires collection of tumor 
assessment data after radiographic progression per RECIST v1.1.  Details regarding 
lesion evaluation are described below.  When not otherwise specified, RECIST v1.1 
conventions will apply. 
Criteria for determining overall response at a single timepoint per iRECIST are also 
summarized below.  Of note, overall response per iRECIST will not be captured in the 
electronic Case Report Form (eCRF), but will instead be calculated programmatically by 
the Sponsor on the basis of investigator-assessed individual lesion data recorded in the 
eCRF. 
iRECIST response status is not a specific component of treatment discontinuation 
criteria, including decisions about whether to continue treatment beyond progression per 
RECIST v1.1.  Investigators should instead take into account radiologic data and clinical 
status in making such decisions, as described in Section 3.1.1. 
A2–1.1 
EVALUATION OF LESIONS TO SUPPORT IRECIST RESPONSE 
ASSESSMENT AFTER DISEASE PROGRESSION PER 
RECIST V1.1 
iRECIST is an extension of RECIST v1.1 that allows for response assessment following 
disease progression per RECIST v1.1.  RECIST v1.1 rules for categorizing lesions as 
measurable or non-measurable and measuring lesions (see Appendix 1) also apply to 
iRECIST.  After disease progression per RECIST v1.1, the same target and non-target 
lesions selected at baseline will continue to be followed, along with any new lesions that 
develop, to support iRECIST response evaluations, as described below and summarized 
in Table A2-1.  Once a lesion has been categorized as a target, non-target, or new 
lesion, it will remain classified as such. 


Appendix 2:  Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
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A2–1.1.1 
Target Lesions 
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions. 
A2–1.1.2 
Non-Target Lesions 
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1.  At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (progressive disease [PD]), or 
"present without unequivocal progression" (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were categorized as PD at the 
previous timepoint should be evaluated to determine whether there has been any further 
increase in size. 
A2–1.1.3 
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 v1.1 
(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 (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint.  New lesions that are 
not measurable at first appearance but meet measurability criteria at a subsequent 
timepoint should be measured from that point on, if the maximum number of measurable 
new lesions has not been reached.  However, for calculation of the sum of diameters for 
new lesions, iRECIST excludes measurements from new lesions that were not 
measurable at first appearance. 
All non-measurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions (in excess of five total or two per organ) should 
be assessed to determine whether there is any increase in size relative to the previous 
assessment timepoint. 
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 


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axis of a lymph node is  10 mm, the lymph node should not be considered pathologic 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is  15 mm.  Measurable new lymph node lesions 
should continue to be measured at all subsequent timepoints, even if the short axis 
decreases to  15 mm (or even  10 mm). 
Table A2-1 Guidelines for Evaluation of Lesions to Support iRECIST 
Response Assessment after Disease Progression per 
RECIST v1.1 
Lesion Type 
Evaluation of Lesions to Support iRECIST Response Assessment after 
Disease Progression per RECIST v1.1 
Target lesions 
Measurements should be continued according to RECIST v1.1 
conventions. 
Non-target lesions 
Non-target lesions should continue to be categorized as absent (CR), 
unequivocal progression (PD), or present without unequivocal 
progression (non-CR/non-PD), as defined by RECIST v1.1.  In addition, 
any non-target lesions that were categorized as PD at the previous 
timepoint should be evaluated to determine whether there has been any 
further increase in size. 
New lesions 
New lesions should be evaluated for measurability per RECIST v1.1. 
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 (with a maximum 
of two lesions per organ) should be selected and measured at each 
timepoint. 
All non-measurable new lesions (including those that subsequently 
become measurable) and additional measurable new lesions (in excess 
of five total or two per organ) should be assessed to determine whether 
there is any increase in size relative to the previous assessment 
timepoint. 
CR  complete response; iRECIST  immune RECIST; PD  progressive disease; RECIST 
v1.1  Response Evaluation Criteria in Solid Tumors, Version 1.1. 
 
A2–1.2 
SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A 
SINGLE TIMEPOINT 
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  
A complete description of the iRECIST criteria can be found in a publication by Seymour 
et al. (2017). 


Appendix 2:  Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
  
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129/Protocol BO43328, Version 4 
A2–2 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
Lancet Oncol 2017;18:e14352. 


 
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Appendix 3  
Pathologic Assessment of Resection Specimens 
After Neoadjuvant Therapy for Metastatic Melanoma 
 
 


Appendix 3:  Pathologic Assessment of Resection Specimens After Neoadjuvant Therapy 
for Metastatic Melanoma 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
131/Protocol BO43328, Version 4 
REFERENCES 
Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection 
specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol 
2018;29:18618. 


 
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Appendix 4  
Criteria for Adequate Surgical Procedures for  
Therapeutic Lymph Node Dissection 
Complete lymph node dissection (CLND) after neoadjuvant melanoma treatment should 
be performed as planned if the patient is receiving corticosteroids or other 
anti-inflammatory drugs for the management of immune-mediated adverse events, 
provided these are being given at a stable or tapering dose and the severity of adverse 
events is Grade 2 or better.  CLND may be delayed for up to 2 weeks if study 
treatment-related adverse events have not improved sufficiently at the time of planned 
surgery (see Section 3.1.3). 
Criteria for adequate surgical procedures for therapeutic lymph node dissection: 
Head and Neck 
 
Minimum of 15 pathologically investigated nodes 
 
Face, ear, and anterior scalp:  parotidectomy plus (modified) radical neck dissection 
 
Posterior scalp:  (modified or posterior) radical neck dissection plus suboccipital 
nodes.  For this specific localization, a CLND will be considered as adequate if at 
least 5 lymph nodes (LN) have been investigated 
 
Upper Extremity 
 
Minimum of 10 pathologically investigated nodes 
 
Axillary node dissection included at least 10 nodes taken from Levels I and II 
 
It is advised to routinely include the Level III nodes too 
 
Level III nodes should always be dissected if they were clinically involved 
 
Lower Extremity 
 
Minimum of 5 pathologically investigative nodes 
 
If Cloquet’s node is positive, a deep groin (external iliac and obturator) node 
dissection should be performed 
 
(Modified) Radical Neck Dissection: 
Classic or modified radical neck dissection may be performed for patients with 
melanoma of the head and neck.  Minimum of 15 nodes must be pathologically 
investigated.  As noted above, patients with melanoma located on the ear and anterior 
scalp and face will require superficial parotidectomy along with a (modified) radical neck 
procedure.  The boundaries of the radical neck dissection are inferiorly the clavicle; the 
mandible, the mastoid and the tail of the parotid gland superiorly; the anterior border of 
the trapezius muscle posteriorly and the strap muscle of the larynx anteriorly.  The 
sternocleidomastoid muscle, internal jugular vein, and/or spinal accessory nerve may be 
sacrificed or preserved at the surgeon's discretion.  For posterior lesions the radical neck 
incision must be extended posteriorly or a second incision must be made so that the 


Appendix 4:  Criteria for Adequate Surgical Procedures for Therapeutic Lymph Node 
Dissection 
  
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133/Protocol BO43328, Version 4 
sub-occipital/postauricular nodal group can be sampled.  For posterior neck dissection, 
surgical and pathologic exploration of 5 nodes are sufficient to consider the procedure is 
adequate. 
Axillary Lymphadenectomy: 
For this study a complete axillary lymph node dissection will be performed including 
nodes at Levels I, II, and III (Level III does not have to be removed routinely, but is 
advised.  In any case Level III should be dissected in case of preoperative nodal 
involvement).  Axillary node dissection must include at least 10 nodes taken from Levels 
I and II and the Level III nodes dissected for palpable axillary nodes.  Minimum of 10 
nodes must be pathologically investigated.  The boundaries of the dissection should 
include the axillary vein superiorly beginning at the thoracic outlet and coursing to the 
latissimus dorsi tendon.  The lateral border of the dissection is the anterior edge of the 
lattisimus dorsi muscle.  The posterior boundary is the subscapular muscle.  The anterior 
border of the resection is the pectoralis major group.  The inferior boundary of the 
dissection should be the juncture of the latissimus dorsi and the serratus anterior 
muscles. 
The contents within these boundaries should be completely removed with the exception 
of the long thoracic nerve and the thoracodorsal nerve which should be identified during 
the dissection and preserved throughout.  As stated, the pectoralis minor muscle may be 
divided or sacrificed with the specimen at the discretion of the surgeon.  The preferable 
approach to the axilla is through a horizontal incision in the line of the skin crease, 3 or 
4 cm below the apex of the skin fold of the axilla. 
Inguinal Lymphadenectomy (Superficial Groin Dissection): 
A superficial groin (femoral/inguinal) node dissection should be performed by excising all 
of the nodes inferior to the inguinal ligament and bounded by the medial border of the 
sartorius muscle in the lateral border of the adductor magnus muscle.  The fatty and 
lymphatic tissues should be dissected carefully off of the femoral vessels and nerves all 
the way up to the inguinal canal and for 23 cm superior to the inguinal ligament (the 
superficial subcutaneous tissue cranial to the exit of the femoral canal).  The saphenous 
vein is resected to ensure complete excision of the lymph nodes.  Transposition of the 
sartorius muscle should be considered (but is not mandatory) to cover the femoral 
vessels after complete lymphatic excision.  Ideally, this area should be entered through a 
curvilinear incision staring laterally over the inguinal ligament and curving medially and 
inferiorly ending over the mid-point of the adductor magnus muscle.  For a superficial 
groin node dissection, a minimum of 5 nodes must be pathologically investigated. 


Appendix 4:  Criteria for Adequate Surgical Procedures for Therapeutic Lymph Node 
Dissection 
  
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134/Protocol BO43328, Version 4 
Deep Groin (External Iliac and Obturator) Node Dissection: 
Deep Inguinal and External Iliac Node Dissection can be most easily approached by 
incising the abdominal wall musculature 3 or 4 cm superior to the inguinal ligament.  
This incision is taken down through the external oblique, internal oblique and 
transversus muscles and the surgeon at that point stays extraperitoneal as in the 
approach to the iliac vessels for renal transplantation.  With this approach, the external, 
internal, and common iliac arteries are exposed and the lymphatics coursing among the 
iliac vessels are excised.  The obturator nodes along the obturator nerve and artery 
should also be resected through this approach.  A full combined superficial and deep 
groin (ilio-inguinal) node dissection is advised in case of when Cloquet’s node is positive 
or if there is other evidence of extended involvement to the deep nodes preoperatively. 
 


 
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Appendix 5  
Classification of Surgical Complications 
 
Grade 
Definition 
Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic, and radiological 
interventions 
Allowed therapeutic regimens are:  drugs as antiemetics, antipyretics, 
analgetics, diuretics, electrolytes, and physiotherapy.  This grade also 
includes wound infections opened at the bedside 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for 
grade I complications 
Blood transfusions and total parenteral nutrition are also included 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
 
Grade IIIa 
Intervention not under general anesthesia 
 
Grade IIIb 
Intervention under general anesthesia 
Grade IV 
Life-threatening complication (including CNS complications)a requiring IC/ICU 
management 
 
Grade IVa 
Single organ dysfunction (including dialysis) 
 
Grade IVb 
Multiorgan dysfunction 
Grade V 
Death of a patient 
Suffix “d” 
If the patient suffers from a complication at the time of discharge,b the suffix 
“d” (for “disability”) is added to the respective grade of complication.  This 
label indicates the need for a follow-up to fully evaluate the complication. 
CNS  central nervous system; IC  intermediate care; ICU  intensive care unit. 
a Brain hemorrhage, ischemic stroke, subarrachnoidal bleeding, but excluding transient 
ischemic attacks. 
b For examples of complication grades, see Table 2 in Dindo et al. (2004). 
  
REFERENCE 
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann 
Surg 2004; 240:20513.


 
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Appendix 6  
ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active; able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework or 
office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about  50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
ECOG  Eastern Cooperative Oncology Group. 
 


  
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Appendix 7  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of autoimmune-
related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible 
for this study.  In addition, transient autoimmune manifestations of an acute infectious 
disease that resolved upon treatment of the infectious agent are not excluded 
(e.g., acute Lyme arthritis).  Caution should be used when considering atezolizumab, 
tiragolumab, or RO7247669 for patients who have previously experienced a severe or 
lifethreatening skin adverse reaction or pericardial disorder while receiving another 
immunostimulatory anti-cancer agent.  The Medical Monitor is available to advise on 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 myelitis 
 Autoimmune 
myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic 
purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue 
syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease 
 Dermatomyositis 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Graves disease 
 Guillain-Barré syndrome 
 Granulomatosis with 
polyaniitis 
 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 cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada disease 
 


  
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Appendix 8  
Anaphylaxis Precautions 
A8–1 
EQUIPMENT NEEDED 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
A8–2 
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. 
Maintain an adequate airway. 
3. 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
4. 
Continue to observe the patient and document observations. 
 


 
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Appendix 9  
Guidelines for Management of Atezolizumab-, Tiragolumab-, 
and/or RO7247669-Specific Adverse Events 
TABLE OF CONTENTS 
A9–1 
Dose Modifications .................................................................... 141 
A9–2 
Treatment Interruption .............................................................. 142 
A9–3 
Pulmonary Events ..................................................................... 142 
A9–4 
Hepatic Events .......................................................................... 144 
A9–5 
Gastrointestinal Events ............................................................. 145 
A9–6 
Endocrine Events ...................................................................... 148 
A9–7 
Ocular Events ........................................................................... 152 
A9–8 
Immune-Mediated Cardiac Events ............................................ 153 
A9–9 
Immune-Mediated Myocarditis .................................................. 154 
A9–10 
Immune-Mediated Pericardial Disorders ................................... 154 
A9–11 
Infusion-Related Reactions ....................................................... 155 
A9–12 
Cytokine-Release Syndrome .................................................... 156 
A9–13 
Pancreatic Events ..................................................................... 159 
A9–14 
Dermatologic Events ................................................................. 162 
A9–15 
Neurologic Disorders ................................................................ 164 
A9–16 
Immune-Mediated Meningoencephalitis ................................... 167 
A9–17 
Renal Events ............................................................................. 168 
A9–18 
Immune-mediated Myositis ....................................................... 170 
A9–19 
Hemophagocytic Lymphohistiocytosis and Macrophage 
Activation Syndrome ................................................................. 173 
A9–20 
References ................................................................................ 176 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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140/Protocol BO43328, Version 4 
These guidelines are intended to inform rather than supersede an investigator's clinical 
judgment and assessment of the benefit risk balance when managing individual cases.  
Tiragolumab and RO7247669 are in an early phase of clinical development, and not all 
risks are known as clinical evaluation is ongoing.  Please refer to Section 6 of the 
Tiragolumab or RO7247669 Investigator's Brochure for a detailed description of 
anticipated safety risks associated with these molecules.  Risks associated with 
atezolizumab are described in this appendix.  Please refer to Section 6 of the 
Atezolizumab Investigator's Brochure for further information. 
The expected pharmacologic activities of atezolizumab, tiragolumab, and RO7247669 
are similar for checkpoint inhibitors as a class.  Accordingly, the adverse event 
management guidelines described in this appendix, including those for continuing, 
withholding, resuming, and discontinuing study treatment, are applicable to 
atezolizumab, tiragolumab, and RO7247669, with these exceptions: 
 
For infusion-related reactions (IRRs) associated with RO7247669 as a 
monotherapy, please refer to Table A12-3 in Appendix 12 and Table A15-3 in 
Appendix 15. 
 
For IRRs associated with tiragolumab in combination with atezolizumab, please 
refer to Table A13-5 in Appendix 13. 
 
For IRRs associated with RO7247669 in combination with tiragolumab, please refer 
to Table A14-4 in Appendix 14 and Table A16-4 in Appendix 16. 
 
Toxicities associated or possibly associated with atezolizumab, tiragolumab, and/or 
RO7247669 treatment should be managed according to standard medical practice.  
Additional tests, such as autoimmune serology or biopsies, should be used to evaluate 
for a possible immunogenic etiology when clinically indicated. 
Although most immune-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, tiragolumab, and/or RO7247669 may not have an immediate therapeutic 
effect, and in severe cases, immune-mediated toxicities may require acute management 
with topical corticosteroids, systemic corticosteroids, or other immunosuppressive 
agents.  The investigator should consider the benefitrisk balance a given patient may 
be experiencing prior to further administration or resumption of atezolizumab, 
tiragolumab, or RO724669. 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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141/Protocol BO43328, Version 4 
The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in the following subsections in this 
appendix or the treatment arm-specific appendices.  
 
Patients and family caregivers should receive timely and up-to-date information 
about immunotherapies, their mechanism of action, and the clinical profile of 
possible immune-related adverse events prior to initiating therapy and throughout 
treatment and long-term follow-up.  There should be a high level of suspicion that 
new symptoms are treatment related. 
 
In general, atezolizumab, tiragolumab, and/or RO7247669 therapy should be 
continued with close monitoring for Grade 1 toxicities, with the exception of some 
neurologic toxicities. 
 
Consider holding atezolizumab, tiragolumab, and/or RO7247669 for most Grade 2 
toxicities and resume when symptoms and/or laboratory values resolve to Grade 1 
or better.  Corticosteroids (initial dose of 0.51 mg/kg/day of prednisone or 
equivalent) may be administered. 
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
 
Hold atezolizumab, tiragolumab, and/or RO7247669 for Grade 3 toxicities and 
initiate treatment with high-dose corticosteroids (12 mg/kg/day prednisone or 
equivalent).  Corticosteroids should be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent, before atezolizumab, tiragolumab, and/or RO7247669 can 
be resumed.  If symptoms do not improve within 48 to 72 hours of high-dose 
corticosteroid use, other immunosuppressants may be offered for some toxicities. 
 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab, 
tiragolumab, and/or RO7247669 treatment, with the exception of endocrinopathies 
that are controlled by hormone-replacement therapy. 
 
The investigator should consider the benefitrisk balance for a given patient prior 
to further administration of atezolizumab, tiragolumab, and/or RO7247669.  
Resumption of atezolizumab, tiragolumab, and/or RO7247669 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, 
tiragolumab, and/or RO7247669 should be based on the investigator’s assessment 
of the benefits and risks and documented by the investigator.  The Medical Monitor 
is available to advise as needed. 
 
A9–1 
DOSE MODIFICATIONS 
There will be no dose modifications for atezolizumab, tiragolumab, or RO7247669 in this 
study. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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142/Protocol BO43328, Version 4 
A9–2 
TREATMENT INTERRUPTION 
Treatment with atezolizumab, tiragolumab, or RO7247669 may be temporarily 
suspended in patients experiencing toxicity considered to be related to study treatment.  
If corticosteroids are initiated for treatment of the toxicity, they must be tapered over 
 1 month to the equivalent of  10 mg/day oral prednisone before atezolizumab, 
tiragolumab, and/or RO7247669 can be resumed. 
For Cohort 1, treatment with atezolizumab, tiragolumab, and/or RO7247669 should not 
be interrupted unless a patient experiences toxicity.  If toxicity meets criteria for 
interrupting/withholding study drug(s), study drug(s) should be interrupted/withheld.  
After resolution of the toxicity, subsequent treatment cycles should only be considered if 
the benefitrisk profile is acceptable and if the surgery can be conducted within 2 weeks 
of the planned date.  Otherwise, subsequent treatment cycles should be omitted to allow 
the patient to proceed directly to surgery without further delay. 
For Cohort 2, if RO7247669 and tiragolumab are withheld for 12 weeks or longer due to 
toxicity, the patient should be discontinued from RO7247669 and tiragolumab.  However, 
RO7247669 and tiragolumab may be withheld for more than 12 weeks to allow for 
patients to taper off corticosteroids prior to resuming treatment.  RO7247669 and 
tiragolumab may be resumed after being withheld for more than 12 weeks if the patient is 
likely to derive clinical benefit.  RO7247669 and tiragolumab treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures) at the discretion of 
the investigator.  The acceptable length of the extended period of time must be based on 
the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
A9–3 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  COVID-19 evaluation should be performed per institutional guidelines 
where relevant.  Management guidelines for pulmonary events are provided in Table A9-
1. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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143/Protocol BO43328, Version 4 
Table A9-1 Management Guidelines for Pulmonary Events, Including 
Pneumonitis  
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue atezolizumab/tiragolumab/RO7247669 and monitor 
closely. 
 Re-evaluate on serial imaging. 
 Consider patient referral to pulmonary specialist. 
 For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary 
event, Grade 2 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks 
after event onset. a 
 Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial 
biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical 
Monitor. c, d 
 For recurrent events or events with no improvement after 
4872 hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 
and contact the Medical Monitor. c, d 
 Oral or IV broad spectrum antibiotics should be administered in 
parallel to the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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144/Protocol BO43328, Version 4 
Table A9-1 Management Guidelines for Pulmonary Events, Including 
Pneumonitis (cont.) 
BAL  bronchoscopic alveolar lavage. 
a For Cohort 2, RO7247669 and tiragolumab, may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced 
to the equivalent of  10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be based on the investigator’s benefitrisk assessment 
and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 
can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of 
the drug.  For combination regimens, both study drugs should be discontinued.  
d In case of pneumonitis, atezolizumab/tiragolumab/RO7247669 should not be resumed 
after permanent discontinuation. 
  
A9–4 
HEPATIC EVENTS 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases;  liver function will be 
monitored throughout study treatment.  Management guidelines for hepatic events are 
provided in Table A9-2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
 
 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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145/Protocol BO43328, Version 4 
Table A9-2 Management Guidelines for Hepatic Events  
Event 
Management 
Hepatic event, 
Grade 1 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values. 
Events of  5 days duration: 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks after 
event onset. a 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical Monitor. c 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and contact 
the Medical Monitor. c 
 Consider patient referral to gastrointestinal specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
LFT  liver function tests. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
A9–5 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table A9-3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
146/Protocol BO43328, Version 4 
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 A9-3 Management Guidelines for Gastrointestinal Events  
(Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks after 
event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV 
steroids while waiting for definitive diagnosis. 
 Patient referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment with 
corticosteroids equivalent of 12 mg/kg/day oral prednisone.  If the event 
does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical Monitor. c 
GI  gastrointestinal. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
147/Protocol BO43328, Version 4 
Table A9-3 Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
Event 
Management 
Diarrhea or 
colitis, Grade 3 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks 
after event onset. a 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.  If event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical 
Monitor. c 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
 Refer patient to GI specialist for evaluation and confirmatory biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
GI  gastrointestinal. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
148/Protocol BO43328, Version 4 
A9–6 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table A9-4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  Patients should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests 
(e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH 
stimulation test) and magnetic resonance imaging (MRI) of the brain (with detailed 
pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
149/Protocol BO43328, Version 4 
Table A9-4 Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 
hypothyroidism 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
Grade 2 
hypothyroidism 
 Consider withholding atezolizumab/tiragolumab/RO7247669 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab/tiragolumab/RO7247669 when symptoms 
are controlled and thyroid function is improving. 
Grade 3 or 4 
hypothyroidism 
 Withhold atezolizumab/tiragolumab/RO7247669. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer to an endocrinologist. 
 Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status) 
 Resume atezolizumab/tiragolumab/RO7247669 when symptoms 
are controlled and thyroid function is improving. 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 
and contact the Medical Monitor for life-threatening immune-
mediated hypothyroidism. 
Grade 1 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Monitor TSH every 4 weeks. 
 Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider patient referral to endocrinologist. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 
can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
150/Protocol BO43328, Version 4 
Table A9-4 Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Grade 2 
hyperthyroidism 
 Consider withholding atezolizumab/tiragolumab/RO7247669. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider patient referral to endocrinologist. 
 Resume atezolizumab/tiragolumab/RO7247669 when symptoms 
are controlled and thyroid function is improving. 
Grade 3 or 4 
hyperthyroidism 
 Withhold atezolizumab/tiragolumab/RO7247669. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer to endocrinologist. 
 Resume atezolizumab/tiragolumab/RO7247669 when symptoms 
are controlled and thyroid function is improving. 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 
and contact the Medical Monitor for life-threatening immune-
mediated hyperthyroidism. c 
Symptomatic adrenal 
insufficiency, 
Grade 24  
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 
12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab/tiragolumab/ 
RO7247669. b 
 If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical 
Monitor. c 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 
can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
151/Protocol BO43328, Version 4 
Table A9-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hyperglycemia, 
Grade 1 or 2  
 Continue atezolizumab/tiragolumab/RO7247669. 
 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/tiragolumab/RO7247669. 
 Initiate treatment with insulin. 
 Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
 Monitor for glucose control. 
 Resume atezolizumab/tiragolumab/RO7247669 when symptoms 
resolve and glucose levels are stable. 
Hypophysitis 
(panhypopituitarism), 
Grade 2 or 3  
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 
12 weeks after event onset. a 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
IV methylprednisolone and convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 Initiate hormone replacement as clinically needed. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 
can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
152/Protocol BO43328, Version 4 
Table A9-4 Management Guidelines for Endocrine Events (cont.) 
Event 
Management 
Hypophysitis 
(panhypopituitarism), 
Grade 4  
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 
and contact the Medical Monitor. c 
 Refer patient to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 Initiate hormone replacement as clinically needed. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented by 
the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 
can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
A9–7 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table A9-5. 
 
 
 
 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
153/Protocol BO43328, Version 4 
Table A9-5 Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue atezolizumab/tiragolumab/RO7247669. 
 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/tiragolumab/RO7247669 for up to 12 weeks 
after event onset. a 
 Patient referral to ophthalmologist is strongly recommended. 
 Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the Medical 
Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
 Refer patient to ophthalmologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
A9–8 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table A9-6. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
154/Protocol BO43328, Version 4 
A9–9 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory 
(e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Myocarditis may also be 
a clinical manifestation of myositis or associated with pericarditis (see section on 
pericardial disorders below) and should be managed accordingly.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a 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 A9-6. 
A9–10 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac 
injury related (post myocardial infarction or iatrogenic), and autoimmune disorders, and 
should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  
Pericardiocentesis should be considered for diagnostic or therapeutic purposes, if 
clinically indicated. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
155/Protocol BO43328, Version 4 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table A9-6.  Withhold treatment with atezolizumab, 
tiragolumab and/or RO7247669 for Grade 1 pericarditis and conduct a detailed cardiac 
evaluation to determine the etiology and manage accordingly. 
Table A9-6 Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis,  
Grades 24 
 
Immune-mediated 
pericardial disorders, 
Grades 24 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. a 
 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. b, c 
 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 If a study drug warrants permanent discontinuation, there should be no re-challenge of the drug.  
For combination regimens, both study drugs should be discontinued.   
b For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
c If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
 
A9–11 
INFUSION-RELATED REACTIONS 
No premedication is indicated for the administration of the Day 1, Cycle 1 infusion of 
tiragolumab, atezolizumab, or RO7247669.  However, patients who experience an 
infusion-related reaction (IRR) with the Day 1, Cycle 1 infusion of tiragolumab, 
atezolizumab, or RO7247669 may receive premedication with antihistamines, antipyretic 
medication, or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
156/Protocol BO43328, Version 4 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with tiragolumab, atezolizumab, and RO7247669.  These reactions, which 
are thought to be due to release of cytokines and/or other chemical mediators, occur 
within 24 hours of tiragolumab, atezolizumab, or RO7247669 administration and are 
generally mild to moderate in severity.  Refer to the beginning of this appendix 
(Appendix 9) for IRR management guidelines for each treatment arm. 
A9–12 
CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab, 
tiragolumab, or RO7247669.  However, patients who experience cytokine-release 
syndrome (CRS) may receive premedication with antihistamines, anti-pyretic 
medications, and/or analgesics (e.g., acetaminophen) for subsequent infusions.   
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells.  Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019).  CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
Guidelines for medical management of CRS are provided in Table A9-7.  
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to be 
associated with a CRS involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, 
and IFN- (Merad and Martin 2020).  If a patient develops suspected CRS during the 
study, a differential diagnosis should include SARS-CoV-2 infection, which should be 
confirmed or refuted through assessment of exposure history, appropriate laboratory 
testing, and clinical or radiologic evaluations per investigator’s judgment.  If a diagnosis 
of SARS-CoV-2 infection is confirmed, the disease should be managed as per local or 
institutional guidelines. 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
157/Protocol BO43328, Version 4 
Table A9-7 Management Guidelines for Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms  
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
 If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
 In case of rapid decline or prolonged CRS ( 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
 For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretic medications, and/or analgesics, and 
monitor closely for CRS. 
Grade 2 a 
Fever b with at 
least one of the 
following: 
 Hypotension 
not requiring 
vasopressors 
 Hypoxia 
requiring 
low-flow 
oxygen d by 
nasal cannula 
or blowby 
 
 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. e 
 Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab/tiragolumab/RO7247669, and contact the Medical Monitor. 
 If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab/tiragolumab/RO7247669 may be administered.  For 
subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretic medications, and/or analgesics and monitor 
closely for CRS. 
 If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Medical Monitor. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
158/Protocol BO43328, Version 4 
Table A9-7 Management Guidelines for Cytokine-Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with at least 
one of the 
following:  
 Hypotension 
requiring a 
vasopressor 
(with or without 
vasopressin) 
 Hypoxia 
requiring 
high-flow 
oxygen d by 
nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. f 
 Administer symptomatic treatment. c 
 For hypotension, administer IV fluid bolus and vasopressor as 
needed. 
 Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically 
indicated, and manage constitutional symptoms and organ toxicities 
as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS 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. e 
 Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor. 
Grade 4 a 
Fever b with at least 
one of the 
following:  
 Hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 Hypoxia 
requiring oxygen 
by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. f 
 Administer symptomatic treatment. c 
 Admit patient to ICU and initiate hemodynamic monitoring, 
mechanical ventilation, and/or IV fluids and vasopressors as needed.  
Monitor other organ function closely.  Manage constitutional 
symptoms and organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS 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. e  For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered at 
the discretion of the investigator.  The Medical Monitor will be 
available to advise as needed. 
 Hospitalize patient until complete resolution of symptoms. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
159/Protocol BO43328, Version 4 
Table A9-7 Management Guidelines for Cytokine-Release Syndrome (cont.) 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level 
positive airway pressure; CAR  chimeric antigen receptor; CPAP  continuous positive 
airway pressure; CRS  cytokine-release syndrome; CTCAE  Common Terminology 
Criteria for Adverse Events; eCRF  electronic Case Report Form; HLH  hemophagocytic 
lymphohistiocytosis; ICU  intensive care unit; MAS  macrophage activation syndrome; 
NCCN  National Comprehensive Cancer Network; NCI  National Cancer Institute. 
Notes:  The management guidelines have been adapted from the NCCN guidelines for 
the management of CAR T-cellrelated toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading 
scale.  NCI CTCAE v5.0 and the ASTCT CRS consensus grading scale should be used 
when reporting severity of CRS on the Adverse Event eCRF.  NCI CTCAE v5.0 should 
be used when reporting severity of organ toxicities associated with CRS on the 
dedicated Cytokine-Release Syndrome eCRF.  Organ toxicities associated with CRS 
should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause.  In patients 
who develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, 
fever is no longer required when subsequently determining event severity (grade).  
In this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretic medications, 
analgesics, bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as 
oxygen delivered at  6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of 
CRS with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), 
but data are limited, and the role of such treatment in the setting of antibody-associated 
CRS has not been established. 
f If a study drug warrants permanent discontinuation, there should be no re-challenge of 
the drug.  For combination regimens, both study drugs should be discontinued.   
g Refer to Riegler et al. (2019). 
 
A9–13 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table A9-8. 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
160/Protocol BO43328, Version 4 
Table A9-8 Management Guidelines for Pancreatic Events, Including 
Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.52.0  ULN: 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
 Withhold atezolizumab/tiragolumab/RO7247669 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/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 For recurrent events, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
GI  gastrointestinal. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the drug.  
For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
161/Protocol BO43328, Version 4 
Table A9-8 Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.) 
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 Withhold atezolizumab/tiragolumab/RO7247669 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/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while 
withholding atezolizumab/tiragolumab/RO7247669, 
permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 For recurrent events, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
 Permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 Refer patient to GI specialist. 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
162/Protocol BO43328, Version 4 
A9–14 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab, tiragolumab, and/or 
RO7247669 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 A9-9. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
163/Protocol BO43328, Version 4 
Table A9-9 Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic event, 
Grade 1  
 Continue atezolizumab/tiragolumab/RO7247669. 
 Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2  
 Continue atezolizumab/tiragolumab/RO7247669. 
 Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
 If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Dermatologic event, 
Grade 3  
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks 
after event onset. a 
 Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 12 mg/kg/day if event does not 
improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
Dermatologic event, 
Grade 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
 Withhold atezolizumab/tiragolumab/RO7247669 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/tiragolumab/RO7247669. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
164/Protocol BO43328, Version 4 
Table A9-9 Management Guidelines for Dermatologic Events (cont.) 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
A9–15 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic work-up is essential for an accurate characterization to differentiate between 
alternative etiologies.  Management guidelines for neurologic disorders are provided in 
Table A9-10, with specific guidelines for myelitis provided in Table A9-11. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
165/Protocol BO43328, Version 4 
Table A9-10 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-mediated 
neuropathy, 
Grade 1 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be managed 
as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks after 
event onset. a 
 Investigate etiology and refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
– 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume 
atezolizumab/tiragolumab/RO7247669. b 
– 
If event does not resolve fully while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
 
 
 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
166/Protocol BO43328, Version 4 
Table A9-10 
Management Guidelines for Neurologic Disorders (cont.) 
Event 
Management 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
 Refer patient to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. 
 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 For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
Table A9-11 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue atezolizumab/tiragolumab/RO7247669 unless 
symptoms worsen or do not improve. 
 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor.  
 
Investigate etiology and refer patient to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. 
 
Refer patient to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
  


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
167/Protocol BO43328, Version 4 
A9–16 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process. 
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in  
Table A9-12. 
Table A9-12 
Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. a 
 Refer patient to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a If a study drug warrants permanent discontinuation, there should be no re-challenge of the drug.  
For combination regimens, both study drugs should be discontinued.   
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
168/Protocol BO43328, Version 4 
A9–17 
RENAL EVENTS 
Eligible patients must have adequate renal function.  Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including pre-renal and post-renal 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 A9-13. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
169/Protocol BO43328, Version 4 
Table A9-13 
Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Monitor kidney function, including creatinine and urine protein, closely 
until values resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold atezolizumab/tiragolumab/RO7247669 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/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.    
  


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
170/Protocol BO43328, Version 4 
A9–18 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.  
Patients with possible myositis should be referred to a rheumatologist or neurologist.  
Patients with possible myositis should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table A9-14. 
 
 
 
 
 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
171/Protocol BO43328, Version 4 
Table A9-14 
Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
 Continue atezolizumab/tiragolumab/RO7247669. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 
weeks after event onset  a and contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently 
discontinue atezolizumab/tiragolumab/RO7247669 and contact 
the Medical Monitor. c 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of  10 mg/day oral prednisone.  The acceptable length of 
the extended period of time must be based on the investigator’s benefitrisk 
assessment and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before 
atezolizumab/tiragolumab/RO7247669 can be resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of 
the drug.  For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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172/Protocol BO43328, Version 4 
Table A9-14 
Management Guidelines for Immune-Mediated Myositis 
(cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 3 
 Withhold atezolizumab/tiragolumab/RO7247669 for up to 12 weeks 
after event onset a and contact the Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Respiratory support may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume 
atezolizumab/tiragolumab/RO7247669. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab/tiragolumab/RO7247669, permanently discontinue 
atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event.  Permanently 
discontinue atezolizumab/tiragolumab/RO7247669 and contact the 
Medical Monitor. c 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time 
(i.e.,  12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to 
the equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on the investigator’s benefitrisk assessment and in alignment 
with the protocol requirements for the duration of treatment and documented by the 
investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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173/Protocol BO43328, Version 4 
Table A9-14 
Management Guidelines for Immune-Mediated Myositis 
(cont.) 
Event 
Management 
Immune-mediated 
myositis, Grade 4 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 and 
contact the Medical Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory support 
may be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a For Cohort 2, RO7247669 and tiragolumab may be withheld for a longer period of time (i.e., 
 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on the investigator’s benefitrisk assessment and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed.  
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab/tiragolumab/RO7247669 can be 
resumed. 
c If a study drug warrants permanent discontinuation, there should be no re-challenge of the 
drug.  For combination regimens, both study drugs should be discontinued.   
  
A9–19 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND 
MACROPHAGE ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are 
considered to be potential risks for atezolizumab. 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
174/Protocol BO43328, Version 4 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
 
Fever  38.5°C 
 
Splenomegaly 
 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
 
Low or absent natural killer cell activity 
 
Ferritin  500 mg/L (500 ng/mL) 
 
Soluble IL-2 receptor (soluble CD25) elevated  2 standard deviations above 
age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be 
classified as having MAS if the following criteria are met: 
 
Ferritin  684 mg/L (684 ng/mL) 
 
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 A9-15. 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
175/Protocol BO43328, Version 4 
Table A9-15 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue atezolizumab/tiragolumab/RO7247669 
and contact the Medical Monitor. 
 Consider patient referral to hematologist. 
 Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
 Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
 If event does not respond to treatment within 24 hours, contact the 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis; MAS  macrophage activation syndrome. 
 
 
 


Appendix 9:   Guidelines for Management of Atezolizumab-, Tiragolumab-, and/or 
RO7247669-Specific Adverse Events 
  
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176/Protocol BO43328, Version 4 
A9–20 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [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. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:4819. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 






  
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Appendix 11  
Study Details Specific to Nivo  Ipi Arm (Control) 
TABLE OF CONTENTS 
A11–1 
Background on Nivo  Ipi Arm .................................................. 180 
A11–1.1 
Background on Nivolumab ........................................................ 180 
A11–1.2 
Background on Ipilimumab ....................................................... 180 
A11–2 
Rationale for Nivo  Ipi Arm ...................................................... 180 
A11–2.1 
Combination Treatment with Nivolumab and Ipilimumab .......... 180 
A11–2.2 
Clinical Studies of Nivolumab in Combination with 
Ipilimumab in Melanoma ........................................................... 180 
A11–2.3 
BenefitRisk Assessment ......................................................... 181 
A11–3 
Rationale for Dose and Schedule for Nivo  Ipi Arm ................. 181 
A11–4 
Materials and Methods Specific to Nivo  Ipi Arm ..................... 182 
A11–4.1 
Treatment in Nivo  Ipi Arm ...................................................... 182 
A11–4.1.1 
Formulation, Packaging, and Handling ..................................... 182 
A11–4.1.1.1 
Nivolumab ................................................................................. 182 
A11–4.1.1.2 
Ipilimumab................................................................................. 182 
A11–4.1.2 
Dosage, Administration, and Compliance ................................. 182 
A11–4.1.2.1 
Nivolumab ................................................................................. 183 
A11–4.1.2.2 
Ipilimumab................................................................................. 183 
A11–4.2 
Concomitant Therapy for Nivo  Ipi Arm ................................... 183 
A11–4.3 
Contraception Requirements for Nivo  Ipi Arm ........................ 184 
A11–5 
Assessment of Safety for Nivo  Ipi Arm ................................... 185 
A11–5.1 
Safety Plan for Nivo  Ipi Arm ................................................... 185 
A11–5.1.1 
Risks Associated with Nivolumab ............................................. 185 
A11–5.1.2 
Risks Associated with Ipilimumab ............................................. 185 
A11–5.1.2.1 
Risks Associated with Combination Use of Nivolumab and 
Ipilimumab................................................................................. 185 
A11–5.1.2.2 
Management of Patients Who Experience Adverse Events in 
Nivo  Ipi Arm ........................................................................... 185 
A11–5.2 
Reporting Requirements for Pregnancies in Nivo  Ipi Arm ...... 185 
A11–5.2.1 
Pregnancies in Female Patients ............................................... 185 
A11–5.2.2 
Pregnancies in Female Partners of Male Patients .................... 186 
A11–5.2.3 
Abortions ................................................................................... 187 
A11–5.2.4 
Congenital Anomalies/Birth Defects .......................................... 187 
A11–6 
Schedules of Activities and Sample Collection for Nivo  Ipi 
Arm ........................................................................................... 188 
A11–7 
Schedule of Biomarker Samples for Nivo  Ipi Control Arm ...... 193 
A11–8 
References ................................................................................ 194 
 
 


  
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A11–1 
BACKGROUND ON NIVO  IPI ARM 
A11–1.1 
BACKGROUND ON NIVOLUMAB 
Nivolumab (Nivo) is a human monoclonal antibody that targets the human PD-1 
receptor.  Nivolumab is approved for the treatment of several cancer types, including 
melanoma.  It is approved as monotherapy or in combination with ipilimumab for the 
treatment of advanced (unresectable or metastatic) melanoma, and as monotherapy for 
the adjuvant treatment of patients with melanoma. 
For detailed information, refer to the local prescribing information for nivolumab. 
A11–1.2 
BACKGROUND ON IPILIMUMAB 
Ipilimumab (Ipi) is a fully human monoclonal antibody that binds to CTLA-4 and inhibits 
its interaction with ligands on antigen-presenting cells. 
Ipilimumab is approved for the treatment of several cancer types, including melanoma.  
It is approved as monotherapy or in combination with nivolumab for the treatment of 
advanced (unresectable or metastatic) melanoma, and as monotherapy for the adjuvant 
treatment of patients with melanoma. 
For detailed information, refer to the local prescribing information for ipilimumab. 
A11–2 
RATIONALE FOR NIVO  IPI ARM 
A11–2.1 
COMBINATION TREATMENT WITH NIVOLUMAB AND 
IPILIMUMAB 
Nivolumab in combination with ipilimumab is an approved treatment option for advanced 
(unresectable or metastatic) melanoma. 
A11–2.2 
CLINICAL STUDIES OF NIVOLUMAB IN COMBINATION WITH 
IPILIMUMAB IN MELANOMA 
In the Phase III CheckMate 067 study, nivolumab monotherapy or combination therapy 
with nivolumab and ipilimumab was compared with ipilimumab monotherapy in patients 
with metastatic melanoma.  The co-primary endpoints for this study were 
progression-free survival (PFS) and overall survival (OS).  Nivolumab monotherapy and 
combination therapy with nivolumab  ipilimumab demonstrated superior survival benefit 
when compared with ipilimumab monotherapy.  Combination therapy provided the 
greatest clinical benefit, with patients receiving this treatment having the highest overall 
response (OR) and complete response (CR) rates (58% and 22%, respectively, for 
nivolumab  ipilimumab combination therapy; 45% and 19% for nivolumab monotherapy; 
and 19% and 6% for ipilimumab monotherapy) (Larkin et al. 2015; Wolchok et al. 2017; 
Larkin et al. 2019). 
As a result of clinical evidence demonstrated in the metastatic setting, combination 
therapy with nivolumab  ipilimumab was investigated in patients with macroscopic 


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Stage III melanoma.  The OpACIN study (Blank et al. 2018) investigated the benefit of 
neoadjuvant versus adjuvant treatment with nivolumab  ipilimumab on relapse-free 
survival (RFS) and OS, and proposed superior benefit for the neoadjuvant use. 
Combination treatment with nivolumab  ipilimumab presents more safety concerns than 
treatment with either nivolumab or ipilimumab alone, as serious toxicities and the need 
for treatment discontinuation occur more frequently in patients treated with 
nivolumab  ipilimumab (Schadendorf et al. 2017; Shoushtari et al. 2018).  These 
toxicities have also been seen in patients with Stage III melanoma who received 
nivolumab  ipilimumab as neoadjuvant therapy, and they were severe enough to impact 
the timing of surgical intervention.  Therefore, different schedules of treatment with 
nivolumab  ipilimumab combination therapy were explored in the OpACIN-neo study.  
An alternative off-label dosing regimen (nivolumab 3 mg/kg  ipilimumab 1 mg/kg) was 
found to retain comparable pathological response rates while decreasing toxicities 
(Rozeman et al. 2019). 
A11–2.3 
BENEFITRISK ASSESSMENT 
Nivolumab and ipilimumab are approved treatment options for patients with melanoma 
and have demonstrated a favorable benefitrisk assessment.  Moreover, combination 
therapy with nivolumab  ipilimumab is approved in the advanced setting for 
unresectable or metastatic melanoma. 
More detailed information about known and expected benefits in the context of potential 
risks and expected adverse events related to nivolumab and ipilimumab administration is 
provided in the local prescribing information for each agent. 
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, refer to Section 1.3. 
A11–3 
RATIONALE FOR DOSE AND SCHEDULE FOR NIVO  IPI ARM 
The approved combination regimen for metastatic melanoma is nivolumab (1 mg/kg 
every 3 weeks [Q3W] for four doses)  ipilimumab (3 mg/kg Q3W for four doses), 
followed by nivolumab 3 mg/kg every two weeks.  An alternative dosing regimen of 
nivolumab 3 mg/kg and ipilimumab 1 mg/kg was identified in the OpACIN-neo study as 
the optimal neoadjuvant dosing regimen in melanoma, with comparable clinical efficacy 
and improved tolerability (Rozeman et al. 2019). 


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Given the evidence of clinical efficacy in both the neoadjuvant and adjuvant settings, and 
the fact that nivolumab in combination with ipilimumab is approved for patients with 
advanced melanoma, combination treatment with nivolumab 3 mg/kg  ipilimumab 
1 mg/kg was considered to be the best comparator for the anticipated patient population 
in this study (Wolchok et al. 2013; Sznol et al. 2014; Rozeman et al. 2019). 
Nivolumab will be administered at a dose of 3 mg/kg IV and ipilimumab will be 
administered at a dose of 1 mg/kg IV Q3W on Day 1 of each 21-day cycle. 
A11–4 
MATERIALS AND METHODS SPECIFIC TO NIVO  IPI ARM 
A11–4.1 
TREATMENT IN NIVO  IPI ARM 
A11–4.1.1 
Formulation, Packaging, and Handling 
A11–4.1.1.1 Nivolumab 
The nivolumab drug product will be supplied by the Sponsor as a 10 mg/mL concentrate 
for solution for infusion. 
For information on the formulation, packaging, and handling of nivolumab, refer to the 
local prescribing information for nivolumab. 
A11–4.1.1.2 Ipilimumab 
The ipilimumab drug product will be supplied by the Sponsor as a 5 mg/mL concentrate 
for solution for infusion. 
For information on the formulation, packaging, and handling of ipilimumab, refer to the 
local prescribing information for ipilimumab. 
A11–4.1.2 
Dosage, Administration, and Compliance 
Patients in the nivolumab  ipilimumab (Nivo  Ipi) control arm will receive treatment for 
2 cycles (6 weeks) as outlined in Table A11-1 until surgery, or until unacceptable toxicity 
or loss of clinical benefit, whichever occurs first (see Section 3.1.2 for details).  It is 
recommended that treatment be initiated no later than 7 days after randomization. 
Table A11-1 
Treatment Regimen for Nivo  Ipi Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
 Nivolumab 3 mg/kg IV on Day 1 of each cycle 
 Ipilimumab 1 mg/kg IV on Day 1 of each cycle 
Ipi  ipilimumab; Nivo  nivolumab. 
 


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Refer to the local prescribing information for each agent for detailed instructions on drug 
preparation, storage, and administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  For 
information on overdosing of nivolumab or ipilimumab, refer to the local prescribing 
information for each agent. 
A11–4.1.2.1 Nivolumab 
Nivolumab will be administered by IV infusion at a dose of 3 mg/kg on Day 1 of each 
21-day cycle. 
Administration of nivolumab 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 8. 
For information on the formulation, packaging, and handling of nivolumab, refer to the 
local prescribing information. 
A11–4.1.2.2 Ipilimumab 
Ipilimumab will be administered by IV infusion at a dose of 1 mg/kg on Day 1 of each 
21-day cycle. 
Administration of ipilimumab 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 8. 
For information on the formulation, packaging, and handling of ipilimumab, refer to the 
local prescribing information. 
A11–4.2 
CONCOMITANT THERAPY FOR NIVO  IPI ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated study treatment from 7 days prior to 
initiation of study treatment to the treatment discontinuation visit.  All such medications 
should be reported to the investigator and recorded on the Concomitant Medications 
eCRF. 
For information on permitted, prohibited, or cautionary therapy, prohibited foods, and 
other restrictions (as applicable) for nivolumab or ipilimumab, refer to the local 
prescribing information for each agent. 


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A11–4.3 
CONTRACEPTION REQUIREMENTS FOR NIVO  IPI ARM 
Contraception requirements for women and men in the Nivo  Ipi arm are outlined below: 
 
Women of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use contraception methods, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 5 months after the final 
dose of study treatment. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
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). 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
5 months after the final dose of nivolumab and/or ipilimumab to avoid exposing 
the embryo.  Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 


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A11–5 
ASSESSMENT OF SAFETY FOR NIVO  IPI ARM 
A11–5.1 
SAFETY PLAN FOR NIVO  IPI ARM 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Administration of study treatment will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions.  Adverse events will 
be reported as described in Sections 5.25.6. 
For detailed safety information, refer to the local prescribing information for each agent. 
A11–5.1.1 
Risks Associated with Nivolumab 
Nivolumab has been associated with risks such as infusion-related reactions (IRRs) and 
immune-mediated adverse events.  Refer to the local prescribing information for 
nivolumab for a detailed description of anticipated safety risks for nivolumab. 
A11–5.1.2 
Risks Associated with Ipilimumab 
Ipilimumab has been associated with risks such as IRRs and immune-mediated adverse 
events.  Refer to the local prescribing information for ipilimumab for a detailed 
description of anticipated safety risks for ipilimumab. 
A11–5.1.2.1 Risks Associated with Combination Use of Nivolumab and 
Ipilimumab 
Immune-related adverse reactions have occurred at higher frequencies in combination 
treatment of nivolumab with ipilimumab compared with either drug as monotherapy. 
A11–5.1.2.2 Management of Patients Who Experience Adverse Events in 
Nivo  Ipi Arm 
Guidelines for the management of patients who experience adverse events are provided 
in the local prescribing information for each drug. 
A11–5.2 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
NIVO  IPI ARM 
A11–5.2.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the final dose of nivolumab or within 5 months after the final dose 
of ipilimumab.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Pregnancy should not 


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be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A11–5.2.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the final dose of nivolumab or within 5 months after the final dose of 
ipilimumab.  The investigator should report the pregnancy on the paper Clinical Trial 
Pregnancy Reporting Form and submit the form to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for the Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 


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An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A11–5.2.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A11–5.2.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 








Appendix 11:  Study Details Specific to Nivo  Ipi Arm (Control) 
 
TABLE A11-2 SCHEDULE OF ACTIVITIES FOR NIVO  IPI ARM (cont.) 
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Assessment/ 
Procedure a 
Protocol 
Section 
Screening  
(see 
Appendix 
10) 
Treatment Cycles 
(21-Day Cycles) 
Pre-Surgery 
Surgery 
CLND 
Post-Surgery 
Treatment 
Comp./ 
Discon. b 
Long-
Term 
Follow-
Up 
Surgery 
Follow-Up c 
Cycle 1 
Cycle 2 
D 28 
to D 1 
D1 
( 7D after 
randomization) 
D1 
( 1D) 
Wk 6 
( 8D to 
surgery) 
Wk 7 
( 7D) 
Wk 10 
( 20D after 
surgery) 
Wk 13 
Every 
3M 
( 7D) 
6M after 
surgery  
( 7D) 
Tumor biopsy (optional) 
4.5.11 
Perform at the time of unacceptable toxicity, loss of clinical benefit, relapse, 
or at any other time if deemed clinically feasible by the investigator. 
 
CLND  complete lymph node dissection; Comp.  completion; CT  computed tomography; D  day; Discon.  discontinuation; ECOG  Eastern 
Cooperative Oncology Group; IMP  investigational medicinal product; M  month; MUGA  multiple-gated acquisition; T3  triiodothyronine; 
T4  thyroxine; TSH  thyroid-stimulating hormone; TTE  transthoracic echocardiogram; Wk  week. 
Note:  On treatment days, all assessments and procedures should be performed prior to dosing, unless otherwise specified. 
a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will return to the clinic for a treatment completion/discontinuation visit 6 weeks after surgery and patients who do not proceed to surgery will 
return to the clinic for a treatment completion/discontinuation visit not more than 30 days after the final dose of study treatment. 
c Patients who proceed to surgery will have the surgery follow-up 6 months after surgery.  
d Assessment may be performed within 24 hours prior to dosing during the treatment period. 
e The disease status assessments at Week 13 should include a mandatory CT scan 


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TABLE A11-2 SCHEDULE OF ACTIVITIES FOR NIVO  IPI ARM (cont.) 
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f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 135 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on reporting all 
treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each adverse event 
until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-
related procedures until a final outcome can be reported. 
g Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will have their first long-term follow-up visit 3 months after surgery and patients who do not proceed to surgery will have their first long-term 
follow-up visit 3 months after the final dose of study treatment.  Information on long-term follow-up and new anti-cancer therapy (including 
targeted therapy and immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 
3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from 
follow-up, this request must be documented in the source documents and signed by the investigator.  If a patient withdraws from the study, the 
study staff may use a public information source (e.g., county records) to obtain information about survival status only. 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments. 
k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a local 
gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration. 
 
 


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A11–7 
SCHEDULE OF BIOMARKER SAMPLES FOR NIVO  IPI 
CONTROL ARM 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to the first infusion 
(6 hr to 0 hr) 
 Biomarkers (blood, plasma) 
Day 1 of Cycle 2 
Prior to infusion  
(6 hr to 0 hr) 
 Biomarkers (blood, plasma) 
Surgery CLND 
Week 7 
Prior to surgery  
(24 hr to 0 hr) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation visit 
Week 13 
At visit 
 Biomarkers (blood, plasma) 
Long-term follow-up 
Every 3 months ( 7 days) b 
At visit 
 Biomarkers (blood, plasma) 
Surgery follow-up 
6 months after surgery  
( 7 days) 
At visit 
 Biomarkers (blood, plasma) 
CLND  complete lymph node dissection; Ipi  ipilimumab; Nivo  nivolumab. 
a Week 10 biomarker samples must be obtained  20 days post-surgery. 
b To be collected if visit is conducted on site. 
  
 


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A11–8 
REFERENCES 
Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus 
nivolumab in macroscopic stage III melanoma. Nature Med 2018;24:165561. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med 2015;373:234. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined 
nivolumab and ipilimumab in advanced melanoma. N Engl J Med 
2019;381:153546. 
Rozeman EA, Menzies AM, van Akkooi AC, et al. Identification of the optimal 
combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in 
macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, 
randomised, controlled trial. Lancet Oncol 2019;20:94860. 
Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients ith 
advanced melanoma who discontinued treatment with nivolumab and ipilimumab 
because of adverse events: a pooled analysis of randomized phase II and III trials. 
J Clin Oncol 2017;35:380714. 
Shoushtari AN, Friedman CF, Navid-Azarbaijani P, et al. Measuring toxic effects and 
time to treatment failure for nivolumab plus ipilimumab in melanoma. JAMA Oncol. 
2018;4:98101. 
Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by 
BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, 
ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma 
(MEL). J Clin Oncol 2014;32(18 Suppl):9003. 
Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab 
(anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients 
(pts) with advanced melanoma (MEL). J Clin Oncol 2013;31(15 Suppl):9012. 
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined 
nivolumab and ipilimumab in advanced melanoma. N Engl J 
Med 2017;377:134556. 
 


  
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Appendix 12  
Study Details Specific to RO7247669 2100 mg Arm 
TABLE OF CONTENTS 
A12–1 
Background on RO7247669 2100 mg Arm ............................... 197 
A12–2 
Rationale for RO7247669 2100 mg Arm ................................... 197 
A12–2.1 
Targeting the PD-1 and LAG-3 Antigens .................................. 197 
A12–2.2 
Clinical Studies of Agents Targeting the PD-1 and LAG-3 
Pathways .................................................................................. 198 
A12–2.2.1 
Study NP41300 ......................................................................... 200 
A12–2.3 
BenefitRisk Assessment ......................................................... 200 
A12–3 
Rationale for Dose and Schedule for RO7247669 2100 mg 
Arm ........................................................................................... 201 
A12–3.1 
Rationale for RO7247669 Dose and Schedule ......................... 201 
A12–4 
Materials and Methods Specific to RO7247669 2100 mg Arm .. 202 
A12–4.1 
Treatment in RO7247669 2100 mg Arm ................................... 202 
A12–4.1.1 
Formulation, Packaging, and Handling ..................................... 202 
A12–4.1.2 
Dosage, Administration, and Compliance ................................. 202 
A12–4.2 
Concomitant Therapy for RO7247669 2100 mg Arm ................ 204 
A12–4.2.1 
Permitted Therapy for RO7247669 2100 mg Arm ..................... 204 
A12–4.2.2 
Cautionary Therapy for RO7247669 2100 mg Arm ................... 205 
A12–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ........................................... 205 
A12–4.2.2.2 
Herbal Therapies ...................................................................... 205 
A12–4.2.3 
Prohibited Therapy for RO7247669 2100 mg Arm .................... 205 
A12–4.3 
Contraception Requirements for RO7247669 2100 mg Arm ..... 206 
A12–5 
Assessment of Safety for RO7247669 2100 mg Arm ................ 207 
A12–5.1 
Safety Plan for RO7247669 2100 mg Arm ................................ 207 
A12–5.1.1 
Risks Associated with RO7247669 ........................................... 207 
A12–5.1.1.1 
Infusion-Related Reactions and Anaphylaxis ............................ 207 
A12–5.1.1.2 
Immunogenicity ......................................................................... 208 
A12–5.1.1.3 
Immune-Mediated Adverse Events ........................................... 208 
A12–5.1.2 
Management of Patients Who Experience Specific Adverse 
Events in RO7247669 2100 mg Arm ......................................... 208 
A12–5.1.2.1 
Dose Modifications .................................................................... 208 
A12–5.1.2.2 
Treatment Interruption for Toxicities ......................................... 208 
A12–5.1.2.3 
Management Guidelines for Adverse Events ............................ 209 
A12–5.2 
Adverse Events of Special Interest for RO7247669 2100 mg 
Arm (Immediately Reportable to the Sponsor) .......................... 212 
A12–5.3 
Reporting Requirements for Pregnancies in RO7247669 
2100 mg Arm ............................................................................. 212 
A12–5.3.1 
Pregnancies in Female Patients ............................................... 212 
A12–5.3.2 
Pregnancies in Female Partners of Male Patients .................... 213 
A12–5.3.3 
Abortions ................................................................................... 213 
A12–5.3.4 
Congenital Anomalies/Birth Defects .......................................... 214 


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A12–6 
Schedules of Activities and Sample Collection for 
RO7247669 2100 mg Arm ........................................................ 215 
A12–7 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for RO7247669 2100 mg Arm ................... 220 
A12–8 
References ................................................................................ 221 
 
 
 
 


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A12–1 
BACKGROUND ON RO7247669 2100 mg ARM 
RO7247669 is a novel, Fc-silent IgG1-based bispecific antibody (bsAb) in 1  1 format 
that incorporates monovalent binding to two immune checkpoint proteins:  PD-1 and 
LAG-3.  RO7247669 is designed to target dysfunctional tumor antigen-specific 
T-lymphocytes expressing PD-1 and LAG-3 to establish or re-establish an effective 
anti-tumor immune response in cancer patients.  This may result in improved therapeutic 
responses over currently available therapies.  In addition, RO7247669 is engineered to 
prevent binding to Fc gamma receptors, thus potentially avoiding tumor-associated 
macrophage resistance mechanisms.  Such mechanisms have been observed with 
IgG4-based antiPD-1 antibodies, such as pembrolizumab and nivolumab (Arlauckas 
et al. 2017).  Clinical evaluation of RO7247669 is ongoing in a first-in-human, 
dose-finding study (NP41300) as a single agent in cancer patients with and without prior 
checkpoint inhibitor (CPI) exposure.   
Refer to the RO7247669 Investigator’s Brochure for details on nonclinical and other 
planned and ongoing clinical studies. 
A12–2 
RATIONALE FOR RO7247669 2100 mg ARM 
A12–2.1 
TARGETING THE PD-1 AND LAG-3 ANTIGENS 
Cancer immunotherapy agents, particularly immune CPIs, have had a significant impact 
on the treatment of patients with advanced malignancies in recent years.  However, 
despite the remarkable clinical efficacy of these therapies, additional treatment options 
targeting immune checkpoints are needed because the majority of patients eventually 
progress after an initial response or else fail to respond to the PD-1/PD-L1 checkpoint 
blockade.  This is believed to be due mainly to primary or secondary resistance 
mechanisms, to immunosuppressive activity of myeloid-derived suppressor cells, and/or 
to T-regulatory cells (Sharma et al. 2017). 
To overcome resistance mechanisms, additional treatment options and multiple 
combinations with antiPD-L1 therapy are being assessed.  One potential reason for 
resistance to antiPD-L1 therapy is the upregulation of alternative immune checkpoints 
with non-redundant regulatory functions (Sharma et al. 2017).  LAG-3 is one such 
alternative immune checkpoint.  LAG-3 is a member of the Ig superfamily that is 
structurally similar to CD4.  LAG-3 is expressed on activated effector T cells and is 
constitutively expressed on T-regulatory cells and natural killer (NK) cells.  The 
expression of both PD-1 and LAG-3 on tumor infiltrating lymphocytes (TILs) correlates 
with the degree of impairment of effector functions, which is associated with poor 
prognosis (Matsuzaki et al. 2010; Baitsch et al. 2011; Thommen et al. 2015).  Hence, 
LAG-3 is a marker of T-cell dysfunctionality.  LAG-3 also regulates T-cell functions, 
presumably including the function of T-regulatory cells.  In chronic infections and cancer, 
LAG-3, together with PD-1, contributes to T-cellacquired dysfunctionality and to the 


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inability of T cells to mount an effective/protective immune response upon interaction 
with the LAG-3 ligand, MHC-II. 
The interaction of LAG-3 with MHC-II inhibits T-cell proliferation, activation, cytolytic 
function, and proinflammatory cytokine production (Goldberg and Drake 2011).  The 
effect of LAG-3 expression on T-regulatory cells is controversial.  An early report 
concluded that LAG-3 promotes T-regulatory cell-mediated immune suppression 
(Camisaschi et al. 2010).  However, a more recent report from the same authors found 
that LAG-3 limits T-regulatory cell-mediated immune suppression (Zhang et al. 2017). 
Expression of LAG-3 has been reported across various tumor types, including breast 
cancer, ovarian cancer, non-small cell lung cancer (NSCLC), melanoma, renal cell 
cancer (RCC), prostate cancer, and hepatocellular carcinoma (HCC).  In patients with 
these tumor types, LAG-3 is associated with poor prognosis (Matsuzaki et al. 2010; 
Baitsch et al. 2011; Thommen et al. 2015; He et al. 2016; Norstrom et al. 2016).  Clinical 
evaluation of antiLAG-3 agents, as single agents and in combination with other CPIs, is 
ongoing in several early phase studies in patients with advanced solid tumors 
(Long et al. 2018).  Preliminary data demonstrate that antiLAG-3 therapy is well 
tolerated, both as single agents and in combination with antiPD-1 therapies, and the 
safety profiles are consistent with those of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018; Stratton et al. 2018).  RO7247669 may therefore be a therapeutic 
option for patients with melanoma. 
Resistance to PD-L1/PD-1 blockade may result in the expression of multiple co-inhibitory 
immune checkpoints on the surface of effector T cells.  LAG-3 is frequently 
co-expressed with PD-1 on TILs, and dual blockade of PD-1 and LAG-3 enhances 
CD8 T-cell effector function and potentiates anti-tumor immunity in nonclinical models.  
Blockade of these two receptors in mice with colon, fibrosarcoma, or ovarian tumors 
resulted in tumor remission in approximately 80% of animals, compared with remission 
in 10% to 40% with blockade of either receptor using a single agent (Woo et al. 2012; 
Huang et al. 2015).  TILs from patients with ovarian cancer showed that antigen-specific 
CD8 T cells co-expressing PD-1 and LAG-3 exhibited greater impairment in their ability 
to respond to cognate antigen stimulation compared with CD8 T cells that expressed 
one checkpoint molecule (Matsuzaki et al. 2010).  In patients with NSCLC, 
overexpression of LAG-3 on TILs correlated with PD-1/PD-L1 expression and was linked 
to higher risk of recurrence and poor survival outcomes (He et al. 2017). 
A12–2.2 
CLINICAL STUDIES OF AGENTS TARGETING THE PD-1 AND 
LAG-3 PATHWAYS 
Clinical data are available for early- and late-phase studies that evaluated the safety, 
tolerability, and preliminary anti-tumor activity of agents that target both the PD-1 and 
LAG-3 pathways.  Evidence of clinical activity has been reported in some of these 


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studies.  Overall, adverse events have been manageable to date, and the safety profiles 
appear similar to those of single-agent CPIs. 
An ongoing Phase I/IIa study is evaluating the safety, tolerability, and clinical activity of 
combination treatment with the antiPD-1 monoclonal antibody nivolumab and the 
antiLAG-3 monoclonal antibody relatlimab in patients with advanced solid tumors.  
Preliminary data suggest that the combination of nivolumab and relatlimab may have an 
increased benefit compared with single-agent antiPD-1.  In a cohort of patients who 
had advanced melanoma who were previously treated with antiPD-1/PD-L1 agents, the 
ORR was 11.5% (n  61) with a disease control rate (DCR) of 49%.  The 
antiPD-1/PD-L1 treatment combination had an acceptable safety profile that was 
similar to the safety profile of nivolumab monotherapy (Ascierto et al. 2017). 
Relativity-047 is a phase III study evaluating the combination of nivolumab 
(antiPD-1) and relatlimab (antiLAG-3) versus nivolumab alone in patients with 
untreated advanced melanoma.  This study demonstrated that nivolumab and relatlimab 
improved progression-free survival (PFS  10.1 months) over nivolumab 
(PFS  4.6 months).  The incidence of Grade 3 or 4 treatment-related adverse events was 
18.9% in patients that received the nivolumab and relatlimab combination and 9.7% in 
patients that received nivolumab alonoe (Tawbi et al. 2022).  
An ongoing Phase I/II study is evaluating the safety, tolerability, and clinical activity of 
combination treatment with the antiPD-1 monoclonal antibody spartalizumab and the 
antiLAG-3 monoclonal antibody LAG525 in patients with advanced solid tumors.  
Preliminary anti-tumor activity was observed during the Phase I dose-escalation portion 
of the study, including durable responses in 2 of 5 patients with triple-negative breast 
cancer (TNBC) and in 2 of 8 patients with mesothelioma.  Analyses of tumor biopsies 
from the TNBC cohort also showed a trend of conversion from an immune-cold to an 
immune-activated phenotype.  Common adverse events, i.e., adverse events reported in 
 10% of patients, included fatigue (18%), diarrhea (15%), and nausea (12%).  
The incidence of Grade 34 adverse events was 8% for both the combination (n  121) 
and monotherapy (n  119) arms (Hong et al. 2018). 
An ongoing, first-in-human, dose-escalation, and dose-expansion Phase I study is 
evaluating the safety, tolerability, and clinical activity of the antiPD-1/LAG-3 dual affinity 
re-targeting protein (DART®) bsAb MGD013 in patients with advanced solid tumors and 
hematologic malignancies.  During the dose-escalation phase of the study, the maximum 
tolerated dose (MTD) was not reached, and the safety profile was consistent with 
antiPD-1 monotherapy.  During the dose-expansion phase, anti-tumor activity was 
observed in patients with TNBC (n  23; ORR, 4.3%; DCR, 39.1%), CPI-naive NSCLC 
(n  14; ORR, 14.3%; DCR, 64.3%), and epithelial ovarian cancer (n  23; ORR, 8.7%; 
DCR, 52.2%).  Expression of LAG-3 and an IFN- gene signature at baseline was 


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associated with objective responses (Luke et al. 2020).  Clinical studies evaluating 
MGD013 as monotherapy and in combination with antiHER-2 agents are ongoing. 
A12–2.2.1 
Study NP41300 
Study NP41300 is an ongoing, first-in-human, dose-escalation, dose-expansion Phase I 
study to evaluate the safety, pharmacokinetics, and therapeutic activity of the 
antiPD-1/LAG-3 bsAb RO7247669 as a single agent in patients with locally advanced 
and/or metastatic solid tumors.  Part A, the dose-escalation phase of the study, is 
designed to determine the MTD and/or recommended dose for expansion (RDE) of 
RO7247669.  Part B of the study is designed to evaluate the anti-tumor activity of 
RO7247669 at the MTD or RDE in tumor-specific expansion cohorts. 
As of the data cut-off date of 1 March 2022, RO7247669 was well tolerated in the 
patients enrolled in Part A of the study.  No unexpected safety concern associated with 
RO7247669 was identified.  No dose-limiting toxicities (DLTs) were observed up to the 
maximum dose tested (2100 mg every 2 weeks [Q2W]), and no MTD was identified.  
The maximum dose of 2100 mg was determined to be the recommended dose for the 
dose-expansion phase (Part B) of Study NP41300.  As of the data cutoff of 
1 March 2022, 83 patients received treatment in Part B.  
As of the data cutoff date of 1 March 2022, the DCR in Part A of the study was 51.4% 
(18 of 35 evaluable patients), and the ORR was 17.1% (6 of 35 patients).  Among the 
patients treated with the proposed dose of 2100 mg Q2W, 7 of 13 patients had a best 
response of stable disease or better (DCR  53.8%), including 4 patients with a 
confirmed partial response (PR; ORR  30.8%).  Besides the confirmed partial responses 
(cPR) observed at the RDE, there were 2 cPRs at the 600 mg dose level (ORR   50.0%). 
As of the data cutoff date, 1 March 2022, in Part B of the study the DCR was 48.3% 
(28 of 58 patients) and the ORR was 5.2% (3 of 58 patients) among patients of the 
study treated at the RDE of 2100 mq Q2W (Cohorts B1, B2, and B3).  Within patients 
treated with 600 mg Q2W (Cohort B5), the DCR was 40% (4 of 10 patients), and the 
ORR was 10% (1 of 10 patients).  Among patients treated with 600 mg Q3W, the DCR 
was 28.6% (2 of 7 patients) and the ORR was 14.3% (1 of 7 patients). 
Refer to the RO7247669 Investigator’s Brochure for additional details on all ongoing and 
planned clinical studies. 
A12–2.3 
BENEFITRISK ASSESSMENT 
Despite limited clinical experience with RO7247669, the clinical efficacy and safety 
profiles of antiPD-1/PD-L1 monoclonal antibodies are well characterized and 
established.  In recent years, four checkpoint inhibitors, namely pembrolizumab, 


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nivolumab, ipilimumab, and relatlimab have been approved by the FDA for the treatment 
of unresectable or advanced melanoma.  
The co-stimulatory action of RO7247669 on PD-1 and LAG-3 receptors may result in 
enhanced and/or more durable responses than either therapy modality alone.  However, 
there may be a risk of exaggerated immune cell activation, particularly given the LAG-3 
modulation of the immune response.  Preliminary data from Study NP41300, and recent 
early phase studies of antiLAG-3 antibodies showed that antiLAG-3 therapy was 
generally well tolerated as monotherapy or in combination with antiPD-1 therapies, and 
that it had a safety profile consistent with the safety profiles of other CPIs (Ascierto et al. 
2017; Hong et al. 2018; Stratton et al. 2018).  The safety and efficacy of CPIs is 
established in the adjuvant setting, and CPIs are now being actively evaluated as 
neoadjuvant treatment and show promising early results (Herrscher and Robert 2020). 
To evaluate the toxicities of the experimental treatments in the neoadjuvant setting, a 
minimum of 6 patients in the RO7247669 2100 mg arm must complete a safety 
evaluation before additional patients can be enrolled in that arm (refer to Section 3.1.3 
for details). 
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please refer to Section 1.3. 
A12–3 
RATIONALE FOR DOSE AND SCHEDULE FOR RO7247669 
2100 mg ARM 
A12–3.1 
RATIONALE FOR RO7247669 DOSE AND SCHEDULE 
RO7247669 will be administered at a fixed dose of 2100 mg Q3W (2100 mg on Day 1 of 
each 21-day cycle).  A fixed dosing regimen of 2100 mg Q3W was selected based on 
available clinical pharmacokinetic, efficacy, and safety data from Study NP41300.  
During the dose-escalation Part A of the study, RO7247669 was well tolerated, and no 
specific safety concern associated with RO7247669 was identified.  No DLT up to the 
highest dose of 2100 mg Q2W was observed, and no MTD was identified.  Anti-tumor 
activity, as measured by radiographic PRs, was observed starting at a dose of 600 mg 
Q2W.  PK results for RO7247669 were dose linear within the dose range tested in 
Study NP41300 and were therefore predicted to be in the range of target saturation.  
Peripheral receptor occupancy was  90% ~80 days after administration; therefore, Q3W 
administration should result in similar receptor occupancy as Q2W administration. 
In addition, RO7247669 was well tolerated in both the dose range finding studies and 
Good Laboratory Practice (GLP) monkey toxicology studies up to the highest dose 
evaluated (100 mg/kg).  Toxicology findings were consistent with the findings in 
cynomolgus monkey studies of marketed CPIs. 


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The supporting data for the selected dose can be found in the RO7247669 Investigator’s 
Brochure. 
A12–4 
MATERIALS AND METHODS SPECIFIC TO RO7247669 2100 mg 
ARM 
A12–4.1 
TREATMENT IN RO7247669 2100 mg ARM 
A12–4.1.1 
Formulation, Packaging, and Handling 
The RO7247669 drug product will be supplied by the Sponsor as a 50 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of RO7247669, refer to the 
pharmacy manual and the RO7247669 Investigator’s Brochure. 
A12–4.1.2 
Dosage, Administration, and Compliance 
Patients in the RO7247669 2100 mg arm will receive treatment for 2 cycles (6 weeks) as 
outlined in Table A12-1 until surgery, or until unacceptable toxicity or loss of clinical 
benefit, whichever occurs first (see Section 3.1.2 for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 
Table A12-1 
Treatment Regimen for RO7247669 2100 mg Arm 
Cycle Length 
Dose, Route, and Regimen 
21 days 
 RO7247669 2100 mg by IV infusion on Day 1 of each cycle 
  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
No safety data related to overdosing of RO7247669 are available to date. 
RO7247669 will be administered by IV infusion at a fixed dose of 2100 mg on Day 1 of 
each 21-day cycle. 
Administration of RO7247669 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 8.  
RO7247669 infusions will be administered per the instructions outlined in Table A12-2. 
 


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Table A12-2 
Administration of First and Second RO7247669 Infusions 
First Infusion 
Second Infusion 
 
No premedication is permitted prior to the 
first RO7247669 infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, pulse oximetry, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO7247669 should be infused over 
60 ( 10) minutes. 
 
After the infusion of RO7247669, the 
patient begins a 60-minute observation 
period. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion.  Record on the eCRF in case of 
abnormalities. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with the 
first infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO77247669 should be infused over 
30 ( 10) minutes if the first infusion was 
tolerated without an IRR, followed by a 
30-minute observation period. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured every 
15 ( 5) minutes during the infusion and 
at 30 ( 10) minutes after the infusion.  
Record on the eCRF in case of 
abnormalities. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
  
For patients who experience a Grade 2 infusion-related reaction (IRR), premedication 
with paracetamol 5001000 mg orally [PO] or IV and diphenhydramine 2550 mg PO or 
IV (or an alternative histamine H1/2 antagonist at an adequate dose) is required prior to 
subsequent infusions.  In case of Grade 3 or 4 IRRs related to study treatment, the 
patient should be permanently discontinued from the study treatment. 
Guidelines for medical management of IRRs for RO7247669 are provided in 
Section A12–5.1.2.3. 
No dose modification for RO7247669 is allowed. Guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section A12–5.1.2.2.   


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A12–4.2 
CONCOMITANT THERAPY FOR RO7247669 2100 mg ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
A12–4.2.1 
Permitted Therapy for RO7247669 2100 mg Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A12–4.2.3) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  Other use of corticosteroids may be at the investigator’s discretion.  
The Medical Monitor is available to advise as needed. 
 
Local therapy (e.g., surgery other than complete lymph node dissection [CLND] that 
is not considered to be related to melanoma) 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second RO7247669 infusion only, at the discretion of the investigator. 
In general, investigators should manage a patient’s care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H1/2-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 2-adrenergic agonists; see Appendix 8). 


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A12–4.2.2 
Cautionary Therapy for RO7247669 2100 mg Arm 
A12–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor 
(TNF)- inhibitors may attenuate potential beneficial immunologic effects of treatment 
with RO7247669.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with RO7247669 therapy (see Appendix 9 for details). 
A12–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A12–4.2.3) may be used during the study at the discretion of the 
investigator. 
A12–4.2.3 
Prohibited Therapy for RO7247669 2100 mg Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until surgery or, if earlier, disease 
progression is documented and the patient has discontinued study treatment. 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with RO7247669, and for 4 months 
after the final dose of RO7247669. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment and during study treatment 
because these agents could potentially increase the risk for autoimmune conditions 
when given in combination with RO7247669. 
 


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A12–4.3 
CONTRACEPTION REQUIREMENTS FOR RO7247669 2100 mg 
ARM 
Contraception requirements for women and men in the RO7247669 2100 mg arm are 
outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 4 months after the final 
dose of RO7247669. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraception, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant or a 
pregnant female partner, men who are not surgically sterile must remain 
abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year during the treatment period, for 
4 months after the last dose of RO7247669 to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
A12–5 
ASSESSMENT OF SAFETY FOR RO7247669 2100 mg ARM 
A12–5.1 
SAFETY PLAN FOR RO7247669 2100 mg ARM 
The safety plan for patients in this study is based on clinical experience with RO7247669 
in ongoing studies.  The potential safety risks are outlined below (see Section A12–
5.1.1).  Guidelines for management of patients who experience specific adverse events 
are provided in Section A12–5.1.2 and Appendix 9. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Special caution will be taken by performing a planned safety 
evaluation phase for patients randomized to this arm (see Section 3.1.3). 
Administration of study treatment will be performed in a monitored setting in which there 
is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Adverse events will be reported as described in 
Sections 5.25.6. 
A12–5.1.1 
Risks Associated with RO7247669 
Clinical evaluation of RO7247669 is ongoing, and not all risks are known.  As an 
antagonist of PD-1 and LAG-3, RO7247669 is anticipated to enhance T-cell and NK-cell 
proliferation, survival, and function.  Based on the mechanism-of-action of RO7247669, 
the safety profile is anticipated to be similar to other CPIs.  Potential risks associated 
with RO7247669 include the following:  IRRs (including anaphylaxis), immunogenicity, 
and immune-mediated adverse events.  Refer to Section 6 of the RO7247669 
Investigator’s Brochure for a detailed description of anticipated safety risks for 
RO7247669. 
A12–5.1.1.1 Infusion-Related Reactions and Anaphylaxis 
Administration of therapeutic antibodies may cause IRRs, which may include symptoms 
such as fever, chills, hypotension, shortness of breath, skin rash, headache, nausea, 
and vomiting.  Such reactions typically occur during or shortly after the infusion and are 
predominantly reported following the first infusion.  The incidence and severity of IRRs 
typically decrease with subsequent infusions.  Based on in vitro data, the risk of 
proinflammatory cytokine-mediated IRRs on first administration of RO7247669 as a 
single agent is considered low. 


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Refer to Section A12–4.1.2 for detailed guidance on administration of RO7247669 in this 
study.  Refer to Appendix 8 for guidance on anaphylaxis precautions and to 
Section A12–5.1.2.3 for guidance on the management of IRRs. 
A12–5.1.1.2 Immunogenicity 
Administration of therapeutic antibodies may cause the formation of anti-drug antibodies, 
which may negatively affect the safety of the therapeutic (e.g., allergic reactions, 
immune complex-mediated diseases). 
A12–5.1.1.3 Immune-Mediated Adverse Events 
The co-stimulatory action of RO7247669, in particular its effects on LAG-3, may lead to 
an exaggerated risk of immune cell activation that may result in the occurrence of 
enhanced, untoward, immune-mediated adverse events and increased 
cytokine release-mediated toxicities. 
Toxicities from PD-1 blocking agents can involve any organ or tissue, although some 
immune-mediated adverse events occur much more frequently than others.  The most 
frequently occurring immune-mediated adverse events affect skin, colon, endocrine 
organs, liver, and lungs.  Others are very infrequent but may be very serious, even 
lethal, such as neurological disorders and myocarditis. 
The limited data from recent early phase studies showed antiLAG-3 therapy was 
generally well tolerated as a monotherapy or in combination with anti-PD-1 therapies, 
and data were consistent with the safety profiles of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018). 
In this study, specified immune-mediated adverse events will be considered adverse 
events of special interest and will be captured accordingly (see Section A12–5.2 for the 
list of adverse events of special interest and Section 5.4.2 for reporting instructions). 
Patients with a history of autoimmune disease will be excluded from this study.  Please 
see Section 4.1.2 for details. 
A12–5.1.2 
Management of Patients Who Experience Specific Adverse 
Events in RO7247669 2100 mg Arm 
A12–5.1.2.1 Dose Modifications 
There will be no dose modifications for RO7247669 in this study. 
A12–5.1.2.2 Treatment Interruption for Toxicities 
RO7247669 treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before RO7247669 can be resumed if warranted.  In the neoadjuvant setting, 


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the study treatment is limited to a pre-surgery window of 6 weeks.  Treatment during this 
period should not be interrupted, unless a patient experiences toxicity.  If toxicity meets 
criteria for interrupting/withholding RO7247669, RO7247669 should be 
interrupted/withheld.  After resolution of the toxicity, subsequent treatment cycles should 
only be considered if the benefit-risk profile is acceptable and if the surgery can be 
conducted within 2 weeks of the planned date.  Otherwise, subsequent treatment cycles 
should be omitted to allow the patient to proceed directly to surgery without further delay. 
A12–5.1.2.3 Management Guidelines for Adverse Events 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A12-3. 
 


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Table A12-3 
Guidelines for Management of Patients Who Experience Adverse Events in RO7247669 2100 mg 
Arm 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions 
General guidance 
 For anaphylaxis precautions, see Appendix 8. 
 For severe hypersensitivity reactions, permanently discontinue RO7247669. 
 For suspected CRS, see Appendix 9 for guidance on supportive care. 
 Determine tryptase concentration and IgE titer if clinical presentation of IRR suggests an anaphylactic or 
hypersensitivity reaction (hives, obstructive shortness of breath, urticaria, other histamine associated 
symptoms) and/or if the first IRR or CRS ( Grade 2) is observed at the second infusion.  If tryptase 
and/or IgE are elevated, collect a second sample for IgE/tryptase analysis at least 48 hours after the 
onset of the reaction to rule out the possibility of an anaphylactic reaction.   
IRR to RO7247669, Grade 1 or 2 
 Slow infusion to 50% or interrupt infusion. 
 Give supportive treatment.  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine, such as diphenhydramine, if they have not been administered in the last 4 hours.  IV fluids 
(e.g., normal saline) may be administered as clinically indicated.  For bronchospasm, urticaria, or 
dyspnea, antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or 
bronchodilators may be administered per institutional practice. 
 Upon symptom resolution, infusion may resume (if interrupted) at 50% starting rate.  The infusion must 
remain at the lower rate resulting in symptom resolution for the remainder of the infusion. 
 For Grade 2 IRRs, subsequent doses of RO7247669 should be administered with pre-medication, 
including acetaminophen/paracetamol and an antihistamine such as diphenhydramine. 
 For Grade 2 wheezing or urticaria, patient must also be pre-medicated prior to subsequent doses 
(as described above). 
 If symptoms recur with the same or greater severity following the slower or interrupted infusion, the 
infusion must be stopped immediately.  No further RO7247669 will be administered for the cycle. 
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome. 
 


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Table A12-3 
Guidelines for Management of Patients Who Experience Adverse Events in RO7247669 2100 mg 
Arm (cont.) 
Event 
Action to Be Taken 
IRR to RO7247669, Grade 34 
 Discontinue infusion immediately. 
 Give supportive treatment. 
 Permanently discontinue study treatment. 
Pulmonary, hepatic, GI, endocrine, 
ocular, immune-mediated myocarditis, 
CRS, pancreatic, dermatologic, 
neurologic, immune-mediated 
meningoencephalitis, renal, myositis, 
HLH, MAS, and systemic immune 
activation 
 Guidelines for the management of these events are provided in Appendix 9. 
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; IRR  infusion-related reaction; 
MAS  macrophage activation syndrome. 
 


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A12–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR 
RO7247669 2100 mg ARM (IMMEDIATELY REPORTABLE TO 
THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.2.3 for reporting instructions).  Adverse events of special interest for the 
RO7247669 2100 mg arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
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. 
 
A12–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
RO7247669 2100 mg ARM 
A12–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 4 months after the final dose of RO7247669.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study treatment and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 


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follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A12–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
4 months after the final dose of RO7247669.  The investigator should report the 
pregnancy on the  paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for the Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A12–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.2.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 


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recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.2.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A12–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.2.2). 








Appendix 12:  Study Details Specific to RO7247669 2100 mg Arm 
  
TABLE A12-4 SCHEDULE OF ACTIVITIES FOR RO7247669 2100 mg ARM (cont.) 
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218/Protocol BO43328, Version 4 
Assessment/ 
Procedure a 
Protocol 
Section 
Screening  
(see 
Appendix 
10) 
Treatment Cycles 
(21-Day Cycles) 
Pre-Surgery 
Surgery 
CLND 
Post-Surgery 
Treatment 
Comp./ 
Discon. b 
Long-
Term 
Follow-
Up 
 
Surgery 
Follow-Up c 
Cycle 1 
Cycle 2 
D 28 
to D 1 
D1 
( 7D after 
randomization) 
D1 
( 1D) 
Wk 6 
( 8D to 
surgery) 
Wk 7 
( 7D) 
Wk 10 
( 20D after 
surgery) 
Wk 13 
Every 
3M 
( 7D) 
6M after 
surgery 
( 7D) 
Blood and plasma 
samples for biomarkers 
 4.5.9.2 
Refer to Section A12–7. 
x  
(only if 
onsite) 
Refer to 
Section  
A12–7. 
Pre-dose tumor biopsy 
 
x l 
 
 
 
 
 
 
Resected tissue 
 
 
 
x 
 
 
 
 
Tumor biopsy (optional) 
4.5.11 
Perform at the time of unacceptable toxicity, loss of clinical benefit, relapse, 
or at any other time if deemed clinically feasible by the investigator. 
ADA  anti-drug antibody; CLND  complete lymph node dissection; Comp.  completion; CT  computed tomography; D  day; 
Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; IMP  investigational medicinal product; M  month; MUGA  multiple-gated 
acquisition; PK  pharmacokinetic; T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone; TTE  transthoracic echocardiogram; 
Wk  week. 
Note:  On treatment days, all assessments and procedures should be performed prior to dosing, unless otherwise specified. 
a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will return to the clinic for a treatment completion/discontinuation visit 6 weeks after surgery  and patients who do not proceed to surgery will 
return to the clinic for a treatment completion/discontinuation visit not more than 30 days after the final dose of study treatment. 
c Patients who proceed to surgery will have the surgery follow-up 6 months after surgery. 
d Assessment may be performed within 24 hours prior to dosing during the treatment period. 
e The disease status assessments at Week 13 should include a mandatory CT scan. 


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TABLE A12-4 SCHEDULE OF ACTIVITIES FOR RO7247669 2100 mg ARM (cont.) 
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f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 135 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on reporting all 
treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each adverse event 
until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-
related procedures until a final outcome can be reported. 
g Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will have their first long-term follow-up visit 3 months after surgery and patients who do not proceed to surgery will have their first long-term 
follow-up visit 3 months after the final dose of study treatment.  Information on long-term follow-up and new anti-cancer therapy (including 
targeted therapy and immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 
3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from 
follow-up, this request must be documented in the source documents and signed by the investigator.  If a patient withdraws from the study, the 
study staff may use a public information source (e.g., county records) to obtain information about survival status only.  For an experimental arm 
in which all patients discontinued treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the 
study, the Sponsor may conclude the arm (the remaining ~20% of patients will be discontinued from the study). 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments. 
k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a local 
gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration. 
 
 


Appendix 12:  Study Details Specific to RO7247669 2100 mg Arm 
 
 
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220/Protocol BO43328, Version 4 
A12–7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR RO7247669 2100 mg ARM 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to first infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the end 
of RO7247669 infusion 
 RO7247669 PK (serum) 
Day 1 of Cycle 2 
Prior to infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the end 
of RO7247669 infusion 
 RO7247669 PK (serum) 
Surgery CLND 
Week 7 
Prior to surgery 
(24 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation 
Week 13 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Long-term follow-up 
Every 3 months ( 7 days) b 
At visit 
 Biomarkers (blood, plasma) 
Surgery follow-up 
6 months after surgery  
( 7 days) 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; CLND  complete lymph node dissection; PK  pharmacokinetic. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples may 
not be analyzed if not warranted.  On the basis of emerging biomarker data, the number of 
biomarker samples may be reduced, or sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained  20 days post-surgery. 
b To be collected if visit is conducted on site. 
 


Appendix 12:  Study Details Specific to RO7247669 2100 mg Arm 
 
 
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A12–8 
REFERENCES 
Arlauckas SP, Garris CS, Kohler RH, et al. In vivo imaging reveals a tumor-associated 
macrophage mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 
2017;9:eaal3604. 
Ascierto PA, Bono P, Bhatia S, et al. 4998Efficacy of BMS-986016, a monoclonal 
antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with 
nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 
therapy (mel prior IO) in all-comer and biomarker-enriched populations. 
Ann Onco 2017;28(Suppl 5):v60549. 
Baitsch L, Baumgaertner P, Devêvre E, et al. Exhaustion of tumor-specific CD8+ T cells 
in metastases from melanoma patients. J Clin Invest 2011;121:235060. 
Camisaschi C, Casati C, Rini F, et al. LAG-3 expression defines a subset of CD4() 
CD25(high) Foxp3() regulatory T cells that are expanded at tumor sites. 
J Immunol 2010;184:654551. 
Goldberg MV and Drake CG. LAG-3 in cancer immunotherapy. Curr Top Microbiol 
Immunol 2011;344:26978. 
He Y, Rivard CJ, Rozeboom L, et al. Lymphocyte-activation gene-3, an important 
immune checkpoint in cancer. Cancer Sci 2016;107:11937. 
He Y, Yu H, Rozenboom L, et al. LAG-3 protein expression in non-small cell lung cancer 
and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac 
Oncol 2017;12:81423. 
Herrscher H and Robert C. Immune checkpoint inhibitors in melanoma in the metastatic, 
neoadjuvant, and adjuvant setting. Curr Opin Oncol 2020;32:10613. 
Hong DS, Schoffski P, Calvo A, et al. Phase I/II study of LAG525  spartalizumab 
(PDR001) in patients (pts) with advanced malignancies. J Clin Oncol 
2018;36:3012. 
Huang RY, Eppolito C, Lele S, et al. LAG3 and PD1 co-inhibitory molecules collaborate 
to limit CD8  T cell signaling and dampen antitumor immunity in a murine ovarian 
cancer model. Oncotarget 2015;6:2735977. 
Huard B, Gaulard P, Faure F, et al. Cellular expression and tissue distribution of the 
human LAG-3-encoded protein, an MHC class II ligand.  Immunogenetics 
1994;39:2137. 


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Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
222/Protocol BO43328, Version 4 
Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor 
microenvironment to cancer immunotherapy. Genes Cancer 2018;9:17689. 
Luke JJ, Patel MR, Hamilton E, et al. A phase 1, first-in-human, open-label, dose 
escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-
3, in patients with unresectable or metastatic neoplasms. J Clin Oncol. 
2020;38:3004. 
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumorinfiltrating NY-ESO-1-
specific CD8  T cells are negatively regulated by LAG-3 and PD-1 in human 
ovarian cancer. Proc Natl Acad Sci USA 2010;107:787580. 
Norstrom MM, Radestad E, Sundberg B, et al. Progression of benign prostatic 
hyperplasia is associated with pro-inflammatory mediators and chronic activation 
of prostate-infiltrating lymphocytes. Oncotarget 2016;7:2358193. 
Sharma P, Hu-Lieskovan S, Wargo J, et al. Primary, adaptive, and acquired resistance 
to cancer immunotherapy. Cell 2017;168:70723. 
Stratton K, Marabelle A, Shapiro G, et al. A phase 1 dose escalation study of TSR-033, 
an anti-LAG3 monoclonal antibody, in patients with advanced solid tumors 
[abstract]. SITC 2018;P325. 
Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus 
nivolumab in untreated advanced melanoma. New Engl J Med 2022;386:2434. 
Thommen DS, Schreiner J, Müller P, et al. Progression of lung cancer is associated with 
increased dysfunction of T cells defined by coexpression of multiple inhibitory 
receptors. Cancer Immunol Res 2015;3:134455. 
Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 
synergistically regulate T-cell function to promote tumoral immune escape. Cancer 
Res 2012;72:91727. 
Zhang Q, Chikina M, Szymczak-Workman AL, et al. LAG3 limits regulatory T cell 
proliferation and function in autoimmune diabetes. Sci Immunol 2017;2:eaah4569. 


 
 
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Appendix 13  
Study Details Specific to AtezoTira Arm 
TABLE OF CONTENTS 
A13–1 
Background on Atezo  Tira Arm .............................................. 225 
A13–1.1 
Background on Atezolizumab ................................................... 225 
A13–1.2 
Background on Tiragolumab ..................................................... 225 
A13–2 
Rationale for Atezo  Tira Arm .................................................. 226 
A13–2.1 
The PD-L1 Pathway .................................................................. 226 
A13–2.2 
The TIGIT Pathway ................................................................... 226 
A13–2.3 
Combination Treatment with AntiPD-L1 and Anti-TIGIT 
Agents ....................................................................................... 227 
A13–2.4 
Clinical Studies of Tiragolumab as a Single Agent or in 
Combination with Atezolizumab ................................................ 228 
A13–2.4.1 
Study GO30103 ........................................................................ 228 
A13–2.4.2 
Study GO40290 ........................................................................ 229 
A13–2.5 
BenefitRisk Assessment ......................................................... 231 
A13–3 
Rationale for Dose and Schedule for Atezo  Tira Arm ............ 231 
A13–3.1 
Rationale for Atezolizumab Dose and Schedule ....................... 231 
A13–3.2 
Rationale for Tiragolumab Dose and Schedule ......................... 231 
A13–4 
Materials and Methods Specific to Atezo  Tira Arm ................ 232 
A13–4.1 
Treatment in Atezo  Tira Arm .................................................. 232 
A13–4.1.1 
Formulation, Packaging, and Handling ..................................... 232 
A13–4.1.1.1 
Atezolizumab ............................................................................ 232 
A13–4.1.1.2 
Tiragolumab .............................................................................. 232 
A13–4.1.2 
Dosage, Administration, and Compliance ................................. 232 
A13–4.1.2.1 
Atezolizumab ............................................................................ 233 
A13–4.1.2.2 
Tiragolumab .............................................................................. 234 
A13–4.2 
Concomitant Therapy for Atezo  Tira Arm ............................... 235 
A13–4.2.1 
Permitted Therapy for Atezo  Tira Arm ................................... 236 
A13–4.2.2 
Cautionary Therapy for Atezo  Tira Arm.................................. 236 
A13–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ........................................... 236 
A13–4.2.2.2 
Herbal Therapies ...................................................................... 237 
A13–4.2.3 
Prohibited Therapy for Atezo  Tira Arm ................................... 237 
A13–4.3 
Contraception Requirements for Atezo  Tira Arm ................... 238 
A13–5 
Assessment of Safety for Atezo  Tira Arm .............................. 239 
A13–5.1 
Safety Plan for Atezo  Tira Arm ............................................... 239 
A13–5.1.1 
Risks Associated with Atezolizumab ......................................... 239 
A13–5.1.2 
Risks Associated with Tiragolumab .......................................... 239 
A13–5.1.2.1 
Infusion-Related Reactions ....................................................... 240 
A13–5.1.2.2 
Immune-Mediated Hepatitis ...................................................... 240 
A13–5.1.2.3 
Immune-Mediated Adverse Events ........................................... 240 
A13–5.1.2.4 
Lymphopenia ............................................................................ 241 
A13–5.1.2.5 
Embryofetal Toxicity .................................................................. 241 


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A13–5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Tiragolumab .............................................................................. 241 
A13–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the Atezo  Tira Arm ................................................. 242 
A13–5.1.4.1 
Dose Modifications .................................................................... 242 
A13–5.1.4.2 
Treatment Interruption for Toxicities ......................................... 242 
A13–5.1.5 
Management Guidelines for Adverse Events ............................ 243 
A13–5.1.5.1 
Infusion-Related Reactions ....................................................... 244 
A13–5.2 
Adverse Events of Special Interest for the Atezo  Tira Arm 
(Immediately Reportable to the Sponsor) ................................. 245 
A13–5.3 
Reporting Requirements for Pregnancies in the Atezo  Tira 
Arm ........................................................................................... 246 
A13–5.3.1 
Pregnancies in Female Patients ............................................... 246 
A13–5.3.2 
Pregnancies in Female Partners of Male Patients .................... 246 
A13–5.3.3 
Abortions ................................................................................... 247 
A13–5.3.4 
Congenital Anomalies/Birth Defects .......................................... 247 
A13–6 
Schedules of Activities and Sample Collection for 
Atezo  Tira Arm ....................................................................... 248 
A13–7 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for Atezo  Tira Arm .................................. 254 
A13–8 
References ................................................................................ 256 
 
 
 
 


Appendix 13:  Study Details Specific to Atezo  Tira Arm 
  
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225/Protocol BO43328, Version 4 
A13–1 
BACKGROUND ON ATEZO  TIRA ARM 
A13–1.1 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits 
the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), 
both of which function as inhibitory receptors expressed on T cells.  Therapeutic 
blockade of PD-L1 binding by atezolizumab enhances the magnitude and quality of 
tumor-specific T-cell responses, resulting in improved anti-tumor activity (Fehrenbacher 
et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding to Fc receptors, 
thus eliminating detectable Fc-effector function and associated antibody-mediated 
clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer, small-cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, 
and melanoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A13–1.2 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT and 
prevents its interaction with CD155 (also known as poliovirus receptor [PVR]).  
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.  This may result in improved meaningful anti-tumor activity when 
tiragolumab is used in combination with other cancer immunotherapies and administered 
with chemotherapy.  The available nonclinical and clinical data provide a strong rationale 
for evaluating the potential clinical benefit of tiragolumab in cancer patients. 
Refer to the Tiragolumab Investigator’s Brochure for details on nonclinical and clinical 
studies. 


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A13–2 
RATIONALE FOR ATEZO  TIRA ARM 
A13–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
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 by 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 its 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. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
nonsmall cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, 
melanoma, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma (see the Atezolizumab Investigator's Brochure for detailed efficacy results). 
Cancer immunotherapy agents, particularly immune checkpoint inhibitors, have had a 
significant impact on the treatment of patients with advanced malignancies in recent 
years.  However, despite the remarkable clinical efficacy of these therapies, it has 
become clear that they are not sufficiently active as monotherapy for many patients. 
A13–2.2 
THE TIGIT PATHWAY 
TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin 
superfamily (Yu et al. 2009).  TIGIT is expressed on the surface of activated T cell and 
natural killer (NK) cell subsets and interacts with high affinity with CD155 (also known as 
PVR) (Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated 
T-cell responses in nonclinical models of autoimmune and viral infections, demonstrating 
the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; Johnston et al. 2014).  
TIGIT expression is elevated in the tumor microenvironment in many human tumors, is 


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concordantly expressed with other checkpoint immune-receptors such as PD-1 on the 
surface of T cells, and is associated with impaired T-cell function and anti-tumor 
immunity (Johnston et al. 2014; Manieri et al. 2017).  Activation of TIGIT on T cells and 
NK cells limits cellular proliferation, effector cytokine production, and killing of target 
tumor cells (Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 
2015; Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors.  It is expressed in most solid 
tumors, such as NSCLC, breast cancer, and melanoma, as well as in hematological 
tumors, such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL).  
Fluorescence activated cell sorting analysis of T cells isolated from fresh tumor samples 
revealed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells 
(Johnston et al. 2014; Yadav et al. 2016; Yang 2016; Guillerey at al. 2018).  TIGIT was 
expressed in 30%80% of tumor-infiltrating CD4 T cells and in 50%80% of tumor-
infiltrating CD8 T cells (Johnston et al. 2014). 
Therefore, TIGIT is a potential target for therapeutic interventions that aim to restore the 
immune response against the tumor.  Agents that inhibit TIGIT’s interaction with PVR 
may inhibit an important source of tumor-associated immune suppression, thereby 
enhancing the activity of other immune-based therapies.  Nonclinical studies using 
genetically deficient mice and blocking antibodies have revealed a key role for TIGIT in 
regulating T-cell responses in cancer.  Taken together, these data support the 
hypothesis that anti-TIGIT therapy may reactivate anti-tumor immunity and provide 
clinical benefits to patients with cancer. 
A13–2.3 
COMBINATION TREATMENT WITH ANTIPD-L1 AND ANTI-TIGIT 
AGENTS 
Durable clinical benefit is limited to a minority of patients treated with single-agent 
PD-L1/PD-1 inhibitors.  Therapies targeting the mechanisms of resistance to 
anti-PD-L1/PD-1 therapies are needed to improve outcomes in patients with solid 
cancers.  Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory receptors on the surface of effector T cells.  Nonclinical tumor models have 
shown that TIGIT selectively suppressed the effector function of chronically stimulated 
CD8 T cells, and that inhibiting both TIGIT and PD-L1/PD-1 resulted in superior efficacy 
compared with single-agent treatments (Johnston et al. 2014).  Hence, targeting both 
TIGIT and PD-L1 with tiragolumab and atezolizumab, respectively, in patients, may 
enhance the efficacy of PD-L1/PD-1 blockade across different cancer types, including 
melanoma. 


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A13–2.4 
CLINICAL STUDIES OF TIRAGOLUMAB AS A SINGLE AGENT 
OR IN COMBINATION WITH ATEZOLIZUMAB 
Tiragolumab is currently under investigation in two ongoing clinical studies in patients 
with solid tumors (Studies GO30103 and GO40290) and in one clinical study in patients 
with in hematological malignancies (Study GO41036). 
A13–2.4.1 
Study GO30103 
Study GO30103 is a first-in-human, open-label, multicenter, global, dose-
escalation/dose-expansion Phase I study.  It was designed to evaluate the safety, 
tolerability, and pharmacokinetics of tiragolumab as a single agent (Phase Ia) and in 
combination with atezolizumab (Phase Ib) in patients with locally advanced, recurrent, or 
metastatic incurable tumors, including urothelial cancer, renal cell cancer, NSCLC, head 
and neck squamous cell carcinoma, esophageal cancer, colorectal cancer (CRC), 
gastric cancer, cholangiocarcinoma, and triple-negative breast cancer. 
As of the clinical cutoff date of 2 December 2020, a total of 236 patients had been 
enrolled in Study GO30103.  Forty-two patients were enrolled in the Phase Ia portion of 
the study to receive single-agent tiragolumab, and 217 patients were enrolled in the 
Phase Ib portion of the study to receive tiragolumab in combination with atezolizumab.  
The latter group included 23 patients who crossed over from the Phase Ia portion of the 
study. 
The best observed response with tiragolumab monotherapy in the Phase Ia portion was 
prolonged stable disease in 8 of 42 patients, with some patients, including 1 patient with 
CRC, experiencing a decrease in tumor size. 
In the Phase Ib portion, complete response was observed in 4 of 217 patients at 
tiragolumab dose levels of 400 mg (n  3/48) and 600 mg (n  1/104) in combination with 
1200 mg atezolizumab.  Partial response was observed in 27  of 217 patients at 
tiragolumab dose levels of 30 mg (n  2/13), 400 mg (n  6/48), and 600 mg (n  18/104) 
in combination with 1200 mg atezolizumab, including two patients who crossed over 
from the Phase Ia portion at the 600 mg dose level.  Stable disease was observed in 
53 of 217 patients at tiragolumab dose levels of 2 mg (n  1/8), 8 mg (n  3/12), 30 mg 
(n  2/13), 100 mg (n  3/8), 400 mg (n  12/48), 600 mg (n  25/104), and 1200 mg 
(n  7/24) in combination with 1200 mg atezolizumab, including 8 patients who crossed 
over from the Phase Ia portion of the study (2 patients at 8 mg, 1 patient at 30 mg, 
2 patients at 100 mg, and 3 patients at 400 mg). 
As of 2 December 2020, safety data were available for 235 safety-evaluable patients in 
Study GO30103.  A total of 42 patients were treated in the Phase Ia portion with 
tiragolumab as a single agent (2 mg to 1200 mg), while 216 patients were treated in the 
Phase Ib portion with tiragolumab at dose levels of 2 mg to 1200 mg in combination with 


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atezolizumab at 1200 mg, including 23 patients who crossed over from the Phase Ia 
portion to the Phase Ib portion. 
Tiragolumab was tolerated across all administered dose levels both as a single agent 
and in combination with atezolizumab.  The maximum tolerated dose (MTD) was not 
reached, and the maximum administered dose was 1200 mg.  No dose-limiting toxicities 
(DLTs) or clear dose-related trends in the incidence of adverse events were observed.  
Grade  3 adverse events, regardless of attribution to the study drug(s), were reported in 
16 patients (38.1%) and 113 patients (52.3%) in the Phase Ia and Phase Ib portions, 
respectively.  There were 14 reported deaths in the Phase Ia portion of the study, 
including 12 deaths due to malignant neoplasm progression, 1 death due to 
gastrointestinal hemorrhage in the context of progressive disease, and 1 death due to 
hepatic failure.  The death due to hepatic failure was considered by the investigator to be 
related to study drug.  One hundred eighteen deaths were reported in the Phase Ib 
portion of the study.  This included 111 deaths due to progressive disease (31 cases 
were reported as adverse events during the adverse event reporting period and coded 
as malignant neoplasm progression or neoplasm malignant), 2 deaths due to pulmonary 
embolism, 1 death due to esophageal hemorrhage, 1 death due to sepsis, 1 death due 
to septic shock, 1 death due to COVID-19, and 1 death due to upper airway obstruction.  
Treatment-related serious adverse events were reported in 1 patient in the Phase Ia 
portion (hepatic failure) and in 10 patients (4.6%) in the Phase Ib portion.  No patient 
discontinued study treatment due to adverse events in the Phase Ia portion of Study 
GO30103.  Adverse events leading to treatment discontinuation were reported in 
12 patients in the Phase Ib portion of the study, with a Grade 4 cardiac tamponade, a 
Grade 4 pneumonitis, and one event of Grade 2 arthralgia considered by the investigator 
to be related to the study drug(s).  Adverse events of special interest were reported in 
5 patients (11.9%) in the Phase Ia portion and 82 patients (38.0%) in the Phase Ib 
portion of the study. 
Overall, tiragolumab as a single agent or in combination with atezolizumab has been 
well tolerated, adverse events have been manageable, and the safety profile has been 
observed to be consistent across different solid tumor indications. 
A13–2.4.2 
Study GO40290 
Study GO40290 is a Phase II, randomized, blinded, placebo-controlled study of 
tiragolumab plus atezolizumab compared with placebo plus atezolizumab in patients with 
previously untreated locally advanced unresectable or metastatic PD-L1positive 
NSCLC (defined as tumor proportion score [TPS]  1%). 
As of the primary clinical cutoff date of 30 June 2019, 135 patients with a PD-L1 TPS 
 1% were included in the intent-to-treat (ITT) population and were randomly assigned to 
receive tiragolumab plus atezolizumab (n  67) or placebo plus atezolizumab (n  68).  


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As of the primary analysis, 47.8% of patients in the tiragolumab plus atezolizumab group 
versus 27.9% of patients in the placebo plus atezolizumab group were still receiving 
study treatment in the ITT population.  In the TPS   50% population, 65.5% of patients in 
the tiragolumab plus atezolizumab group versus 24.1% of patients in the placebo plus 
atezolizumab group were still receiving study treatment. 
In all randomized patients, the combination of tiragolumab plus atezolizumab improved 
the co-primary endpoints of investigator-assessed ORR and progression-free survival 
(PFS) compared with placebo plus atezolizumab, with median follow-up of 5.9 months.  
ORR for tiragolumab plus atezolizumab was 31.3% (95% CI: 19.5, 43.2) compared with 
placebo plus atezolizumab which was 16.2% (95% CI: 6.7, 25.7).  Investigator-assessed 
median PFS for tiragolumab plus atezolizumab was 5.4 months (95% CI: 4.2 months, 
not reached) compared to placebo plus atezolizumab which was 3.6 months (95% CI: 
2.7 months, 4.4 months), with a stratified hazard ratio (HR) of 0.57 (95% CI: 0.37, 0.90).  
Investigator-assessed PFS was improved in the tiragolumab plus atezolizumab group 
over the placebo plus atezolizumab group (unstratified HR  0.33; 95% CI: 0.15, 0.72; 
median PFS not reached vs. 3.9 months, respectively). 
As of 2 December 2020, 67 safety-evaluable patients in the tiragolumab plus 
atezolizumab arm in Study GO40290 were treated with a median of 8 doses of 
tiragolumab and atezolizumab (range: 138) for a median of 5.0 months 
(range: 0.0326.0).  In the placebo plus atezolizumab arm, 68 safety-evaluable patients 
were treated with a median of 5 doses of placebo and atezolizumab (range: 137) for a 
median of 2.8 months (range: 0.0326.3). 
As of 30 June 2020, in the Phase II randomized, placebo-controlled Study GO40290, 
a total of 135 safety-evaluable patients were administered either tiragolumab (600 mg 
recommended Phase II/III dose) in combination with atezolizumab or placebo in 
combination with atezolizumab.  The safety profile of tiragolumab plus atezolizumab was 
similar to that of placebo plus atezolizumab- for all-grade adverse events 
(98.5% vs. 97.1%), Grade  3 adverse events (53.7% vs. 50.0%), serious adverse 
events (47.8% vs. 39.7%), and adverse events leading to treatment discontinuation 
(13.4% vs. 11.8%).  Adverse events of special interest were reported in 58.2% of 
patients in the tiragolumab plus atezolizumab arm and in 32.4% of patients in the 
placebo plus atezolizumab arm.  One death due to Epstein-Barr virus (EBV) reactivation 
and possible secondary hemophagocytic lymphohistiocytosis (HLH) was reported in this 
study, which was considered by the investigator to be related to the study drugs. 
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse 
events have been manageable, and the safety profile seems to be consistent as 
reported across different solid tumor indications. 


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Refer to the Tiragolumab Investigator’s Brochure or additional details on all ongoing and 
planned clinical studies. 
A13–2.5 
BENEFITRISK ASSESSMENT 
The preliminary safety and efficacy data from the ongoing studies of tiragolumab as a 
single agent or in combination with atezolizumab across different solid tumor indications 
including melanoma, and hematologic malignancies support a favorable benefitrisk 
profile for tiragolumab.  This favorable benefitrisk profile, the potential for TIGIT as a 
target for therapeutic intervention in melanoma, and the significant unmet medical need 
in this indication are key reasons for the current study. 
To evaluate overlapping toxicities of the experimental treatments in the neoadjuvant 
setting (refer to Section A13–5.1.3 for details), a minimum of 6 patients in the 
Atezo  Tira arm must complete a safety evaluation before additional patients can be 
enrolled in that arm (refer to Section 3.1.3 for details). 
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please refer to Section 1.3. 
A13–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  TIRA ARM 
A13–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (Q3W) 
(1200 mg on Day 1 of each 21-day cycle), which is an approved dosage for 
atezolizumab. 
A13–3.2 
RATIONALE FOR TIRAGOLUMAB DOSE AND SCHEDULE 
Tiragolumab will be administered at a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of 
each 21-day cycle). 
The fixed dose of 600 mg IV Q3W was selected on the basis of available clinical 
pharmacokinetic, efficacy, and safety data from the combined Phase Ia/Phase Ib Study 
GO30103, with single-agent tiragolumab or tiragolumab in combination with 
atezolizumab.  In the Phase Ia portion of the study with tiragolumab as a single agent, 
the MTD was not reached, and no DLTs were observed in dose-escalation.  As of the 
clinical cutoff date, anti-drug antibodies to tiragolumab were rare in the Phase Ia or 
Phase Ib portions across all dose levels.  Complete occupancy of peripheral TIGIT 
receptors on CD4+, CD8+, and NK cells was observed beginning at 30 mg of tiragolumab 
in both Phase Ia and Phase Ib portions of the study and remained sustained at all higher 
doses (unpublished Roche data on file). 


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Prolonged stable disease was observed in patients in the Phase Ia portion of the study 
at tiragolumab doses beginning at 400 mg.  In the Phase Ib portion of the study with 
tiragolumab plus atezolizumab, the MTD was not reached.  Anti-tumor activity, as 
measured by radiographic partial responses, was observed across doses for 
tiragolumab beginning at 30 mg and ranging up to 600 mg in combination with 1200 mg 
atezolizumab. 
Refer to the Tiragolumab Investigator’s Brochure for additional details. 
A13–4 
MATERIALS AND METHODS SPECIFIC TO ATEZO  TIRA ARM 
A13–4.1 
TREATMENT IN ATEZO  TIRA ARM 
A13–4.1.1 
Formulation, Packaging, and Handling 
A13–4.1.1.1 Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a 60 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of atezolizumab, refer to the 
pharmacy manual and the Atezolizumab Investigator's Brochure. 
A13–4.1.1.2 Tiragolumab 
The tiragolumab drug product will be supplied by the Sponsor as a 60 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of tiragolumab, refer to the 
pharmacy manual and the Tiragolumab Investigator's Brochure. 
A13–4.1.2 
Dosage, Administration, and Compliance 
Patients in the atezolizumab plus tiragolumab (Atezo  Tira) arm will receive treatment 
for 2 cycles (6 weeks) as outlined in Table A13-1 until surgery, or until unacceptable 
toxicity or loss of clinical benefit, whichever occurs first (see Section 3.1.2 for details).  
It is recommended that treatment be initiated no later than 7 days after randomization. 
Table A13-1 
Treatment Regimen for Atezo  Tira Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
 Atezolizumab 1200 mg IV on Day 1 of each cycle 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
Atezo  atezolizumab; Tira  tiragolumab. 
 


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Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
No safety data related to overdosing of atezolizumab or tiragolumab are available to 
date. 
A13–4.1.2.1 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle. 
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 8.  
Atezolizumab infusions will be administered per the instructions outlined in Table A13-2. 
Table A13-2 
Administration of First and Second Atezolizumab Infusions 
First Infusion 
Second Infusion 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
After the infusion of atezolizumab, the 
patient begins a 30-minute observation 
period. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during 
the infusion and 30 ( 10) minutes after the 
infusion.  Record on the eCRF in case of 
abnormalities. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with the 
first infusion, premedication with 
antihistamines, anti-pyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient 
experienced an IRR with the previous 
infusion. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured during the 
infusion and at 30 ( 10) minutes after the 
infusion.  Record on the eCRF in case of 
abnormalities. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction 
 


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Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Table A13-5. 
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A13–5.1.4.2.   
A13–4.1.2.2 Tiragolumab 
Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 
of each 21-day cycle with a post-infusion observation period as described in Table A13-
3. 
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.  For anaphylaxis precautions, see Appendix 8.  
Tiragolumab infusions will be administered per the instructions outlined in Table A13-3. 


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Table A13-3 
Administration of First and Second Tiragolumab Infusions 
First Infusion 
Second Infusion 
 
No premedication is permitted prior to the 
tiragolumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
60 ( 15) minutes. 
 
After the infusion of tiragolumab, the 
patient begins a 60-minute observation 
period. 
 
Record vital signs on the eCRF every 
15 ( 5) minutes during the infusion and at 
30 ( 10) minutes after the infusion. 
 
Patients will be informed about the 
possibility of delayed postinfusion 
symptoms and will be instructed to contact 
their study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with the 
first infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 
Patients should be observed for 
30 minutes after completion of the 
tiragolumab infusion if the previous 
infusion was tolerated without an IRR, or 
for 60 minutes after completion of the 
tiragolumab infusion if the patient 
experienced an IRR with the previous 
infusion. 
 
If clinically indicated, vital signs should be 
recorded on the eCRF every 
15 ( 5) minutes during the infusion and at 
30 ( 10) minutes after the infusion. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
 
Guidelines for medical management of IRRs for tiragolumab are provided in Table A13-
5. 
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section A13–5.1.4.2.   
A13–4.2 
CONCOMITANT THERAPY FOR ATEZO  TIRA ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 


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A13–4.2.1 
Permitted Therapy for Atezo  Tira Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A13–4.2.3) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease (COPD) or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  Other use of corticosteroids may be permitted at the investigator’s 
discretion.  The Medical Monitor is available to advise as needed. 
 
Local therapy (e.g., surgery other than complete lymph node dissection [CLND] that 
is not considered to be related to melanoma) 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second atezolizumab and tiragolumab infusions only, at the discretion of the 
investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., 
famotidine, cimetidine), or equivalent medications per local standard practice.  Serious 
infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; refer to Appendix 8 for details). 
A13–4.2.2 
Cautionary Therapy for Atezo  Tira Arm 
A13–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor- 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab and/or tiragolumab.  Therefore, in situations in which systemic 


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corticosteroids, immunosuppressive medications, or TNF- inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, 
and TNF- inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications, are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab and/or tiragolumab therapy (refer to Appendix 9 for 
details). 
A13–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A13–4.2.3) may be used during the study at the discretion of the 
investigator. 
A13–4.2.3 
Prohibited Therapy for Atezo  Tira Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.4), and during study treatment until surgery, or if earlier, until disease 
progression is documented and the patient has discontinued study treatment. 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with atezolizumab and/or tiragolumab, 
and for 5 months after the final dose of atezolizumab and/or tiragolumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with atezolizumab and/or tiragolumab. 
 


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A13–4.3 
CONTRACEPTION REQUIREMENTS FOR ATEZO  TIRA ARM 
Contraception requirements for men and women in the Atezo  Tira arm are outlined 
below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 5 months after the final 
dose of atezolizumab and for 90 days after the final dose of tiragolumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
90 days after the final dose of tiragolumab.  Men must refrain from donating 
sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 


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A13–5 
ASSESSMENT OF SAFETY FOR ATEZO  TIRA ARM 
A13–5.1 
SAFETY PLAN FOR ATEZO  TIRA ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and tiragolumab in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections A13–5.1.1, A13–5.1.2, and A13–
5.1.3).  Guidelines for management of patients who experience specific adverse events 
are provided in Section A13–5.1.4 and Appendix 9. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Because of the potential for overlapping toxicities for 
atezolizumab and tiragolumab, special caution will be taken by performing a planned 
safety evaluation phase for patients randomized to this arm (see Section 3.1.3). 
Administration of atezolizumab and tiragolumab will be performed in a monitored setting 
in which there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions.  Adverse events will be reported as 
described in Sections 5.25.6. 
A13–5.1.1 
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, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions (SCARs).  In addition, immune-mediated reactions may 
involve any organ system and lead to HLH.  Refer to Appendix 9 of the protocol and 
Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab. 
A13–5.1.2 
Risks Associated with Tiragolumab 
Infusion-related reactions and immune-mediated hepatitis are identified risks of 
tiragolumab.  Lymphopenia is a potential risk with 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 adverse events).   
Refer to Appendix 9 of the protocol and Section 6 of the Tiragolumab Investigator’s 
Brochure for a detailed description of anticipated safety risks of tiragolumab. 


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A13–5.1.2.1 Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, 
IRRs associated with hypersensitivity reactions and/or target-mediated cytokine-release 
may occur.  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
IRRs have been reported in patients treated with tiragolumab, with or without 
atezolizumab.  The majority of events were mild to moderate and manageable. 
To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab will be 
administered over 60 minutes followed by a 60-minute observation period.  Subsequent 
infusions and observation times may be shortened if the preceding infusion was well 
tolerated.  All infusions will be administered in an appropriate medical setting. 
Refer to Section A13–4.1.2 for detailed guidance on administration of tiragolumab in this 
study.  Please see Appendix 8 for guidance on anaphylaxis precautions and Table A13-
5 for guidance on the management of IRRs. 
A13–5.1.2.2 Immune-Mediated Hepatitis 
The use of tiragolumab to block the immune inhibitory receptor TIGIT serves to increase 
a baseline T-cell and NK-cell immune response, especially in combination with other 
checkpoint inhibitors (i.e., atezolizumab).  A disruption in the functioning of immune 
checkpoint molecules may lead to imbalances in immunologic tolerance that results in 
an unchecked immune response, including immune-mediated hepatitis. 
Refer to Appendix 9 for guidance on the management of immune-mediated hepatitis. 
A13–5.1.2.3 Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/ and wild-type B6 mice were immunized with myelin 
oligodendrocyte glycoprotein peptide in an EAE using suboptimal doses.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/ mice developed severe EAE (Joller et 
al. 2011). 
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a general 
risk and may therefore be considered a potential risk of tiragolumab.  Such 
immune-mediated adverse events have been described for virtually all organ systems 
and include, but are not limited to, colitis, pneumonitis, endocrinopathies, ocular toxicity, 


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pancreatic toxicity, neurologic toxicity, cardiac toxicity, nephritis, myositis, and severe 
cutaneous adverse reactions. 
Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2). 
In this study, immune-mediated adverse events will be considered adverse events of 
special interest and will be captured accordingly (see Section A13–5.2 for the list of 
adverse events of special interest and Section 5.4.2 for reporting instructions). 
Suggested management guidelines for individual suspected immune-mediated adverse 
events are provided in Appendix 9. 
A13–5.1.2.4 Lymphopenia 
The IgG1 backbone of tiragolumab with intact Fc-effector function may lead to 
ADCC-mediated reduction in lymphocyte count.  Lymphopenia is a potential risk with 
tiragolumab.  Transient decreases in lymphocyte count without clinical sequelae have 
been observed in patients treated with tiragolumab, with or without atezolizumab. 
Patients with a lymphocyte count  0.5  109/L (500/L) will be excluded from the study 
(see Section 4.1.1), and complete blood counts will be monitored regularly during the 
study (see Appendix A13–6). 
A13–5.1.2.5 Embryofetal Toxicity 
Embryofetal toxicity is a potential risk with tiragolumab.  Administration of tiragolumab is 
expected to have adverse effects on pregnancy based on the expression of TIGIT on 
decidual NK and CD8 T cells (Powell et al. 2017; van der Zwan et al. 2018; 
Vento-Tormo et al. 2018), and the expected role of these cells in the recognition and 
response to foreign fetal, placental, and viral antigens at the maternal-fetal interface as 
well as maintenance of maternal-fetal tolerance.  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 
of tiragolumab in pregnant women.  Tiragolumab should not be administered to pregnant 
women. 
Refer to Section 6 of the Tiragolumab Investigator’s Brochure for a detailed description 
of embryofetal toxicity. 
A13–5.1.3 
Risks Associated with Combination Use of Atezolizumab and 
Tiragolumab 
Based on results from clinical data with tiragolumab and atezolizumab, there are known 
and potential overlapping toxicities in patients treated with tiragolumab plus 
atezolizumab.  Because the expected pharmacologic activity of these two molecules is 


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to increase adaptive T-cell immune responses, there is the possibility of heightened 
immune responses. 
Refer to Section 6 of the Tiragolumab Investigator's Brochure for a list of identified risks 
associated with tiragolumab in combination with atezolizumab.  Based on the 
mechanism of action of tiragolumab and atezolizumab, additional immune-mediated 
adverse events are potential overlapping toxicities associated with combination use of 
tiragolumab plus atezolizumab. 
Based on clinical experience to date, it is anticipated that immune-mediated adverse 
events following treatment with tiragolumab and atezolizumab will be amenable to 
monitoring and manageable in the setting of this combination study.  The extensive 
experience with immune CPIs to date has been incorporated into the design and safety 
management plan (see Section 5.1) in order to reduce the potential risks to participating 
patients.  Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2).  Patients previously treated with approved or experimental CIT will 
also be excluded from participation in Cohort 1.  Owing to the risks of active viral 
infection and viral reactivation, patients with active infection (including, but not limited to, 
HIV, HBV, HCV, EBV, known and/or suspected chronic active EBV infection, or 
tuberculosis) and/or patients with recent severe infections will be excluded from this 
study (see Sections 4.1.1 and 4.1.2). 
A13–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the Atezo  Tira Arm 
A13–5.1.4.1 Dose Modifications 
There will be no dose modifications for atezolizumab or tiragolumab in this study. 
A13–5.1.4.2 Treatment Interruption for Toxicities 
Atezolizumab and tiragolumab treatment may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  If corticosteroids are 
initiated for treatment of the toxicity, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before study treatment can be resumed, if 
warranted.  In the neoadjuvant setting, the study treatment is limited to a pre-surgery 
window of 6 weeks.  Treatment during this period should not be interrupted, unless a 
patient experiences toxicity.  If toxicity meets criteria for interrupting/withholding 
atezolizumab and/or tiragolumab, atezolizumab and tiragolumab should be 
interrupted/withheld.  After resolution of the toxicity, subsequent treatment cycles should 
only be considered if the benefit/risk profile is acceptable and if the surgery can be 
conducted within 2 weeks of the planned date.  Otherwise, subsequent treatment cycles 
should be omitted to allow the patient to proceed directly to surgery without further delay. 


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On the basis of the available characterization of mechanism of action, tiragolumab may 
cause adverse events similar to, but independent of, atezolizumab.  Tiragolumab may 
also exacerbate the frequency or severity of atezolizumab-related adverse events or 
may have non-overlapping toxicities with atezolizumab.  Because these scenarios may 
not be distinguishable from each other in the clinical setting, adverse events should 
generally be attributed to both agents, and dose interruptions or treatment 
discontinuation in response to adverse events should be applied to both tiragolumab and 
atezolizumab.  If atezolizumab is withheld or discontinued, tiragolumab should also be 
withheld or discontinued.  If tiragolumab is withheld or discontinued, atezolizumab 
should also be withheld or discontinued. 
A13–5.1.5 
Management Guidelines for Adverse Events 
Guidelines for the management of patients who experience specific adverse events are 
provided in Table A13-4, Table A13-5, and Appendix 9. 
For cases in which management guidelines are not covered in Appendix 9, patients 
should be managed and treatments should be withheld or discontinued as deemed 
appropriate by the investigator according to best medical judgment. 
Table A13-4 
Guidelines for Management of Patients Who Experience 
Adverse Events in the Atezo  Tira Arm 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity 
reactions 
 Guidelines for management of IRRs are provided in 
Table A13-5.  
 For anaphylaxis precautions, see Appendix 8. 
 For severe hypersensitivity reactions, permanently 
discontinue the causative agent. 
Pulmonary, hepatic, GI, endocrine, ocular, 
immune-mediated myocarditis, CRS, 
pancreatic, dermatologic, neurologic, 
immune-mediated meningoencephalitis, 
renal, and systemic immune activation 
 Guidelines for management of these events are 
provided in Appendix 9.  
CRS  cytokine-release syndrome; GI  gastrointestinal; IRR  infusion-related reaction. 
 


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A13–5.1.5.1 Infusion-Related Reactions 
No premedication is indicated for the administration of the Day 1, Cycle 1 infusion of 
tiragolumab or atezolizumab.  However, patients who experience an IRR with the Day 1, 
Cycle 1 infusion of tiragolumab or atezolizumab may receive premedication with 
antihistamines, antipyretic medication, or analgesics (e.g., acetaminophen) for 
subsequent infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with tiragolumab and atezolizumab.  These reactions, which are thought 
to be due to release of cytokines and/or other chemical mediators, occur within 24 hours 
of tiragolumab or atezolizumab administration and are generally mild to moderate in 
severity.  Guidelines for medical management of IRRs during Cycle 1 are provided in 
Table A13-5.  For subsequent cycles, IRRs should be managed according to institutional 
guidelines. 
Table A13-5 
Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1  
 Reduce infusion rate to half the rate being given at the time of 
event onset. 
 After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
 If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate. 
IRR, Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset. 
 For subsequent infusions, consider administration of oral 
premedication with antihistamines, antipyretic medications, and/or 
analgesics and monitor closely for IRRs. 
IRR, Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, antipyretic medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 Permanently discontinue tiragolumab and atezolizumab and 
contact the Medical Monitor. a 
IRR  infusion-related reaction. 
a If a study drug warrants permanent discontinuation, there should be no re-challenge of 
the drug.  For combination regimens, both study drugs should be discontinued. 
 


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A13–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR THE 
ATEZO  TIRA ARM (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.2.3 for reporting instructions).  Adverse events of special interest for the 
Atezo  Tira arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
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  upper limit of normal 
 
Systemic lupus erythematosus 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis) 
 
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) 


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 
Myelitis 
 
Facial paresis 
 
A13–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN THE 
ATEZO  TIRA ARM 
A13–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the final dose of atezolizumab or within 90 days after the final dose 
of tiragolumab.  A paper Clinical Trial Pregnancy Reporting Form should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the pregnancy), either by faxing or by scanning and e-mailing the form 
using the fax number or e-mail address provided to investigators.  Pregnancy should not 
be recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A13–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the final dose of tiragolumab.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and e-mailing the form using the fax number 
or e-mail address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for the Use and Disclosure of Pregnancy Health 


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Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A13–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A13–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.2.2). 










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a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will return to the clinic for a treatment completion/discontinuation visit 6 weeks after surgery and patients who do not proceed to surgery will 
return to the clinic for a treatment completion/discontinuation visit not more than 30 days after the final dose of study treatment. 
c Patients who proceed to surgery will have the surgery follow-up 6 months after surgery.  
d Assessment may be performed within 24 hours prior to dosing during the treatment period. 
e The disease status assessments at Week 13 should include a mandatory CT scan. 
f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 135 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on reporting all 
treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each adverse event 
until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-
related procedures until a final outcome can be reported. 
g Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to surgery 
will have their first long-term follow-up visit 3 months after surgery and patients who do not proceed to surgery will have their first long-term 
follow-up visit 3 months after the final dose of study treatment.  Information on follow-up and new anti-cancer therapy (including targeted therapy 
and immunotherapy) will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death 
(unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this request 
must be documented in the source documents and signed by the investigator.  If a patient withdraws from the study, the study staff may use a 
public information source (e.g., county records) to obtain information about survival status only.  For an experimental arm in which all patients 
discontinued treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor 
may conclude the arm (the remaining ~20% of patients will be discontinued from the study). 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments. 


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k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a local 
gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration. 
 
 
 


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A13–7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR ATEZO  TIRA ARM 
Visit a 
Time 
Sample 
Day 1 of Cycle 1 
Prior to first infusion 
(6 hr to 0 hr) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the 
end of atezolizumab 
infusion 
 Atezolizumab PK (serum) 
30 ( 10) minutes after the 
end of tiragolumab infusion 
 Tiragolumab PK (serum) 
Day 1 of Cycle 2 
Prior to infusion 
(6 hr to 0 hr) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Surgery CLND 
Week 7 
Prior to surgery  
(24 hr to 0 hr) 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation 
Week 13 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; Atezo   atezolizumab; CLND  complete lymph node dissection; 
PK  pharmacokinetic; Tira  tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may 
be reduced or sample collection may cease altogether.  Additionally, collected samples may not 
be analyzed if not warranted.  On the basis of emerging biomarker data, the number of biomarker 
samples may be reduced or sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained  20 days post-surgery. 
b To be collected if visit is conducted on site. 
 


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Table A13-7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, 
AND BIOMARKER SAMPLES FOR ATEZO    TIRA ARM 
(cont.) 
Visit 
Time 
Sample Type 
Long-term follow-up 
Every 3 months ( 7 days) b 
At visit 
 Biomarkers (blood, plasma) 
Surgery follow-up 
6 months after surgery 
(7 days) 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; Atezo   atezolizumab; CLND  complete lymph node dissection; 
PK  pharmacokinetic; Tira  tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may 
be reduced or sample collection may cease altogether.  Additionally, collected samples may not 
be analyzed if not warranted.  On the basis of emerging biomarker data, the number of biomarker 
samples may be reduced or sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained  20 days post-surgery. 
b To be collected if visit is conducted on site. 
 


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A13–8 
REFERENCES 
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 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. 
Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts 
specifically with the B7-1 costimulatory molecule to inhibit T cell responses. 
Immunity 2007;27:11122. 
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation 
immunotherapyinhibiting programmed death-ligand 1 and programmed death-1. 
Clin Cancer Res 2012;18:65807. 
Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, 
open-label, phase 2 randomised controlled trial. Lancet 2016;387:183746. 
Guillerey C, Harjunpää H, Carrié N, et al. TIGIT immune checkpoint blockade restores 
CD8+ T cell immunity against multiple myeloma. Blood 2018;132:168994. 
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363:71123. 
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 N, Hafler JP, Brynedal B, et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory 
functions. J Immunol 2011;186:133842. 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for 
castration-resistant prostate cancer. N Engl J Med 2010;363:41122. 
Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677704. 
Manieri NA, Chiang EY, and Grogan JL. TIGIT: a key inhibitor of the cancer immunity 
cycle. Trends Immunol 2017;38:208. 
Powell RM, Lissauer D, Tamblyn J, et al. Decidual T cells exhibit a highly differentiated 
phenotype and demonstrate potential fetal specificity and a strong transcriptional 
response to IFN. J Immunol 2017;199:340617. 
 


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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;387:190920. 
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. 
van der Zwan A, Bi K, Norwitz ER, et al. Mixed signature of activation and dysfunction 
allows human decidual CD8 T cells to provide both tolerance and immunity. Proc 
Natl Acad Sci USA 2018;115:38590. 
Vento-Tormo R, Efremova M, Botting RA, et al. Single-cell reconstruction of the early 
maternal-fetal interface in humans. Nature 2018;563:34753. 
Wang F, Hou H, Wu S, et al. TIGIT expression levels on human NK cells correlate with 
functional heterogeneity among healthy individuals. Eur J Immunol 
2015;45:288697. 
Yadav M, Green C, Ma C, et al. Tigit, CD226 and PD-L1/PD-1 are highly expressed by 
marrow-infiltrating T cells in patients with multiple myeloma. Blood 2016;128:2102. 
Yang Z. Expression and function of tigit in B-cell non-Hodgkin lymphoma. Blood 
2016;128:4138. 
Yang J, Riella LV, Chock S, et al. 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 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. 
 


  
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Appendix 14  
Study Details Specific to RO7247669 2100 mg  Tira Arm 
(Cohorts 1 and 2) 
TABLE OF CONTENTS 
A14–1 
Background on RO7247669 2100 mg  Tira Arm ..................... 260 
A14–1.1 
Background on RO7247669 ...................................................... 260 
A14–1.2 
Background on Tiragolumab ..................................................... 260 
A14–2 
Rationale for RO7247669 2100 mg  Tira Arm ......................... 260 
A14–2.1 
Targeting the PD-1 and LAG-3 Antigens .................................. 260 
A14–2.2 
The TIGIT Pathway ................................................................... 262 
A14–2.3 
Combination Treatment with AntiPD-1/AntiLAG-3 and 
Anti-TIGIT Agents ..................................................................... 263 
A14–2.4 
Clinical Studies of Agents Targeting the PD-1 and LAG-3 
Pathways .................................................................................. 263 
A14–2.4.1 
Study NP41300 ......................................................................... 264 
A14–2.5 
Clinical Studies of Tiragolumab ................................................. 265 
A14–2.5.1 
Study GO30103 ........................................................................ 265 
A14–2.5.2 
Study GO40290 ........................................................................ 267 
A14–2.6 
BenefitRisk Assessment ......................................................... 268 
A14–3 
Rationale for Dose and Schedule for RO7247669 
2100 mg  Tira Arm................................................................... 269 
A14–3.1 
Rationale for RO7247669 Dose and Schedule ......................... 269 
A14–3.2 
Rationale for Tiragolumab Dose and Schedule ......................... 270 
A14–4 
Materials and Methods Specific to RO7247669 2100 mg 
 Tira Arm ................................................................................. 271 
A14–4.1 
Treatment in RO7247669 2100 mg  Tira Arm ......................... 271 
A14–4.1.1 
Formulation, Packaging, and Handling ..................................... 271 
A14–4.1.1.1 
RO7247669 ............................................................................... 271 
A14–4.1.1.2 
Tiragolumab .............................................................................. 271 
A14–4.1.2 
Dosage, Administration, and Compliance ................................. 271 
A14–4.1.2.1 
RO7247669 ............................................................................... 272 
A14–4.1.2.2 
Tiragolumab .............................................................................. 274 
A14–4.2 
Concomitant Therapy for RO7247669 2100 mg  Tira Arm ...... 276 
A14–4.2.1 
Permitted Therapy for RO7247669 2100 mg  Tira Arm ........... 276 
A14–4.2.2 
Additional Permitted Therapy for RO7247669 2100 mg  Tira 
Arm in Cohort 2 ......................................................................... 276 
A14–4.2.3 
Cautionary Therapy for RO7247669 2100 mg  Tira Arm ......... 277 
A14–4.2.3.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ........................................... 277 
A14–4.2.3.2 
Herbal Therapies ...................................................................... 278 
A14–4.2.4 
Prohibited Therapy for RO7247669 2100 mg  Tira Arm .......... 278 
A14–4.3 
Contraception Requirements for RO7247669 2100 mg  Tira 
Arm ........................................................................................... 278 


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A14–5 
Assessment of Safety for RO7247669 2100 mg  Tira Arm ...... 279 
A14–5.1 
Safety Plan for RO7247669 2100 mg  Tira Arm ...................... 279 
A14–5.1.1 
Risks Associated with RO7247669 ........................................... 280 
A14–5.1.1.1 
Infusion-Related Reactions and Anaphylaxis ............................ 280 
A14–5.1.1.2 
Immunogenicity ......................................................................... 280 
A14–5.1.1.3 
Immune-Mediated Adverse Events ........................................... 280 
A14–5.1.2 
Risks Associated with Tiragolumab .......................................... 281 
A14–5.1.2.1 
Infusion-Related Reactions ....................................................... 281 
A14–5.1.2.2 
Immune-Mediated Hepatitis ...................................................... 282 
A14–5.1.2.3 
Immune-Mediated Adverse Events ........................................... 282 
A14–5.1.2.4 
Lymphopenia ............................................................................ 283 
A14–5.1.2.5 
Embryofetal Toxicity .................................................................. 283 
A14–5.1.3 
Risks Associated with Combination Use of RO7247669 and 
Tiragolumab .............................................................................. 283 
A14–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the RO7247669 2100 mg  Tira Arm ......................... 284 
A14–5.1.4.1 
Dose Modifications .................................................................... 284 
A14–5.1.4.2 
Treatment Interruption for Toxicities ......................................... 284 
A14–5.1.4.3 
Management Guidelines for Adverse Events ............................ 285 
A14–5.2 
Adverse Events of Special Interest for the RO7247669 2100 
mg  Tira Arm (Immediately Reportable to the Sponsor) .......... 287 
A14–5.3 
Reporting Requirements for Pregnancies in the RO7247669 
2100 mg  Tira Arm................................................................... 288 
A14–5.3.1 
Pregnancies in Female Patients ............................................... 288 
A14–5.3.2 
Pregnancies in Female Partners of Male Patients .................... 288 
A14–5.3.3 
Abortions ................................................................................... 289 
A14–5.3.4 
Congenital Anomalies/Birth Defects .......................................... 289 
A14–6 
Schedules of Activities and Sample Collection for 
RO7247669 2100 mg   Tira Arm (Cohort 1) ............................ 290 
A14–7 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for RO7247669 2100 mg  Tira Arm 
(Cohort 1) .................................................................................. 295 
A14–8 
Schedules of Activities and Sample Collection for 
RO7247669 2100 mg  Tira Arm (Cohort 2) ............................. 296 
A14–9 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for RO7247669 2100 mg  Tira Arm 
(Cohort 2) .................................................................................. 300 
A14–10 
References ................................................................................ 302 
 
 
 
 


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A14–1 
BACKGROUND ON RO7247669 2100 mg  TIRA ARM 
A14–1.1 
BACKGROUND ON RO7247669 
RO7247669 is a novel, Fc-silent IgG1-based bispecific antibody (bsAb) in 1  1 format 
that incorporates monovalent binding to two immune checkpoint proteins:  PD-1 and 
LAG-3.  RO7247669 is designed to target dysfunctional tumor antigen-specific 
T lymphocytes expressing PD-1 and LAG-3 to establish or re-establish an effective 
anti-tumor immune response in cancer patients.  This may result in improved therapeutic 
responses over currently available therapies.  In addition, RO7247669 is engineered to 
prevent binding to Fc gamma receptors, thus potentially avoiding tumor-associated 
macrophage resistance mechanisms.  Such mechanisms have been observed with 
IgG4-based antiPD-1 antibodies, such as pembrolizumab and nivolumab (Arlauckas et 
al. 2017).  Clinical evaluation of RO7247669 is ongoing in a first-in-human, dose-finding 
study (Study NP41300), as a single agent in cancer patients with and without prior CPI 
exposure.   
Refer to the RO7247669 Investigator’s Brochure for details on nonclinical and other 
planned and ongoing clinical studies. 
A14–1.2 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT and 
prevents its interaction with CD155 (also known as poliovirus receptor [PVR]).  
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.  This may result in improved meaningful anti-tumor activity when 
tiragolumab is used in combination with other cancer immunotherapies and administered 
with chemotherapy.  The available nonclinical and clinical data provide a strong rationale 
for evaluating the potential clinical benefit of tiragolumab in cancer patients. 
Refer to the Tiragolumab Investigator’s Brochure for details on nonclinical and clinical 
studies. 
A14–2 
RATIONALE FOR RO7247669 2100 mg  TIRA ARM 
A14–2.1 
TARGETING THE PD-1 AND LAG-3 ANTIGENS 
Cancer immunotherapy agents, particularly immune CPIs, have had a significant impact 
on the treatment of patients with advanced malignancies in recent years.  However, 
despite the remarkable clinical efficacy of these therapies, additional treatment options 
targeting immune checkpoints are needed, because the majority of patients eventually 
progress after an initial response or fail to respond to the PD-1/PD-L1 checkpoint 
blockade.  This is believed to be mainly due to primary or secondary resistance 


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mechanisms, immunosuppressive activity of myeloid-derived suppressor cells and/or 
T-regulatory cells (Sharma et al. 2017). 
To overcome resistance mechanisms, additional treatment options and multiple 
combinations with antiPD-L1 are being assessed.  One potential reason for resistance 
to antiPD-L1 therapy is the upregulation of alternative immune checkpoints with 
non-redundant regulatory functions (Sharma et al. 2017).  LAG-3 is one such alternative 
immune checkpoint.  Structurally similar to CD4, LAG-3 is a member of the Ig 
superfamily.  LAG-3 is expressed on activated effector T cells and is constitutively 
expressed on T-regulatory cells and natural killer (NK) cells.  The expression of both 
PD-1 and LAG-3 on tumor infiltrating lymphocytes (TILs) correlates with the degree of 
impairment of effector functions, which is associated with poor prognosis 
(Matsuzaki et al. 2010; Baitsch et al. 2011; Thommen et al. 2015).  Hence, LAG-3 is a 
marker of T-cell dysfunctionality.  LAG-3 also regulates T-cell functions, presumably 
including the function of T-regulatory cells.  In chronic infections and cancer, LAG-3, 
together with PD-1, contributes to T-cellacquired dysfunctionality and to the inability of 
T cells to mount an effective/protective immune response upon interaction with the 
LAG-3 ligand, MHC-II. 
The interaction of LAG-3 with MHC-II inhibits T-cell proliferation, activation, cytolytic 
function, and proinflammatory cytokine production (Goldberg and Drake 2011).  The 
effect of LAG-3 expression on T-regulatory cells is controversial.  An early report 
concluded that LAG-3 promotes T-regulatory cell-mediated immune suppression 
(Camisaschi et al. 2010).  However, a more recent report from the same authors found 
that LAG-3 limits T-regulatory cell-mediated immune suppression (Zhang et al. 2017). 
Expression of LAG-3 has been reported across various tumor types, including breast 
cancer, ovarian cancer, non-small cell lung cancer (NSCLC), melanoma, renal cell 
cancer (RCC), prostate cancer, and hepatocellular carcinoma (HCC).  In patients with 
these tumor types, LAG-3 is associated with poor prognosis (Matsuzaki et al. 2010; 
Baitsch et al. 2011; Thommen et al. 2015; He et al. 2016; Norstrom et al. 2016).  Clinical 
evaluation of antiLAG-3 agents, as a single-agent and in combination with other CPIs, 
is ongoing in several early phase studies in patients with advanced solid tumors 
(Long et al. 2018).  Preliminary data demonstrate that antiLAG-3 therapy is well 
tolerated, both as a single agent and in combination with antiPD-1 therapies, and the 
safety profiles were consistent with those of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018; Stratton et al. 2018).  RO7247669 therefore has the potential to be a 
therapeutic option for patients with melanoma. 
Resistance to PD-L1/PD-1 blockade may result in the expression of multiple co-inhibitory 
immune checkpoints on the surface of effector T cells.  LAG-3 is frequently 
co-expressed with PD-1 on TILs, and dual blockade of PD-1 and LAG-3 enhances CD8 


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T-cell effector function and potentiates anti-tumor immunity in nonclinical models.  
Blockade of these two receptors in mice with colon, fibrosarcoma, or ovarian tumors 
resulted in tumor remission in approximately 80% of animals compared with 10% to 40% 
with blockade of either receptor using a single agent (Woo et al. 2012; Huang et al. 
2015).  TILs from patients with ovarian cancer showed that antigen-specific CD8 T cells 
co-expressing PD-1 and LAG-3 exhibited greater impairment in their ability to respond to 
cognate antigen stimulation compared with CD8 T cells that expressed one checkpoint 
molecule (Matsuzaki et al. 2010).  In patients with NSCLC, overexpression of LAG-3 on 
TILs correlated with PD-1/PD-L1 expression and was linked to higher risk of recurrence 
and poor survival outcomes (He et al. 2017). 
A14–2.2 
THE TIGIT PATHWAY 
TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin 
superfamily (Yu et al. 2009).  TIGIT is expressed on the surface of activated T cell and 
NK cell subsets and interacts with high affinity with CD155 (also known as PVR) 
(Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated 
T-cell responses in nonclinical models of autoimmune and viral infections, demonstrating 
the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; Johnston et al. 2014).  
TIGIT expression is elevated in the tumor microenvironment in many human tumors, is 
concordantly expressed with other checkpoint immune-receptors such as PD-1 on the 
surface of T cells, and is associated with impaired T-cell function and anti-tumor 
immunity (Johnston et al. 2014; Manieri et al. 2017).  Activation of TIGIT on T cells and 
NK cells limits cellular proliferation, effector cytokine production, and killing of target 
tumor cells (Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 
2015; Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors.  It is expressed in most solid 
tumors, such as NSCLC, breast cancer, and melanoma, as well as in hematological 
tumors, such as multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL).  
Fluorescence activated cell sorting analysis of T cells isolated from fresh tumor samples 
revealed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells 
(Johnston et al. 2014; Yadav et al. 2016; Yang 2016; Guillerey et al. 2018).  TIGIT was 
expressed in 30%80% of tumor-infiltrating CD4 T cells and in 50%80% of 
tumor-infiltrating CD8 T cells (Johnston et al. 2014). 
Therefore, TIGIT is a potential target for therapeutic interventions that aim to restore the 
immune response against the tumor.  Agents that inhibit TIGIT’s interaction with PVR 
may inhibit an important source of tumor-associated immune suppression, thereby 
enhancing the activity of other immune-based therapies.  Nonclinical studies using 
genetically deficient mice and blocking antibodies have revealed a key role for TIGIT in 
regulating T-cell responses in cancer.  Taken together, these data support the 


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hypothesis that anti-TIGIT therapy may reactivate anti-tumor immunity and provide 
clinical benefits to patients with cancer. 
A14–2.3 
COMBINATION TREATMENT WITH ANTIPD-1/ANTILAG-3 
AND ANTI-TIGIT AGENTS 
Durable clinical benefit is limited to a minority of patients treated with single-agent 
PD-L1/PD-1 inhibitors.  Therapies targeting the mechanisms of resistance to 
anti-PD-L1/PD-1 therapies are needed to improve outcomes in patients with solid 
cancers.  Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory receptors on the surface of effector T cells including TIGIT and LAG-3.  
Nonclinical tumor models have shown that TIGIT selectively suppressed the effector 
function of chronically stimulated CD8 T cells, and that inhibiting both TIGIT and 
PD-L1/PD-1 resulted in superior efficacy compared with single-agent treatments 
(Johnston et al. 2014).  Similarly, in-vivo proof-of-concept studies using different tumor 
mouse models have shown PD1-LAG-3 bsAbs to be superior in controlling tumor growth 
and promoting tumor eradication when compared with anti-PD-1 antibodies as 
monotherapy.  Hence, targeting PD-1/LAG-3 and TIGIT with RO7247669 and 
tiragolumab, respectively, may enhance the efficacy of PD-L1/PD-1 blockade across 
different cancer types, including melanoma. 
A14–2.4 
CLINICAL STUDIES OF AGENTS TARGETING THE PD-1 AND 
LAG-3 PATHWAYS 
Clinical data are available for early- and late-phase studies that evaluated the safety, 
tolerability, and preliminary anti-tumor activity of agents that target both the PD-1 and 
LAG-3 pathways.  Evidence of clinical activity has been reported in some of these 
studies.  Overall, adverse events have been manageable to date, and the safety profiles 
appear similar to those of single-agent CPIs. 
An ongoing Phase I/IIa study is evaluating the safety, tolerability, and clinical activity of 
combination treatment with the antiPD-1 monoclonal antibody nivolumab and the 
antiLAG-3 monoclonal antibody relatlimab in patients with advanced solid tumors.  
Preliminary data suggest that the combination of nivolumab and relatlimab may have an 
increased benefit compared with single-agent antiPD-1.  In a cohort of patients who 
had advanced melanoma who were previously treated with antiPD-1/PD-L1 agents, the 
objective response rate (ORR) was 11.5% (n  61) with a disease control rate of 49%.  
The antiPD-1/PD-L1 treatment combination had an acceptable safety profile that was 
similar to the safety profile of nivolumab monotherapy (Ascierto et al. 2017). 
Relativity-047 is a phase III study evaluating the combination of nivolumab 
(antiPD-1) and relatlimab (antiLAG-3) versus nivolumab alone in patients with 
untreated advanced melanoma.  This study demonstrated that nivolumab and relatlimab 


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improved progression-free survival (PFS  10.1 months) over nivolumab 
(PFS  4.6 months).  The incidence of Grade 3 or 4 treatment-related adverse events was 
18.9% in patients that received the nivolumab and relatlimab combination and 9.7% in 
patients that received nivolumab alonoe (Tawbi et al. 2022). 
An ongoing Phase I/II study is evaluating the safety, tolerability, and clinical activity of 
combination treatment with the antiPD-1 monoclonal antibody spartalizumab and the 
antiLAG-3 monoclonal antibody LAG525 in patients with advanced solid tumors.  
Preliminary anti-tumor activity was observed during the Phase I dose-escalation portion 
of the study, including durable responses in 2 of 5 patients with triple-negative breast 
cancer (TNBC) and in 2 of 8 patients with mesothelioma.  Analyses of tumor biopsies 
from the TNBC cohort also showed a trend of conversion from an immune-cold to an 
immune-activated phenotype.  Common adverse events, i.e., adverse events reported in 
10% of patients, included fatigue (18%), diarrhea (15%), and nausea (12%).  
The incidence of Grade 34 adverse events was 8% for both the combination (n  121) 
and monotherapy (n  119) arms (Hong et al. 2018). 
An ongoing, first-in-human, dose-escalation, and dose-expansion Phase I study is 
evaluating the safety, tolerability, and clinical activity of the antiPD-1/LAG-3 dual affinity 
re-targeting protein (DART®) bsAb MGD013 in patients with advanced solid tumors and 
hematologic malignancies.  During the dose-escalation phase of the study, the maximum 
tolerated dose (MTD) was not reached, and the safety profile was consistent with 
antiPD-1 monotherapy.  During the dose-expansion phase, anti-tumor activity was 
observed in patients with TNBC (n  23; ORR, 4.3%; disease control rate [DCR], 39.1%), 
CPI-naive NSCLC (n  14; ORR, 14.3%; DCR, 64.3%), and epithelial ovarian cancer 
(n  23; ORR, 8.7%; DCR, 52.2%).  Expression of LAG-3 and an IFN- gene signature at 
baseline was associated with objective responses (Luke et al. 2020).  Clinical studies 
evaluating MGD013 as monotherapy and in combination with antiHER-2 agents are 
ongoing. 
A14–2.4.1 
Study NP41300 
Study NP41300 is an ongoing, first-in-human, dose-escalation, dose-expansion Phase I 
study to evaluate the safety, pharmacokinetics, and therapeutic activity of the 
antiPD-1/LAG-3 bsAb RO7247669 as a single-agent in patients with locally advanced 
and/or metastatic solid tumors.  Part A, the dose-escalation phase of the study, is 
designed to determine the MTD and/or recommended dose for expansion (RDE) of 
RO7247669.  Part B of the study is designed to evaluate the anti-tumor activity of 
RO7247669 at the MTD or RDE in tumor-specific expansion cohorts. 
As of the data cutoff date, 1 March 2022, RO7247669 was well tolerated in the patients 
enrolled in Part A of the study.  No unexpected safety concern associated with 


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RO7247669 was identified.  No dose-limiting toxicities (DLTs) were observed up to the 
maximum dose tested (2100 mg every 2 weeks [Q2W]), and no MTD was identified.  
The maximum dose of 2100 mg was determined to be the recommended dose for the 
dose-expansion phase (Part B) of Study NP41300.  As of the data cutoff of 
1 March 2022, 83 patients received treatment in Part B.  
As of the data cutoff date, 1 March 2022, the DCR in Part A of the study was 51.4% 
(18 of 35 evaluable patients), and the ORR was 17.1% (6 of 35 patients).  Among the 
patients treated with the proposed dose of 2100 mg Q2W, 7 of 13 patients had a best 
response of stable disease or better (DCR  53.8%), including 4 patients with a 
confirmed partial response (PR, ORR  30.8%).  Besides the confirmed partial responses 
(cPR) observed at the RDE, there were 2 cPRs at the 600 mg dose level (ORR   50.0%). 
As of the data cutoff date, 1 March 2022, in Part B of the study the DCR was 48.3% 
(28 of 58 patients) and the ORR was 5.2% (3 of 58 patients) among patients of the 
study treated at the RDE of 2100 mq Q2W (Cohorts B1, B2, and B3).  Within patients 
treated with 600 mg Q2W (Cohort B5), the DCR was 40% (4 of 10 patients), and the 
ORR was 10% (1 of 10 patients).  Among patients treated with 600 mg Q3W, the DCR 
was 28.6% (2 of 7 patients) and the ORR was 14.3% (1 of 7 patients). 
Refer to the RO7247669 Investigator’s Brochure for additional details on all ongoing and 
planned clinical studies. 
A14–2.5 
CLINICAL STUDIES OF TIRAGOLUMAB 
Tiragolumab is currently under investigation in two ongoing clinical studies in patients 
with solid tumors (Studies GO30103 and GO40290) and in one clinical study in patients 
with hematological malignancies (Study GO41036). 
A14–2.5.1 
Study GO30103 
Study GO30103 is a first-in-human, open-label, multicenter, global, 
dose-escalation/dose-expansion Phase I study.  It was designed to evaluate the safety, 
tolerability, and pharmacokinetics of tiragolumab as a single agent (Phase Ia) and in 
combination with atezolizumab (Phase Ib) in patients with locally advanced, recurrent, or 
metastatic incurable tumors, including urothelial cancer, renal cell cancer, NSCLC, head 
and neck squamous cell carcinoma, esophageal cancer, colorectal cancer (CRC), 
gastric cancer, cholangiocarcinoma, and triple-negative breast cancer. 
As of the clinical cutoff date of 2 December 2020, a total of 236 patients had been 
enrolled in Study GO30103.  Forty-two patients were enrolled in the Phase Ia portion of 
the study to receive single-agent tiragolumab, and 217 patients were enrolled in the 
Phase Ib portion of the study to receive tiragolumab in combination with atezolizumab.  


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The latter group included 23 patients who crossed over from the Phase Ia portion of the 
study. 
The best observed response with tiragolumab monotherapy in the Phase Ia portion was 
prolonged stable disease in 8 of 42 patients, with some patients, including 1 patient with 
CRC, experiencing a decrease in tumor size. 
In the Phase Ib portion, complete response was observed in 4 of 217 patients at 
tiragolumab dose levels of 400 mg (n  3/48) and 600 mg (n  1/104) in combination with 
1200 mg atezolizumab.  Partial response was observed in 27  of 217 patients at 
tiragolumab dose levels of 30 mg (n  2/13), 400 mg (n  6/48), and 600 mg (n  18/104) 
in combination with 1200 mg atezolizumab, including two patients who crossed over 
from the Phase Ia portion at the 600 mg dose level.  Stable disease was observed in 
53 of 217 patients at tiragolumab dose levels of 2 mg (n  1/8), 8 mg (n  3/12), 30 mg 
(n  2/13), 100 mg (n  3/8), 400 mg (n  12/48), 600 mg (n  25/104), and 1200 mg 
(n  7/24) in combination with 1200 mg atezolizumab, including 8 patients who crossed 
over from the Phase Ia portion of the study (2 patients at 8 mg, 1 patient at 30 mg, 
2 patients at 100 mg, and 3 patients at 400 mg). 
As of 2 December 2020, safety data were available for 235 safety-evaluable patients in 
Study GO30103.  A total of 42 patients were treated in the Phase Ia portion with 
tiragolumab as a single agent (2 mg to 1200 mg), while 216 patients were treated in the 
Phase Ib portion with tiragolumab at dose levels of 2 mg to 1200 mg in combination with 
atezolizumab at 1200 mg, including 23 patients who crossed over from the Phase Ia 
portion to the Phase Ib portion. 
Tiragolumab was tolerated across all administered dose levels both as a single agent 
and in combination with atezolizumab.  The MTD was not reached, and the maximum 
administered dose was 1200 mg.  No DLTs or clear dose-related trends in the incidence 
of adverse events were observed.  Grade  3 adverse events, regardless of attribution to 
the study drug(s), were reported in 16 patients (38.1%) and 113 patients (52.3%) in the 
Phase Ia and Phase Ib portions, respectively.  There were 14 reported deaths in the 
Phase Ia portion of the study, including 12 deaths due to malignant neoplasm 
progression, 1 death due to gastrointestinal hemorrhage in the context of progressive 
disease, and 1 death due to hepatic failure.  The death due to hepatic failure was 
considered by the investigator to be related to study drug.  One hundred eighteen deaths 
were reported in the Phase Ib portion of the study.  This included 111 deaths due to 
progressive disease (31 cases were reported as adverse events during the adverse 
event reporting period and coded as malignant neoplasm progression or neoplasm 
malignant), 2 deaths due to pulmonary embolism, 1 death due to esophageal 
hemorrhage, 1 death due to sepsis, 1 death due to septic shock, 1 death due to 
COVID-19, and 1 death due to upper airway obstruction.  Treatment-related serious 


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adverse events were reported in 1 patient in the Phase Ia portion (hepatic failure) and in 
10 patients (4.6%) in the Phase Ib portion.  No patient discontinued study treatment due 
to adverse events in the Phase Ia portion of Study GO30103.  Adverse events leading to 
treatment discontinuation were reported in 12 patients in the Phase Ib portion of the 
study, with a Grade 4 cardiac tamponade, a Grade 4 pneumonitis, and one event of 
Grade 2 arthralgia considered by the investigator to be related to the study drug(s).  
Adverse events of special interest were reported in 5 patients (11.9%) in the Phase Ia 
portion and 82 patients (38.0%) in the Phase Ib portion of the study. 
Overall, tiragolumab as a single agent or in combination with atezolizumab has been 
well tolerated, adverse events have been manageable, and the safety profile has been 
observed to be consistent across different solid tumor indications. 
A14–2.5.2 
Study GO40290 
Study GO40290 is a Phase II, randomized, blinded, placebo-controlled study of 
tiragolumab plus atezolizumab compared with placebo plus atezolizumab in patients with 
previously untreated locally advanced unresectable or metastatic PD-L1positive 
NSCLC (defined as tumor proportion score [TPS]  1%). 
As of the primary clinical cutoff date of 30 June 2019, 135 patients with a PD-L1 TPS 
 1% were included in the intent-to-treat (ITT) population and were randomly assigned to 
receive tiragolumab plus atezolizumab (n  67) or placebo plus atezolizumab (n  68).  
As of the primary analysis, 47.8% of patients in the tiragolumab plus atezolizumab group 
versus 27.9% of patients in the placebo plus atezolizumab group were still receiving 
study treatment in the ITT population.  In the TPS  50% population, 65.5% of patients in 
the tiragolumab plus atezolizumab group versus 24.1% of patients in the placebo plus 
atezolizumab group were still receiving study treatment. 
In all randomized patients, the combination of tiragolumab plus atezolizumab improved 
the co-primary endpoints of investigator-assessed ORR and progression-free survival 
(PFS) compared to placebo plus atezolizumab, with median follow-up of 5.9 months.  
ORR for tiragolumab plus atezolizumab was 31.3% (95% CI: 19.5, 43.2) compared with 
placebo plus atezolizumab which was 16.2% (95% CI: 6.7, 25.7).  Investigator-assessed 
median PFS for tiragolumab plus atezolizumab was 5.4 months (95% CI: 4.2 months, 
not reached) compared with placebo plus atezolizumab which was 3.6 months 
(95% CI: 2.7 months, 4.4 months), with a stratified hazard ratio (HR) of 0.57 
(95% CI: 0.37, 0.90).  Investigator-assessed PFS was improved in the tiragolumab plus 
atezolizumab group over the placebo plus atezolizumab group (unstratified HR  0.33; 
95% CI: 0.15, 0.72; median PFS not reached vs. 3.9 months, respectively). 
As of 2 December 2020, 67 safety-evaluable patients in the tiragolumab plus 
atezolizumab arm in Study GO40290 were treated with a median of 8 doses of 


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tiragolumab and atezolizumab (range: 138) for a median of 5.0 months 
(range: 0.0326.0).  In the placebo plus atezolizumab arm, 68 safety-evaluable patients 
were treated with a median of 5 doses of placebo and atezolizumab (range: 137) for a 
median of 2.8 months (range: 0.0326.3). 
As of 30 June 2020, in the Phase II randomized, placebo-controlled Study GO40290, 
a total of 135 safety-evaluable patients were administered either tiragolumab (600 mg 
recommended Phase II/III dose) in combination with atezolizumab or placebo in 
combination with atezolizumab.  The safety profile of tiragolumab plus atezolizumab was 
similar to that of placebo plus atezolizumab- for all-grade adverse events 
(98.5% vs. 97.1%), Grade  3 adverse events (53.7% vs. 50.0%), serious adverse 
events (47.8% vs. 39.7%), and adverse events leading to treatment discontinuation 
(13.4% vs. 11.8%).  Adverse events of special interest were reported in 58.2% of 
patients in the tiragolumab plus atezolizumab arm and in 32.4% of patients in the 
placebo plus atezolizumab arm.  One death due to Epstein-Barr virus (EBV) reactivation 
and possible secondary hemophagocytic lymphohistiocytosis (HLH) was reported in this 
study, which was considered by the investigator to be related to the study drugs. 
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse 
events have been manageable, and the safety profile seems to be consistent as 
reported across different solid tumor indications. 
Refer to the Tiragolumab Investigator’s Brochure for additional details on all ongoing and 
planned clinical studies. 
A14–2.6 
BENEFITRISK ASSESSMENT 
The combination of RO7247669 and tiragolumab has not yet been clinically tested.  
The combination of atezolizumab and tiragolumab has a favorable emergent benefitrisk 
profile, and early clinical experience with RO7247669 suggest a safety profile 
comparable to that of atezolizumab and other PD-1/PD-L1 blocking antibodies 
(Appendix 12).  The combination of nivolumab (antiPD-1) and relatlimab (antiLAG-3) 
improved PFS over nivolumab alone as first-line therapy in melanoma patients in the 
Phase III Relativity-047 study (Tawbi et al. 2022), which supports the expected benefit 
from RO7247669 (antiPD-1/antiLAG-3 bispecific therapy) in combination with 
tiragolumab.  Taking into account the potentially synergistic mechanisms of action of 
RO7247669 and tiragolumab, as well as their manageable and tolerable safety profiles 
(see Section A14–5), combination treatment with these two agents has promise as a 
potential therapy in solid tumors such as melanoma. 
A minimum of 6 patients in Cohort 2 must complete the initial safety run-in phase.  If the 
combination is determined to be tolerable, enrollment into the preliminary phase may be 
opened, and the same arm in Cohort 1 can be opened for enrollment (refer to 


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Sections 3.1.23.1.4 for details).  Patients in the safety run-in phase will be enrolled and 
treated in a sequential manner, with at least one week between the first patient and the 
remaining patients. 
The assessment will be based on safety data from a minimum of 6 patients who have 
received at least one dose of treatment (i.e., one dose of each agent) and who have 
completed safety follow-up assessments for at least 28 days.  If   30% of patients 
experience a treatment-related Grade  3 adverse event, enrollment in the safety run-in 
phase will be stopped.  There will be an evaluation of the benefitrisk profile of that 
treatment by the Sponsor. 
After Cohort 2 safety run-in patients have completed 2 cycles of 2100 mg RO7247669 
Q3W in combination with 600 mg tiragolumab Q3W in addition to the required safety 
follow-up of 28 days, and the safety of the combination has been assessed and deemed 
appropriate, the combination may be investigated in additional Cohort 2 arms.  These 
arms will investigate administration of RO7247669 at doses lower than 2100 mg, 
e.g., 1200 mg and 600 mg.  This will further inform safety, pharmacokinetics, 
pharmacodynamics, and preliminary anti-tumor activity of RO7247669 in combination 
with tiragolumab. 
If the stopping criteria are not met during the safety run-in phase, enrollment in Cohort 1 
will proceed. 
In addition, a minimum of 6 patients in Cohort 1 in the RO7247669 2100 mg  Tira arm 
must complete a safety evaluation before additional patients can be enrolled in that arm 
(refer to Section 3.1.3 for details). 
For the evaluation of the impact of the COVID-19 pandemic on the benefitrisk 
assessment, please refer to Section 1.3. 
A14–3 
RATIONALE FOR DOSE AND SCHEDULE FOR RO7247669 
2100 mg  TIRA ARM 
A14–3.1 
RATIONALE FOR RO7247669 DOSE AND SCHEDULE 
RO7247669 will be administered at a fixed dose of 2100 mg every 3 weeks (Q3W) 
(2100 mg on Day 1 of each 21-day cycle).  A fixed dosing regimen of 2100 mg Q3W was 
selected based on available clinical pharmacokinetic, efficacy, and safety data from 
Study NP41300.  During the dose-escalation Part A of the study, RO7247669 was well 
tolerated, and no specific safety concern associated with RO7247669 was identified.  
No DLT up to the highest dose of 2100 mg Q2W was observed, and no MTD was 
identified.  Anti-tumor activity, as measured by radiographic PRs, was observed starting 
at a dose of 600 mg Q2W.  PK results for RO7247669 were dose linear within the dose 


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range tested in Study NP41300 and therefore predicted to be in the range of target 
saturation.  Peripheral receptor occupancy was  90% ~80 days after administration.  
Therefore, Q3W administration should result in similar receptor occupancy to Q2W on 
treatment.  A Q3W regimen for RO7247669 is also more convenient when it is 
administered with tiragolumab, which is administered Q3W. 
In addition, RO7247669 was well tolerated in both the dose-range finding studies and 
Good Laboratory Practice (GLP) monkey toxicology studies up to the highest dose 
evaluated (100 mg/kg).  Toxicology findings were consistent with the findings in 
cynomolgus monkey studies of marketed CPIs. 
The supporting data for the selected dose can be found in the current RO7247669 
Investigator’s Brochure. 
A14–3.2 
RATIONALE FOR TIRAGOLUMAB DOSE AND SCHEDULE 
Tiragolumab will be administered at a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of 
each 21-day cycle). 
The fixed dose of 600 mg IV Q3W was selected on the basis of available clinical 
pharmacokinetic, efficacy, and safety data from the combined Phase Ia/Phase Ib Study 
GO30103 with single-agent tiragolumab or tiragolumab in combination with 
atezolizumab.  In the Phase Ia portion of the study with tiragolumab as a single agent, 
the MTD was not reached, and no DLTs were observed during dose-escalation.  As of 
the clinical cutoff date, anti-drug antibodies (ADAs) to tiragolumab were rare in the 
Phase Ia or Phase Ib portions across all dose levels.  Complete occupancy of peripheral 
TIGIT receptors on CD4+, CD8+, and NK cells was observed beginning at 30 mg of 
tiragolumab in both the Phase Ia and Phase Ib portions of the study and remained 
sustained at all higher doses (unpublished Roche data on file). 
Prolonged stable disease was observed in patients in the Phase Ia portion of the study 
at tiragolumab doses beginning at 400 mg.  In the Phase Ib portion of the study with 
tiragolumab plus atezolizumab, the MTD was not reached.  Anti-tumor activity, as 
measured by radiographic partial responses, was observed across doses for 
tiragolumab beginning at 30 mg and ranging up to 600 mg in combination with 1200 mg 
atezolizumab.  Refer to the Tiragolumab Investigator’s Brochure for additional details. 


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A14–4 
MATERIALS AND METHODS SPECIFIC TO RO7247669 2100 mg 
 TIRA ARM 
A14–4.1 
TREATMENT IN RO7247669 2100 mg  TIRA ARM 
A14–4.1.1 
Formulation, Packaging, and Handling 
A14–4.1.1.1 RO7247669 
The RO7247669 drug product will be supplied by the Sponsor as a 50 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of RO7247669, refer to the 
pharmacy manual and the RO7247669 Investigator’s Brochure. 
A14–4.1.1.2 Tiragolumab 
The tiragolumab drug product will be supplied by the Sponsor as a 60 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of tiragolumab, refer to the 
pharmacy manual and the Tiragolumab Investigator's Brochure. 
A14–4.1.2 
Dosage, Administration, and Compliance 
Patients in the RO7247669 plus tiragolumab (RO7247669  Tira 2100 mg) arm will 
receive treatment as outlined in Table A14-1.  Patients in Cohort 1 will receive treatment 
for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical 
benefit, whichever occurs first (see Section 3.1.2 for details). 
Patients in Cohort 2 will receive treatment until unacceptable toxicity or loss of clinical 
benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease) (see Section 3.1.2 
for details).  It is recommended that treatment be initiated no later than 7 days after 
randomization (Cohort 1) or enrollment (Cohort 2). 
Table A14-1 
Treatment Regimen for RO7247669 2100 mgTira Arm 
Cycle Length 
Dose, Route, and Regimen  
(drugs listed in order of administration) 
21 days 
 RO7247669 2100 mg IV on Day 1 of each cycle a 
 Tiragolumab 600 mg IV on Day 1 of each cycle 
Tira  tiragolumab. 
a After the safety run-in has been completed, the Sponsor may explore lower doses  
(e.g., 1200 mg and 600 mg). 
 


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Refer to the pharmacy manuals for detailed instructions on drug preparation, storage, 
and administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
No safety data related to overdosing of RO7247669 or tiragolumab are available to date. 
A14–4.1.2.1 RO7247669 
RO7247669 will be administered by IV infusion at a fixed dose of 2100 mg on Day 1 of 
each 21-day cycle. 
Administration of RO7247669 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 8.  
RO7247669 infusions will be administered per the instructions outlined in Table A14-2. 


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Table A14-2 
Administration of First, Second, and Subsequent 
RO7247669 Infusions 
First and Second Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
first RO7247669 infusion. 
 
Vital signs (respiratory rate, pulse rate, 
blood pressure, pulse oximetry, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
For the first infusion, RO7247669 should be 
infused over 60 ( 10) minutes. 
 
After the infusion of RO7247669, the 
patient begins a 60-minute observation 
period. 
 
For the second infusion, RO7247669 
should be infused over 30 ( 10) minutes if 
the first infusion was tolerated without an 
IRR. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion.  Record on the eCRF in case of 
abnormalities. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with 
any previous infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO77247669 should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR. 
 
If the patient tolerated the previous 
infusion of RO77247669 well without 
infusion-associated adverse events, the 
observation period may be reduced to 
30 minutes. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be measured every 
15 ( 5) minutes during the infusion and 
at 30 ( 10) minutes after the infusion.  
Record on the eCRF in case of 
abnormalities. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
  
For patients who experience a Grade  2 infusion-related reaction (IRR), premedication 
with paracetamol 5001000 mg orally [PO] or IV and diphenhydramine 2550 mg PO or 
IV (or an alternative histamine H1/2 antagonist at an adequate dose) is required prior to 
subsequent infusions.  In case of Grade 3 or 4 IRRs related to study treatment, the 
patient should be permanently discontinued from the study treatment. 
Guidelines for medical management of IRRs for RO7247669 are provided in 
Section A14–5.1.2.1. 
No dose modification for RO7247669 is allowed.  However, based on emerging safety 
and efficacy data, the Sponsor may explore lower doses (e.g., 1200 mg and 600 mg).  
Guidelines for treatment interruption or discontinuation because of toxicities are provided 
in Section A14–5.1.4.2 and Appendix 9.  RO7247669 treatment may be interrupted for 
reasons other than toxicity (e.g., surgical procedures).  The acceptable length of 


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treatment interruption must be based on the investigator’s benefitrisk assessment and 
in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
A14–4.1.2.2 Tiragolumab 
Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 
of each 21-day cycle with a post-infusion observation period as described in Table A14-
3. 
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.  For anaphylaxis precautions, see Appendix 8.  
Tiragolumab infusions will be administered per the instructions outlined in Table A14-3. 
 


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Table A14-3 
Administration of First and Subsequent Tiragolumab 
Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
tiragolumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
60 ( 15) minutes. 
 
After the infusion of tiragolumab, the 
patient begins a 60-minute observation 
period. 
 
Record vital signs on the eCRF every 
15 ( 5) minutes during the infusion and at 
30 ( 10) minutes after the infusion. 
 
Patients will be informed about the 
possibility of delayed postinfusion 
symptoms and will be instructed to contact 
their study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with the 
first infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 
Patients should be observed for 
30 minutes after completion of the 
tiragolumab infusion if the previous 
infusion was tolerated without an IRR, or 
for 60 minutes after completion of the 
tiragolumab infusion if the patient 
experienced an IRR with the previous 
infusion. 
 
If clinically indicated, vital signs should be 
recorded on the eCRF every 
15 ( 5) minutes during the infusion and at 
30 ( 10) minutes after the infusion. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
 
Guidelines for medical management of IRRs for tiragolumab are provided in  Table A14-
4.   
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section A14–5.1.4.2.  Tiragolumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on the investigator’s 
benefitrisk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 


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A14–4.2 
CONCOMITANT THERAPY FOR RO7247669 2100 mg  TIRA 
ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
A14–4.2.1 
Permitted Therapy for RO7247669 2100 mg  Tira Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A14–4.2.4) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease (COPD) or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  Other use of corticosteroids may be permitted at the investigator’s 
discretion.  The Medical Monitor is available to advise as needed 
 
Local therapy (e.g., surgery other than complete lymph node dissection [CLND] that 
is not considered to be related to melanoma) 
 
A14–4.2.2 
Additional Permitted Therapy for RO7247669 2100 mg  Tira 
Arm in Cohort 2 
Patients are permitted to use the following therapies during the study: 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with tiragolumab may be 
continued during palliative radiotherapy. 


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Treatment with RO7247669 may be continued during palliative radiotherapy 
with one exception:  palliative radiotherapy is not permitted on days when 
RO7247669 is administered. 
 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation) as outlined below: 
Patients experiencing a mixed response requiring local therapy for control of 
three or fewer lesions may still be eligible to continue study treatment.  Patients 
who receive local therapy directed at a target lesion will no longer be evaluable 
for radiographic response but will remain evaluable for progression. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered 
for the second and subsequent RO7247669 and tiragolumab infusions only, at the 
discretion of the investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; refer to Appendix 8 for details). 
A14–4.2.3 
Cautionary Therapy for RO7247669 2100 mg  Tira Arm 
A14–4.2.3.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor- 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with RO7247669 and/or tiragolumab.  Therefore, in situations in which systemic 
corticosteroids, immunosuppressive medications, or TNF- inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, 
and TNF- inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications, are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with RO7247669 and/or tiragolumab therapy (refer to Appendix 9 for details). 


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A14–4.2.3.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A14–4.2.3) may be used during the study at the discretion of the 
investigator. 
A14–4.2.4 
Prohibited Therapy for RO7247669 2100 mg  Tira Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, is prohibited for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.4), and during study treatment until surgery, or unacceptable toxicity 
(Cohort 1), or until disease progression is documented and the patient has 
discontinued study treatment (Cohort 2), with the exception of palliative radiotherapy 
(see Section A14–4.2.1 for details). 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with RO7247669 and/or tiragolumab, 
and for 4 months after the last dose of RO7247669 and/or tiragolumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment and during study treatment because 
these agents could potentially increase the risk for autoimmune conditions when 
given in combination with RO7247669 and/or tiragolumab. 
 
A14–4.3 
CONTRACEPTION REQUIREMENTS FOR RO7247669 
2100 mg  TIRA ARM 
Contraception requirements for women and men in the RO7247669 2100 mg  Tira arm 
are outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period, for 4 months after the last dose of 
RO7247669, and for 90 days after the last dose of tiragolumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 


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and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraception, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant or a 
pregnant female partner, men who are not surgically sterile must remain 
abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year during the treatment period, for 
4 months after the last dose of RO7247669, and for 90 days after the last dose 
of tiragolumab to avoid exposing the embryo.  Men must refrain from donating 
sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
A14–5 
ASSESSMENT OF SAFETY FOR RO7247669 2100 mg  TIRA 
ARM 
A14–5.1 
SAFETY PLAN FOR RO7247669 2100 mg  TIRA ARM 
The safety plan for patients in this study is based on clinical experience with RO7247669 
and tiragolumab in completed and ongoing studies.  The anticipated important safety 
risks are outlined below (see Sections A14–5.1.1, A14–5.1.2, A14–5.1.3, and A14–
5.1.4).  Guidelines for the management of patients who experience specific adverse 
events are provided in Section A14–5.1.4 and Appendix 9. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 


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patients during the study.  Because of the potential for overlapping toxicities for 
RO7247669 and tiragolumab, special caution will be taken by performing a planned 
safety run-in for patients randomized to this arm in Cohort 2, and a planned safety 
evaluation phase in Cohort 1 (see Section 3.1.4). 
Administration of RO7247669 and tiragolumab will be performed in a monitored setting 
in which there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions.  Adverse events will be reported as 
described in Sections 5.25.6. 
A14–5.1.1 
Risks Associated with RO7247669 
Clinical evaluation of RO7247669 is ongoing, and not all risks are known.  As an 
antagonist of PD-1 and LAG-3, RO7247669 is anticipated to enhance T-cell and NK-cell 
proliferation, survival, and function.  Based on the mechanism-of-action of RO7247669, 
the safety profile is anticipated to be similar to other CPIs.  Potential risks associated 
with RO7247669 include the following:  IRRs (including anaphylaxis), immunogenicity, 
and immune-mediated adverse events.  Refer to Section 6 of the RO7247669 
Investigator’s Brochure for a detailed description of anticipated safety risks for 
RO7247669. 
A14–5.1.1.1 Infusion-Related Reactions and Anaphylaxis 
Administration of therapeutic antibodies may cause IRRs, which may include symptoms 
such as fever, chills, hypotension, shortness of breath, skin rash, headache, nausea, 
and vomiting.  Such reactions typically occur during or shortly after the infusion and are 
predominantly reported following the first infusion.  The incidence and severity of IRRs 
typically decrease with subsequent infusions.  Based on in vitro data, the risk of 
proinflammatory cytokine-mediated IRRs on first administration of RO7247669 as single 
agent is considered low. 
Refer to Section A14–4.1.2 for detailed guidance on administration of RO7247669 in this 
study.  Refer to Appendix 8 for guidance on anaphylaxis precautions and Section  
A14–5.1.4.3 for guidance on the management of IRRs. 
A14–5.1.1.2 Immunogenicity 
Administration of therapeutic antibodies may cause the formation of anti-drug antibodies, 
which may negatively affect the safety of the therapeutic (e.g., allergic reactions, 
immune complex-mediated diseases). 
A14–5.1.1.3 Immune-Mediated Adverse Events 
The co-stimulatory action of RO7247669, particularly given the LAG-3 modulation, might 
bear the risk of exaggerated immune cell activation that may result in the occurrence of 


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enhanced, untoward, immune-mediated adverse events and increased 
cytokine-releasemediated toxicities. 
Toxicities from PD-1 blocking agents can involve any organ or tissue, although some 
immune-mediated adverse events occur much more frequently than others.  The most 
frequently occurring immune-mediated adverse events affect skin, colon, endocrine 
organs, liver, and lungs.  Others are very infrequent but may be very serious, even 
lethal, such as neurological disorders and myocarditis. 
The limited data from recent early phase studies showed that antiLAG-3therapy was 
generally well tolerated as a monotherapy or in combination with anti-PD-1 therapies, 
and consistent with the safety profiles of other CPIs (Ascierto et al. 2017; Hong et al. 
2018). 
In this study, specified immune-mediated adverse events will be considered adverse 
events of special interest and will be captured accordingly (see Section A14–5.2 for the 
list of adverse events of special interest and Section 5.4.2 for reporting instructions). 
Patients with a history of autoimmune disease will be excluded from this study.  Please 
see Section 4.1.2 for details. 
A14–5.1.2 
Risks Associated with Tiragolumab 
Infusion-related reactions and immune-mediated hepatitis are identified risks of 
tiragolumab.  Lymphopenia is a potential risk with 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 adverse events).   
Refer to Appendix 9 of the protocol and the Tiragolumab Investigator’s Brochure for a 
detailed description of anticipated safety risks of tiragolumab. 
A14–5.1.2.1 Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, 
IRRs associated with hypersensitivity reactions, and/or target-mediated cytokine 
releasemay occur.  Clinical signs and symptoms of such reactions may include rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
IRRs have been reported in patients treated with tiragolumab.  The majority of events 
were mild to moderate and manageable. 


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To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab will be 
administered over 60 minutes followed by a 60-minute observation period.  Subsequent 
infusions and observation times may be shortened if the preceding infusion was well 
tolerated.  All infusions will be administered in an appropriate medical setting. 
Refer to Section A14–4.1.2 for detailed guidance on administration of tiragolumab in this 
study.  Please see Appendix 8 for guidance on anaphylaxis precautions and Table A14-
4 for guidance on the management of IRRs. 
A14–5.1.2.2 Immune-Mediated Hepatitis 
The use of tiragolumab to block the immune inhibitory receptor TIGIT serves to increase 
a baseline T-cell and NK-cell immune response, especially in combination with other 
checkpoint inhibitors.  A disruption in the functioning of immune checkpoint molecules 
may lead to imbalances in immunologic tolerance that results in an unchecked immune 
response, including immune-mediated hepatitis. 
Refer to Appendix 9 for guidance on the management of immune-mediated hepatitis. 
A14–5.1.2.3 Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/ and wild-type B6 mice were immunized with myelin 
oligodendrocyte glycoprotein peptide in an EAE using suboptimal doses.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/ mice developed severe EAE 
(Joller et al. 2011). 
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a general 
risk and may therefore be considered a potential risk of tiragolumab.  Such 
immune-mediated adverse events have been described for virtually all organ systems 
and include, but are not limited to, colitis, pneumonitis, endocrinopathies, ocular toxicity, 
pancreatic toxicity, neurologic toxicity, cardiac toxicity, nephritis, myositis, and severe 
cutaneous adverse reactions. 
Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2). 
In this study, immune-mediated adverse events will be considered adverse events of 
special interest and will be captured accordingly (see Section A14–5.2 for the list of 
adverse events of special interest and Section 5.4.2 for reporting instructions). 


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Suggested management guidelines for individual suspected immune-mediated adverse 
events are provided in Appendix 9. 
A14–5.1.2.4 Lymphopenia 
The IgG1 backbone of tiragolumab with intact Fc-effector function may lead to 
ADCC-mediated reduction in lymphocyte count.  Lymphopenia is a potential risk with 
tiragolumab.  Transient decreases in lymphocyte count without clinical sequelae have 
been observed in patients treated with tiragolumab. 
Patients with a lymphocyte count  0.5  109/L (500/L) will be excluded from the study 
(see Section 4.1.1), and complete blood counts will be monitored regularly during the 
study (see Appendix A14–6). 
A14–5.1.2.5 Embryofetal Toxicity 
Embryofetal toxicity is a potential risk with tiragolumab.  Administration of tiragolumab is 
expected to have adverse effects on pregnancy based on the expression of TIGIT on 
decidual NK and CD8 T cells (Powell et al. 2017; van der Zwan et al. 2018; 
Vento-Tormo et al. 2018), and the expected role of these cells in the recognition and 
response to foreign fetal, placental, and viral antigens at the maternal-fetal interface as 
well as maintenance of maternal-fetal tolerance.  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 
of tiragolumab in pregnant women.  Tiragolumab should not be administered to pregnant 
women. 
Refer to Section 6 of the Tiragolumab Investigator’s Brochure for a detailed description 
of embryofetal toxicity. 
A14–5.1.3 
Risks Associated with Combination Use of RO7247669 and 
Tiragolumab 
The blockade of inhibitory checkpoints leads to increase adaptive T-cell immune 
responses via complementary targets, and the combination targeting multiple 
checkpoints may be associated with heightened immune-mediated toxicity relative to 
either agent alone.  Such toxicity could manifest as a higher incidence or greater severity 
of autoimmune inflammation events, or potentially the development of HLH and MAS.  
The following adverse events are potential overlapping toxicities associated with 
combination use of RO7247669 plus tiragolumab:  IRR and immune-mediated toxicities, 
(see Appendix 9 for complete list). 


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A14–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the RO7247669 2100 mg  Tira Arm 
A14–5.1.4.1 Dose Modifications 
There will be no dose modifications for RO7247669 or tiragolumab in this study.  
However, based on emerging safety and efficacy data, the Sponsor may explore lower 
doses of RO7247669 (e.g., 1200 mg and 600 mg). 
A14–5.1.4.2 Treatment Interruption for Toxicities 
Treatment with RO7247669 and tiragolumab may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  If corticosteroids are 
initiated for treatment of the toxicity, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before study treatment can be resumed, if 
warranted.   
For Cohort 1, in the neoadjuvant setting the study treatment is limited to a pre-surgery 
window of 6 weeks.  Treatment during this period should not be interrupted unless a 
patient experiences toxicity.  If toxicity meets criteria for interrupting/withholding 
RO7247669 and tiragolumab, RO7247669 and tiragolumab should be 
interrupted/withheld.  After resolution of the toxicity, subsequent treatment cycles should 
only be considered if the benefit/risk profile is acceptable and if the surgery can be 
conducted within 2 weeks of the planned date.  Otherwise, subsequent treatment cycles 
should be omitted to allow the patient to proceed directly to surgery without further delay. 
For Cohort 2, if RO7247669 and tiragolumab are withheld for 12 weeks or longer due to 
toxicity, the patient should be discontinued from RO7247669 and tiragolumab.  However, 
RO7247669 and tiragolumab may be withheld for more than 12 weeks to allow for 
patients to taper off corticosteroids prior to resuming treatment.  RO7247669 and 
tiragolumab may be resumed after being withheld for more than 12 weeks if the patient is 
likely to derive clinical benefit.  RO7247669 and tiragolumab treatment may be 
suspended for reasons other than toxicity (e.g., surgical procedures) at the discretion of 
the investigator.  The acceptable length of the extended period of time must be must be 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  The 
Medical Monitor is available to advise as needed.  


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On the basis of the available characterization of mechanism-of-action, tiragolumab may 
cause adverse events similar to, but independent of, RO7247669.  Tiragolumab may 
also exacerbate the frequency or severity of RO7247669-related adverse events or may 
have non-overlapping toxicities with RO7247669.  Because these scenarios may not be 
distinguishable from each other in the clinical setting, adverse events should generally 
be attributed to both agents, and dose interruptions or treatment discontinuation in 
response to adverse events should be applied to both tiragolumab and RO7247669.  
If RO7247669 is withheld or discontinued, tiragolumab should also be withheld or 
discontinued.  If tiragolumab is withheld or discontinued, RO7247669 should also be 
withheld or discontinued. 
A14–5.1.4.3 Management Guidelines for Adverse Events 
Guidelines for the management of patients who experience specific adverse events are 
provided in Table A14-4 and Appendix 9. 
For cases in which management guidelines are not covered in Appendix 9, patients 
should be managed and treatments should be withheld or discontinued as deemed 
appropriate by the investigator according to best medical judgment. 
Table A14-4 
Guidelines for Management of Patients Who Experience 
Adverse Events in the RO7247669 2100 mg  Tira Arm 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions 
General guidance 
 For anaphylaxis precautions, see Appendix 8. 
 For severe hypersensitivity reactions, permanently 
discontinue RO7247669 and tiragolumab. 
 For suspected CRS, see Appendix 9 for guidance on 
supportive care. 
 Determine tryptase concentration and IgE titer if clinical 
presentation of IRR suggests an anaphylactic or 
hypersensitivity reaction (hives, obstructive shortness of 
breath, urticaria, other histamine associated symptoms) 
and/or if the first IRR or CRS ( Grade 2) is observed at 
the second infusion.  If tryptase and/or IgE are elevated, 
collect a second sample for IgE/tryptase analysis at 
least 48 hours after the onset of the reaction to rule out 
the possibility of an anaphylactic reaction.   
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; 
IRR  infusion-related reaction; MAS  macrophage activation syndrome. 
 


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Table A14-4 
Guidelines for Management of Patients Who Experience 
Adverse Events in the RO7247669 2100 mg  Tira Arm 
(cont.)  
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions (cont.) 
IRR to RO7247669 and/or tiragolumab 
Grade 1 
 Reduce infusion rate to half the rate being given at the 
time of event onset. 
 After the event has resolved, the investigator should 
wait for 30 minutes while delivering the infusion at the 
reduced rate. 
 If the infusion is tolerated at the reduced rate for 
30 minutes after symptoms have resolved, the infusion 
rate may be increased to the original rate. 
IRR to RO7247669 and/or tiragolumab 
Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment (e.g., oral 
or IV antihistamine, anti-pyretic medication, 
glucocorticoids, epinephrine, bronchodilators, oxygen, 
IV fluids). 
 After symptoms have resolved to baseline, resume 
infusion at half the rate being given at the time of event 
onset. 
 For subsequent infusions, consider administration of 
oral premedication with antihistamines, antipyretic 
medications, and/or analgesics and monitor closely for 
IRRs. 
IRR to RO7247669 and/or tiragolumab, 
Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment (e.g., oral 
or IV antihistamine, anti-pyretic medication, 
glucocorticoids, epinephrine, bronchodilators, oxygen, 
IV fluids). 
 Permanently discontinue RO7247669 and tiragolumab 
and contact the Medical Monitor. 
Pulmonary, hepatic, GI, endocrine, 
ocular, immune-mediated myocarditis, 
CRS, pancreatic, dermatologic, 
neurologic, immune-mediated 
meningoencephalitis, renal, myositis, 
HLH, MAS, and systemic immune 
activation 
 Guidelines for the management of these events are 
provided in Appendix 9.   
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; 
IRR  infusion-related reaction; MAS  macrophage activation syndrome. 
 


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A14–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR THE 
RO7247669 2100 mg  TIRA ARM (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.2.3 for reporting instructions).  Adverse events of special interest for the 
RO7247669 2100 mg  Tira arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either elevated bilirubin or clinical jaundice, as defined by Hy's Law 
(see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
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  upper limit of normal 
 
Systemic lupus erythematosus 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis) 
 
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, or 
toxic epidermal necrolysis) 


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A14–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN THE 
RO7247669 2100 mg  TIRA ARM 
A14–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 4 months after the last dose of RO7247669 or within 90 days after the last dose of 
tiragolumab.  A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and e-mailing the form using 
the fax number or e-mail address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study 
treatment and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Any serious adverse events associated with the pregnancy (e.g., an 
event in the fetus, an event in the mother during or after the pregnancy, or a congenital 
anomaly/birth defect in the child) should be reported on the Adverse Event eCRF.  In 
addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A14–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
4 months after the last dose of RO7247669 or within 90 days after the last dose of 
tiragolumab.  The investigator should report the pregnancy on the paper Clinical Trial 
Pregnancy Reporting Form and submit the form to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and e-mailing the form using the fax number or e-mail address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for the Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 


Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
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289/Protocol BO43328, Version 4 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A14–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A14–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
treatment or the female partner of a male patient exposed to study treatment should be 
classified as a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.2.2). 










Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
Table A14-5 
SCHEDULE OF ACTIVITIES FOR RO7247669 2100 mg  TIRA ARM (COHORT 1) (cont.) 
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294/Protocol BO43328, Version 4 
f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of new 
systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 135 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  After 
this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on reporting all 
treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each adverse event 
until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the 
patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-
related procedures until a final outcome can be reported. 
g Patients who complete the treatment period, regardless of whether they complete the study drug treatment period or discontinue study drug 
prematurely, patients who proceed to surgery will have their first long-term follow-up visit 3 months after surgery and patients who do not 
proceed to surgery will have their first long-term follow-up visit 3 months after the final dose of study treatment.  Information on survival follow-up 
and new anti-cancer therapy (including targeted therapy and immunotherapy) will be collected via telephone calls, patient medical records, 
and/or clinic visits approximately every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a 
patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator.  If a 
patient withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain information about survival 
status only.  For an experimental arm in which all patients discontinued treatment and passed the safety follow-up window, as well as 
approximately 80% of patients discontinued the study, the Sponsor may conclude the arm (the remaining ~20% of patients will be discontinued 
from the study). 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments. 
k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a local 
gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration. 
 
 


Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
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295/Protocol BO43328, Version 4 
A14–7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR RO7247669 2100 mg  TIRA ARM 
(COHORT 1) 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to first infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the 
end of tiragolumab infusion 
 Tiragolumab PK (serum) 
30 ( 10) minutes after the 
end of RO7247669 infusion 
 RO7247669 PK (serum) 
Day 1 of Cycle 2 
Prior to infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the 
end of RO7247669 infusion 
 RO7247669 PK (serum) 
Surgery CLND 
Week 7 
Prior to surgery  
(24 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation 
Week 13 
At visit 
 RO7247669 ADA (serum) 
 RO7247669 PK (serum) 
 Biomarkers (blood, plasma) 
Long-term follow-up 
Every 3 months (7 days) b 
At visit b 
 Biomarkers (blood, plasma) 
Surgery follow-up 
6 months after surgery 
(7 days) 
At visit 
 RO7247669 ADA (serum) 
 RO7247669 PK (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; CLND  complete lymph node dissection; PK  pharmacokinetic; Tira  tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may be reduced 
or sample collection may cease altogether.  Additionally, collected samples may not be analyzed if not 
warranted.  On the basis of emerging biomarker data, the number of biomarker samples may be reduced or 
sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained  20 days post-surgery. 
b To be collected if visit is conducted on site. 








Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
TABLE A14-6 SCHEDULE OF ACTIVITIES FOR RO7247669 2100 mg  TIRA ARM (COHORT 2) (cont.) 
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
299/Protocol BO43328, Version 4 
ADA  anti-drug antibody; D  day; Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; HBcAb  hepatitis core antibody; 
HBsAg  hepatitis B surface antigen; HBV  hepatitis B virus; HCV  hepatitis C virus; IMP  investigational medicinal product; M  month; 
MUGA  multiple-gated acquisition; PK  pharmacokinetic; T3  triiodothyronine; T4  thyroxine; TSH  thyroid-stimulating hormone; 
TTE  transthoracic echocardiogram; Wk  week. 
Note:  On treatment days, all assessments and procedures should be performed prior to dosing, unless otherwise specified. 
a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the final dose 
of study treatment.  The visit at which loss of clinical benefit is confirmed by the investigator (see Section 3.1.2 for details) may be used as the 
treatment discontinuation visit.  For an experimental arm in which all patients discontinued treatment and passed the safety follow-up window, 
as well as approximately 80% of patients discontinued the study, the Sponsor may conclude the arm (the remaining ~20% of patients will be 
discontinued from the study). 
c Assessment may be performed within 24 hours prior to dosing during the treatment period. 
d After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of 
new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to 
be reported until 135 days after the final dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on 
reporting all treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study 
treatment or trial-related procedures until a final outcome can be reported. 
e Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
f TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every 3 cycles 
thereafter (i.e., Cycles 4, 7, 10, etc.). 


Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
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300/Protocol BO43328, Version 4 
A14–9 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR RO7247669 2100 mg  TIRA ARM 
(COHORT 2) 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to first infusion (6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the end of 
tiragolumab infusion 
 Tiragolumab PK (serum) 
30 ( 10) minutes after the end of 
RO7247669 infusion 
 RO7247669 PK (serum) 
Day 8 of Cycle 1  
At visit ( 24 hr) 
 RO7247669 PK (serum) 
 Biomarkers (blood, plasma) 
Day 15 of Cycle 1  
At visit ( 72 hr) 
 RO7247669 PK (serum) 
 Biomarkers (blood, plasma) 
Day 1 of Cycle 2 
Prior to infusion (6 hr to 0 hr) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
30 ( 10) minutes after the end of 
RO7247669 infusion 
 RO7247669 PK (serum) 
Day 8 of Cycle 2 
At visit ( 24 hr) 
 Biomarkers (blood, plasma) 
Day 1 of Cycles 3 and 4 Prior to infusion (6 hr to 0 hr) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
End of RO7247669 infusion 
 RO7247669 PK (serum) 
ADA  anti-drug antibody; CLND  complete lymph node dissection; PK  pharmacokinetic; 
Tira  tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may 
be reduced or sample collection may cease altogether.  Additionally, collected samples may not 
be analyzed if not warranted.  On the basis of emerging biomarker data, the number of biomarker 
samples may be reduced or sample collection may cease altogether. 
 


Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
301/Protocol BO43328, Version 4 
A14-9 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR RO7247669 2100 mg  TIRA ARM  
(COHORT 2) (cont.) 
 
Visit 
Time 
Sample Type 
Day 1 of Cycles 8, 12, 
and 16 
Prior to infusion (6 hr to 0 hr) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment 
discontinuation visit 
( 30 days after last 
dose) 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; CLND  complete lymph node dissection; PK  pharmacokinetic; 
Tira  tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may 
be reduced or sample collection may cease altogether.  Additionally, collected samples may not 
be analyzed if not warranted.  On the basis of emerging biomarker data, the number of biomarker 
samples may be reduced or sample collection may cease altogether. 


Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
302/Protocol BO43328, Version 4 
A14–10 
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Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
303/Protocol BO43328, Version 4 
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Appendix 14:  Study Details Specific to RO7247669 2100 mg  Tira Arm (Cohorts 1 and 2) 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
304/Protocol BO43328, Version 4 
Wang F, Hou H, Wu S, et al. TIGIT expression levels on human NK cells correlate with 
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Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
305/Protocol BO43328, Version 4 
Appendix 15  
Study Details Specific to RO7247669 600 mg Arm 
TABLE OF CONTENTS 
A15–1 
Background on RO7247669 600 mgArm .................................. 307 
A15–2 
Rationale for RO7247669 600 mg Arm .................................... 307 
A15–2.1 
Targeting the PD-1 and LAG-3 Antigens ................................ 307 
A15–2.2 
Clinical Studies of Agents Targeting the PD-1 and LAG-3 
Pathways................................................................................... 308 
A15–2.2.1 
Study NP41300 ........................................................................ 310 
A15–2.3 
BenefitRisk Assessment .......................................................... 310 
A15–3 
Rationale for Dose and Schedule for RO7247669 600 mg 
Arm ........................................................................................... 311 
A15–3.1 
Rationale for RO7247669 Dose and Schedule ........................... 311 
A15–4 
Materials and Methods Specific to RO7247669 600 mg Arm ... 312 
A15–4.1 
Treatment in RO7247669 600 mg Arm .................................... 312 
A15–4.1.1 
Formulation, Packaging, and Handling .................................... 312 
A15–4.1.2 
Dosage, Administration, and Compliance ................................ 312 
A15–4.2 
Concomitant Therapy for RO7247669 600 mg Arm ................. 314 
A15–4.2.1 
Permitted Therapy for RO7247669 600 mg Arm ...................... 314 
A15–4.2.2 
Cautionary Therapy for RO7247669 600 mg Arm ................... 315 
A15–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ......................................... 315 
A15–4.2.2.2 
Herbal Therapies ....................................................................... 315 
A15–4.2.3 
Prohibited Therapy for RO7247669 600 mg Arm ..................... 315 
A15–4.3 
Contraception Requirements for RO7247669 600 mg Arm ...... 316 
A15–5 
Assessment of Safety for RO7247669 600 mg Arm .................. 317 
A15–5.1 
Safety Plan for RO7247669 600 mg Arm ................................. 317 
A15–5.1.1 
Risks Associated with RO7247669 ........................................... 317 
A15–5.1.1.1 
Infusion-Related Reactions and Anaphylaxis ........................... 317 
A15–5.1.1.2 
Immunogenicity ........................................................................ 318 
A15–5.1.1.3 
Immune-Mediated Adverse Events ........................................... 318 
A15–5.1.2 
Management of Patients Who Experience Specific Adverse 
Events in RO7247669 600 mg Arm .......................................... 318 
A15–5.1.2.1 
Dose Modifications ................................................................... 318 
A15–5.1.2.2 
Treatment Interruption for Toxicities ....................................... 318 
A15–5.1.2.3 
Management Guidelines for Adverse Events ............................ 319 
A15–5.2 
Adverse Events of Special Interest for RO7247669 600 mg 
Arm (Immediately Reportable to the Sponsor) .......................... 322 
A15–5.3 
Reporting Requirements for Pregnancies in RO7247669 600 
mg Arm ..................................................................................... 322 
A15–5.3.1 
Pregnancies in Female Patients ................................................ 322 
A15–5.3.2 
Pregnancies in Female Partners of Male Patients..................... 323 
A15–5.3.3 
Abortions .................................................................................. 323 


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A15–5.3.4 
Congenital Anomalies/Birth Defects ......................................... 324 
A15–6 
Schedules of Activities and Sample Collection for 
RO7247669 600 mg Arm .......................................................... 325 
A15–7 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for RO7247669 600 mg Arm ..................... 330 
A15–8 
References ................................................................................. 331 
 
 
 


Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
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307/Protocol BO43328, Version 4 
A15–1 
BACKGROUND ON RO7247669 600 mg ARM 
RO7247669 is a novel, Fc-silent IgG1-based bispecific antibody (bsAb) in 1   1 format 
that incorporates monovalent binding to two immune checkpoint proteins:  PD-1 and 
LAG-3.  RO7247669 is designed to target dysfunctional tumor antigen-specific 
T-lymphocytes expressing PD-1 and LAG-3 to establish or re-establish an effective 
anti-tumor immune response in cancer patients.  This may result in improved 
therapeutic responses over currently available therapies.  In addition, RO7247669 is 
engineered to prevent binding to Fc gamma receptors, thus potentially avoiding 
tumor-associated macrophage resistance mechanisms.  Such mechanisms have been 
observed with IgG4-based antiPD-1 antibodies, such as pembrolizumab and nivolumab 
(Arlauckas et al. 2017).  Clinical evaluation of RO7247669 is ongoing in a 
first-in-human, dose-finding study (NP41300) as a single agent in cancer patients with 
and without prior checkpoint inhibitor (CPI) exposure.   
Refer to the RO7247669 Investigator’s Brochure for details on nonclinical and other 
planned and ongoing clinical studies. 
A15–2 
RATIONALE FOR RO7247669 600 mg ARM 
A15–2.1 
TARGETING THE PD-1 AND LAG-3 ANTIGENS 
Cancer immunotherapy agents, particularly immune CPIs, have had a significant 
impact on the treatment of patients with advanced malignancies in recent years.  
However, despite the remarkable clinical efficacy of these therapies, additional 
treatment options targeting immune checkpoints are needed because the majority of 
patients eventually progress after an initial response or else fail to respond to the 
PD-1/PD-L1 checkpoint blockade.  This is believed to be due mainly to primary or 
secondary resistance mechanisms, to immunosuppressive activity of myeloid-derived 
suppressor cells, and/or to T-regulatory cells (Sharma et al. 2017). 
To overcome resistance mechanisms, additional treatment options and multiple 
combinations with antiPD-L1 therapy are being assessed.  One potential reason for 
resistance to antiPD-L1 therapy is the upregulation of alternative immune checkpoints 
with non-redundant regulatory functions (Sharma et al. 2017).  LAG-3 is one such 
alternative immune checkpoint.  LAG-3 is a member of the Ig superfamily that is 
structurally similar to CD4.  LAG-3 is expressed on activated effector T cells and is 
constitutively expressed on T-regulatory cells and natural killer (NK) cells.  
The expression of both PD-1 and LAG-3 on tumor infiltrating lymphocytes (TILs) 
correlates with the degree of impairment of effector functions, which is associated with 
poor prognosis (Matsuzaki et al. 2010; Baitsch et al. 2011; Thommen et al. 2015).  
Hence, LAG-3 is a marker of T-cell dysfunctionality.  LAG-3 also regulates T-cell 
functions, presumably including the function of T-regulatory cells.  In chronic 
infections and cancer, LAG-3, together with PD-1, contributes to T-cellacquired 


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dysfunctionality and to the inability of T cells to mount an effective/protective immune 
response upon interaction with the LAG-3 ligand, MHC-II. 
The interaction of LAG-3 with MHC-II inhibits T-cell proliferation, activation, 
cytolytic function, and proinflammatory cytokine production (Goldberg and Drake 
2011).  The effect of LAG-3 expression on T-regulatory cells is controversial.  An early 
report concluded that LAG-3 promotes T-regulatory cell-mediated immune suppression 
(Camisaschi et al. 2010).  However, a more recent report from the same authors found 
that LAG-3 limits T-regulatory cell-mediated immune suppression (Zhang et al. 2017). 
Expression of LAG-3 has been reported across various tumor types, including breast 
cancer, ovarian cancer, non-small cell lung cancer (NSCLC), melanoma, renal cell 
cancer (RCC), prostate cancer, and hepatocellular carcinoma (HCC).  In patients with 
these tumor types, LAG-3 is associated with poor prognosis (Matsuzaki et al. 2010; 
Baitsch et al. 2011; Thommen et al. 2015; He et al. 2016; Norstrom et al. 2016).  
Clinical evaluation of antiLAG-3 agents, as single agents and in combination with 
other CPIs, is ongoing in several early phase studies in patients with advanced solid 
tumors (Long et al. 2018).  Preliminary data demonstrate that antiLAG-3 therapy is 
well tolerated, both as single agents and in combination with antiPD-1 therapies, and 
the safety profiles are consistent with those of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018; Stratton et al. 2018).  RO7247669 may therefore be a therapeutic 
option for patients with melanoma. 
Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory immune checkpoints on the surface of effector T cells.  LAG-3 is 
frequently co-expressed with PD-1 on TILs, and dual blockade of PD-1 and LAG-3 
enhances CD8+ T-cell effector function and potentiates anti-tumor immunity in 
nonclinical models.  Blockade of these two receptors in mice with colon, fibrosarcoma, 
or ovarian tumors resulted in tumor remission in approximately 80% of animals, 
compared with remission in 10% to 40% with blockade of either receptor using a single 
agent (Woo et al. 2012; Huang et al. 2015).  TILs from patients with ovarian cancer 
showed that antigen-specific CD8+ T cells co-expressing PD-1 and LAG-3 exhibited 
greater impairment in their ability to respond to cognate antigen stimulation compared 
with CD8+ T cells that expressed one checkpoint molecule (Matsuzaki et al. 2010).  
In patients with NSCLC, overexpression of LAG-3 on TILs correlated with 
PD-1/PD-L1 expression and was linked to higher risk of recurrence and poor survival 
outcomes (He et al. 2017). 
A15–2.2 
CLINICAL STUDIES OF AGENTS TARGETING THE PD-1 
AND LAG-3 PATHWAYS 
Clinical data are available for early- and late-phase studies that evaluated the safety, 
tolerability, and preliminary anti-tumor activity of agents that target both the PD-1 


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and LAG-3 pathways.  Evidence of clinical activity has been reported in some of these 
studies.  Overall, adverse events have been manageable to date, and the safety profiles 
appear similar to those of single-agent CPIs. 
An ongoing Phase I/IIa study is evaluating the safety, tolerability, and clinical activity 
of combination treatment with the antiPD-1 monoclonal antibody nivolumab and the 
antiLAG-3 monoclonal antibody relatlimab in patients with advanced solid tumors.  
Preliminary data suggest that the combination of nivolumab and relatlimab may have 
an increased benefit compared with single-agent antiPD-1.  In a cohort of patients 
who had advanced melanoma who were previously treated with antiPD-1/PD-L1 
agents, the ORR was 11.5% (n  61) with a disease control rate (DCR) of 49%.  
The antiPD-1/PD-L1 treatment combination had an acceptable safety profile that was 
similar to the safety profile of nivolumab monotherapy (Ascierto et al. 2017). 
Relativity-047 is a Phase III study evaluating the combination of nivolumab 
(antiPD-1) and relatlimab (antiLAG-3) versus nivolumab alone in patients with 
untreated advanced melanoma.  This study demonstrated that nivolumab and relatlimab 
improved progression-free survival (PFS  10.1 months) over nivolumab 
(PFS  4.6 months).  The incidence of Grade 3 or 4 treatment-related adverse events was  
18.9% in patients that received the nivolumab and relatlimab combination and 9.7% in 
patients that received nivolumab alone (Tawbi et al. 2022). 
An ongoing Phase I/II study is evaluating the safety, tolerability, and clinical activity 
of combination treatment with the antiPD-1 monoclonal antibody spartalizumab and 
the antiLAG-3 monoclonal antibody LAG525 in patients with advanced solid tumors.  
Preliminary anti-tumor activity was observed during the Phase I dose-escalation 
portion of the study, including durable responses in 2 of 5 patients with triple-negative 
breast cancer (TNBC) and in 2 of 8 patients with mesothelioma.  Analyses of tumor 
biopsies from the TNBC cohort also showed a trend of conversion from an immune-cold 
to an immune-activated phenotype.  Common adverse events, i.e., adverse events 
reported in  10% of patients, included fatigue (18%), diarrhea (15%), and nausea 
(12%).  The incidence of Grade 34 adverse events was 8% for both the combination 
(n  121) and monotherapy (n  119) arms (Hong et al. 2018). 
An ongoing, first-in-human, dose-escalation, and dose-expansion Phase I study is 
evaluating the safety, tolerability, and clinical activity of the antiPD-1/LAG-3 dual 
affinity re-targeting protein (DART) bsAb MGD013 in patients with advanced solid 
tumors and hematologic malignancies.  During the dose-escalation phase of the study, 
the maximum tolerated dose (MTD) was not reached, and the safety profile was 
consistent with antiPD-1 monotherapy.  During the dose-expansion phase, anti-tumor 
activity was observed in patients with TNBC (n   23; ORR, 4.3%; DCR, 39.1%), 
CPI-naive NSCLC (n  14; ORR, 14.3%; DCR, 64.3%), and epithelial ovarian cancer 


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(n  23; ORR, 8.7%; DCR, 52.2%).  Expression of LAG-3 and an IFN- gene signature 
at baseline was associated with objective responses (Luke et al. 2020).  Clinical studies 
evaluating MGD013 as monotherapy and in combination with antiHER-2 agents are 
ongoing. 
A15–2.2.1 
Study NP41300 
Study NP41300 is an ongoing, first-in-human, dose-escalation, dose-expansion Phase I 
study to evaluate the safety, pharmacokinetics, and therapeutic activity of the 
antiPD-1/LAG-3 bsAb RO7247669 as a single agent in patients with locally advanced 
and/or metastatic solid tumors.  Part A, the dose-escalation phase of the study, is 
designed to determine the MTD and/or recommended dose for expansion (RDE) of 
RO7247669.  Part B of the study is designed to evaluate the anti-tumor activity of 
RO7247669 at the MTD or RDE in tumor-specific expansion cohorts. 
As of the data cutoff date, 1 March 2022, RO7247669 was well tolerated in the patients 
enrolled in Part A of the study.  No unexpected safety concern associated with 
RO7247669 was identified.  No dose-limiting toxicities (DLTs) were observed up to the 
maximum dose tested (2100 mg every 2 weeks [Q2W]), and no MTD was identified.  
The maximum dose of 2100 mg was determined to be the recommended dose for the 
dose-expansion phase (Part B) of Study NP41300. As of the data cutoff of 1 March 
2022, 83 patients received treatment in Part B.  
As of the data cut-off date of 1 March 2022, the DCR in Part A of the study was 51.4% 
(18 of 35 evaluable patients), and the ORR was 17.1% (6 of 35 patients).  Among the 
patients treated with the proposed dose of 2100 mg Q2W, 7 of 13 patients had a best 
response of stable disease or better (DCR   53.8%), including 4 patients with a 
confirmed partial response (PR; ORR   30.8%).  Besides the confirmed partial responses 
(cPR) observed at the RDE, there were 2 cPRs at the 600 mg dose level (ORR   50.0%). 
As of the data cut-off date, 1 March 2022, in Part B of the study the DCR was 48.3% 
(28 of 58 patients) and the ORR was 5.2% (3 of 58 patients) among patients of the 
study treated at the RDE of 2100 mq Q2W (Cohorts B1, B2, and B3).  Within patients 
treated with 600 mg Q2W (cohort B5), the DCR was 40% (4 of 10 patients), and the 
ORR was 10% (1 of 10 patients).  Among patients treated with 600 mg Q3W, the DCR 
was 28.6% (2 of 7 patients) and the ORR was 14.3% (1 of 7 patients). 
Refer to the RO7247669 Investigator’s Brochure for additional details on all ongoing 
and planned clinical studies. 
A15–2.3 
BENEFITRISK ASSESSMENT 
Despite limited clinical experience with RO7247669, the clinical efficacy and safety 
profiles of antiPD-1/PD-L1 monoclonal antibodies are well characterized and 


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established.  In recent years, four checkpoint inhibitors, namely pembrolizumab, 
nivolumab, ipilimumab, and relatlimab have been approved by the FDA for the 
treatment of unresectable or advanced melanoma. 
The co-stimulatory action of RO7247669 on PD-1 and LAG-3 receptors may result in 
enhanced and/or more durable responses than either therapy modality alone.  However, 
there may be a risk of exaggerated immune cell activation, particularly given the LAG-3 
modulation of the immune response.  Preliminary data from Study NP41300, and 
recent early phase studies of antiLAG-3 antibodies showed that antiLAG-3 therapy 
was generally well tolerated as monotherapy or in combination with antiPD-1 
therapies, and that it had a safety profile consistent with the safety profiles of other 
CPIs (Ascierto et al. 2017; Hong et al. 2018; Stratton et al. 2018).  The safety and 
efficacy of CPIs is established in the adjuvant setting, and CPIs are now being actively 
evaluated as neoadjuvant treatment and show promising early results (Herrscher and 
Robert 2020). 
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please refer to Section 1.3. 
A15–3 
RATIONALE FOR DOSE AND SCHEDULE FOR RO7247669 
600 mg ARM 
A15–3.1 
RATIONALE FOR RO7247669 DOSE AND SCHEDULE 
RO7247669 will be administered at a fixed dose of 600 mg every 3 weeks (Q3W) 
(600 mg on Day 1 of each 21-day cycle).  A fixed dosing regimen of 600 mg Q3W was 
selected based on available clinical pharmacokinetic, efficacy, and safety data from 
Study NP41300.  During the dose-escalation Part A of the study, RO7247669 was well 
tolerated, and no specific safety concern associated with RO7247669 was identified.  No 
DLT up to the highest dose of 2100 mg Q2W was observed, and no MTD was identified.  
Anti-tumor activity, as measured by radiographic partial responses, was observed 
starting at a dose of 600 mg Q2W.  The pharmacokinetics of RO7247669 were dose 
linear within the dose range tested in Study NP41300.  Greater than 90% occupancy of 
peripheral PD-1 and LAG3 receptors on CD8+ cells was observed at 50 mg of 
RO7247669 and was sustained at all higher doses (unpublished Roche data on file).  
Further modelling of intratumoral PD-1 and LAG3 target engagement using estimated 
target properties was performed.  A dose regimen of 600 mg Q3W was selected for this 
study (BO43328) to ensure that the majority of participants have at least 90% PD-1 
and LAG3 tumor receptor saturation by RO7247669, irrespective of intratumoral 
spatial heterogeneity and intersubject variability.  A dose greater than 600 mg would 
not be expected to result in further clinical activity. 
In Study NP41300, persistent anti-drug antibodies (ADAs) formed in approximately 
18% of the total population and the incidence rate was not dose dependent.  An impact 


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on exposure was observed at 50, 150 and 300 mg; therefore, 600 mg will be used in 
Study BO43328 to minimize the risk of a loss in exposure due to ADAs.  
In addition, RO7247669 was well tolerated in both the dose range finding studies and 
Good Laboratory Practice (GLP) monkey toxicology studies up to the highest dose 
evaluated (100 mg/kg).  Toxicology findings were consistent with the findings in 
cynomolgus monkey studies of marketed CPIs.  In the current study (BO43328), the 
safety evaluation of the first 6 patients enrolled in the RO7247669 2100 mg arm was 
completed with no safety signals identified.  
The supporting data for the selected dose can be found in the RO7247669 Investigator’s 
Brochure. 
A15–4 
MATERIALS AND METHODS SPECIFIC TO RO7247669 
600 mg ARM 
A15–4.1 
TREATMENT IN RO7247669 600 mg ARM 
A15–4.1.1 
Formulation, Packaging, and Handling 
The RO7247669 drug product will be supplied by the Sponsor as a 50 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of RO7247669, refer to 
the pharmacy manual and the RO7247669 Investigator’s Brochure. 
A15–4.1.2 
Dosage, Administration, and Compliance 
Patients in the RO7247669 600 mg arm will receive treatment for 2 cycles (6 weeks) as 
outlined in Table A15-1 until surgery, or until unacceptable toxicity or loss of clinical 
benefit, whichever occurs first (see Section 3.1.2 for details).  It is recommended that 
treatment be initiated no later than 7 days after randomization. 
Table A15-1 
Treatment Regimen for RO7247669 600 mg Arm 
Cycle Length 
Dose, Route, and Regimen 
21 days 
 RO7247669 600 mg by IV infusion on Day 1 of each cycle 
  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, 
and administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
No safety data related to overdosing of RO7247669 are available to date. 


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RO7247669 will be administered by IV infusion at a fixed dose of 600 mg on Day 1 of 
each 21-day cycle. 
Administration of RO7247669  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 8.  
RO7247669 infusions will be administered per the instructions outlined in 
Table A15-2. 
Table A15-2 
Administration of First and Second RO7247669 Infusions 
First Infusion 
Second Infusion 
 
No premedication is permitted prior to the 
first RO7247669 infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, pulse oximetry, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO7247669 should be infused over 
60 (  10) minutes. 
 
After the infusion of RO7247669, the 
patient begins a 60-minute observation 
period. 
 
If clinically indicated, vital signs should 
be measured every 15 (  5) minutes during 
the infusion and at 30 (  10) minutes after 
the infusion.  Record on the eCRF in case 
of abnormalities. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with 
the first infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO77247669 should be infused over 
30 (  10) minutes if the first infusion 
was tolerated without an IRR, followed 
by a 30-minute observation period. 
 
If the patient experienced an IRR with 
the previous infusion or if clinically 
indicated, vital signs should be measured 
every 15 (  5) minutes during the 
infusion and at 30 (  10) minutes after 
the infusion.  Record on the eCRF in 
case of abnormalities. 
eCRF  electronic Case Report Form; IRR   infusion-related reaction. 
  
For patients who experience a Grade 2 infusion-related reaction (IRR), premedication 
with paracetamol 5001000 mg orally [PO] or IV and diphenhydramine 2550 mg PO 
or IV (or an alternative histamine H1/2 antagonist at an adequate dose) is required prior 
to subsequent infusions.  In case of Grade 3 or 4 IRRs related to study treatment, the 
patient should be permanently discontinued from the study treatment. 
Guidelines for medical management of IRRs for RO7247669 are provided in 
Section A15–5.1.2.3. 


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No dose modification for RO7247669 is allowed. Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A15–5.1.2.2. 
A15–4.2 
CONCOMITANT THERAPY FOR RO7247669 600 mg ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
A15–4.2.1 
Permitted Therapy for RO7247669 600 mg Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A15–4.2.3) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  Other use of corticosteroids may be at the investigator’s discretion.  
The Medical Monitor is available to advise as needed. 
 
Local therapy (e.g., surgery other than complete lymph node dissection [CLND] that 
is not considered to be related to melanoma) 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be 
administered for the second RO7247669 infusion only, at the discretion of the 
investigator. 
In general, investigators should manage a patient’s care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H 1/2-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 


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be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 8). 
A15–4.2.2 
Cautionary Therapy for RO7247669 600 mg Arm 
A15–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor 
(TNF)- inhibitors may attenuate potential beneficial immunologic effects of treatment 
with RO7247669.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with RO7247669 therapy (see Appendix 9 for details). 
A15–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A15–4.2.3) may be used during the study at the discretion of the 
investigator. 
A15–4.2.3 
Prohibited Therapy for RO7247669 600 mg Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and 
herbal therapy), whether health authorityapproved or experimental, is prohibited 
for various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until surgery or, if earlier, disease 
progression is documented and the patient has discontinued study treatment. 
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with RO7247669, and for 4 months 
after the final dose of RO7247669. 


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 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 drug-elimination half-lives 
(whichever is longer) prior to initiation of study treatment and during study 
treatment because these agents could potentially increase the risk for autoimmune 
conditions when given in combination with RO7247669. 
 
A15–4.3 
CONTRACEPTION REQUIREMENTS FOR RO7247669 
600 mg ARM 
Contraception requirements for women and men in the RO7247669 600 mg arm are 
outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 4 months after the final 
dose of RO7247669. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (  12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of   1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.  If required per local guidelines or regulations, locally 
recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraception, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant or a 
pregnant female partner, men who are not surgically sterile must remain 
abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of   1% per year during the treatment period, 
for 4 months after the last dose of RO7247669 to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 


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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
preventing drug exposure.  If required per local guidelines or regulations, 
information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
A15–5 
ASSESSMENT OF SAFETY FOR RO7247669 600 mg ARM 
A15–5.1 
SAFETY PLAN FOR RO7247669 600 mg ARM 
The safety plan for patients in this study is based on clinical experience with 
RO7247669 in ongoing studies.  The potential safety risks are outlined below (see 
Section A15–5.1.1).  Guidelines for management of patients who experience specific 
adverse events are provided in Section A15–5.1.2 and Appendix 9. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.   
Administration of study treatment will be performed in a monitored setting in which 
there is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Adverse events will be reported as described in 
Sections 5.25.6. 
A15–5.1.1 
Risks Associated with RO7247669 
Clinical evaluation of RO7247669 is ongoing, and not all risks are known.  As an 
antagonist of PD-1 and LAG-3, RO7247669 is anticipated to enhance T-cell and 
NK-cell proliferation, survival, and function.  Based on the mechanism-of-action of 
RO7247669, the safety profile is anticipated to be similar to other CPIs.  Potential risks 
associated with RO7247669 include the following:  IRRs (including anaphylaxis), 
immunogenicity, and immune-mediated adverse events.  Refer to Section 6 of the 
RO7247669 Investigator’s Brochure for a detailed description of anticipated safety risks 
for RO7247669. 
A15–5.1.1.1 Infusion-Related Reactions and Anaphylaxis 
Administration of therapeutic antibodies may cause IRRs, which may include 
symptoms such as fever, chills, hypotension, shortness of breath, skin rash, headache, 
nausea, and vomiting.  Such reactions typically occur during or shortly after the 
infusion and are predominantly reported following the first infusion.  The incidence 
and severity of IRRs typically decrease with subsequent infusions.  Based on in vitro 
data, the risk of proinflammatory cytokine-mediated IRRs on first administration of 
RO7247669 as a single agent is considered low. 


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Refer to Section A15–4.1.2 for detailed guidance on administration of RO7247669 in 
this study.  Refer to Appendix 8 for guidance on anaphylaxis precautions and to 
Section A15–5.1.2.3 for guidance on the management of IRRs. 
A15–5.1.1.2 Immunogenicity 
Administration of therapeutic antibodies may cause the formation of anti-drug 
antibodies, which may negatively affect the safety of the therapeutic (e.g., allergic 
reactions, immune complex-mediated diseases). 
A15–5.1.1.3 Immune-Mediated Adverse Events 
The co-stimulatory action of RO7247669, in particular its effects on LAG-3, may lead 
to an exaggerated risk of immune cell activation that may result in the occurrence of 
enhanced, untoward, immune-mediated adverse events and increased 
cytokine release-mediated toxicities. 
Toxicities from PD-1 blocking agents can involve any organ or tissue, although some 
immune-mediated adverse events occur much more frequently than others.  The most 
frequently occurring immune-mediated adverse events affect skin, colon, endocrine 
organs, liver, and lungs.  Others are very infrequent but may be very serious, even 
lethal, such as neurological disorders and myocarditis. 
The limited data from recent early phase studies showed antiLAG-3 therapy was 
generally well tolerated as a monotherapy or in combination with anti-PD-1 therapies, 
and data were consistent with the safety profiles of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018). 
In this study, specified immune-mediated adverse events will be considered adverse 
events of special interest and will be captured accordingly (see Section A15–5.2 for the 
list of adverse events of special interest and Section 5.4.2 for reporting instructions). 
Patients with a history of autoimmune disease will be excluded from this study.  Please 
see Section 4.1.2 for details. 
A15–5.1.2 
Management of Patients Who Experience Specific Adverse 
Events in RO7247669 600 mg Arm 
A15–5.1.2.1 Dose Modifications 
There will be no dose modifications for RO7247669 in this study. 
A15–5.1.2.2 Treatment Interruption for Toxicities 
RO7247669 treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for 
treatment of the toxicity, they must be tapered over   1 month to  10 mg/day oral 
prednisone or equivalent before RO7247669 can be resumed if warranted.  In the 


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neoadjuvant setting, the study treatment is limited to a pre-surgery window of 6 weeks.  
Treatment during this period should not be interrupted, unless a patient experiences 
toxicity.  If toxicity meets criteria for interrupting/withholding RO7247669, 
RO7247669 should be interrupted/withheld.  After resolution of the toxicity, 
subsequent treatment cycles should only be considered if the benefit-risk profile is 
acceptable and if the surgery can be conducted within 2 weeks of the planned date.  
Otherwise, subsequent treatment cycles should be omitted to allow the patient to 
proceed directly to surgery without further delay. 
A15–5.1.2.3 Management Guidelines for Adverse Events 
Guidelines for management of patients who experience specific adverse events are 
provided in Table A15-3. 
 


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320/Protocol BO43328, Version 4 
Table A15-3 
Guidelines for Management of Patients Who Experience Adverse Events in RO7247669 600 mg 
Arm 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions 
General guidance 
 For anaphylaxis precautions, see Appendix 8. 
 For severe hypersensitivity reactions, permanently discontinue RO7247669. 
 For suspected CRS, see Appendix 9 for guidance on supportive care. 
 Determine tryptase concentration and IgE titer if clinical presentation of IRR suggests an anaphylactic 
or hypersensitivity reaction (hives, obstructive shortness of breath, urticaria, other histamine 
associated symptoms) and/or if the first IRR or CRS (   Grade 2) is observed at the second infusion.  
If tryptase and/or IgE are elevated, collect a second sample for IgE/tryptase analysis at least 48 hours 
after the onset of the reaction to rule out the possibility of an anaphylactic reaction.   
IRR to RO7247669, Grade 1 or 2 
 Slow infusion to  50% or interrupt infusion. 
 Give supportive treatment.  Patients should be treated with acetaminophen/paracetamol and an 
antihistamine, such as diphenhydramine, if they have not been administered in the last 4 hours.  
IV fluids (e.g., normal saline) may be administered as clinically indicated.  For broncho spasm, 
urticaria, or dyspnea, antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or 
equivalent), and/or bronchodilators may be administered per institutional practice.  
 Upon symptom resolution, infusion may resume (if interrupted) at 50% starting rate.  The infusion 
must remain at the lower rate resulting in symptom resolution for the remainder of the infusion.  
 For Grade 2 IRRs, subsequent doses of RO7247669 should be administered with pre-medication, 
including acetaminophen/paracetamol and an antihistamine such as diphenhydramine. 
 For Grade 2 wheezing or urticaria, patient must also be pre-medicated prior to subsequent doses 
(as described above). 
 If symptoms recur with the same or greater severity following the slower or interrupted infusion, the 
infusion must be stopped immediately.  No further RO7247669 will be administered for the cycle.  
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; IRR   infusion-related reaction; 
MAS  macrophage activation syndrome. 
 


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Table A15-3 
Guidelines for Management of Patients Who Experience Adverse Events in RO7247669 600 mg 
Arm (cont.) 
Event 
Action to Be Taken 
IRR to RO7247669, Grade 34 
 Discontinue infusion immediately. 
 Give supportive treatment. 
 Permanently discontinue study treatment. 
Pulmonary, hepatic, GI, endocrine, 
ocular, immune-mediated myocarditis, 
CRS, pancreatic, dermatologic, 
neurologic, immune-mediated 
meningoencephalitis, renal, myositis, 
HLH, MAS, and systemic immune 
activation 
 Guidelines for the management of these events are provided in Appendix 9. 
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic lymphohistiocytosis; IRR   infusion-related reaction; 
MAS  macrophage activation syndrome. 
 


Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
  
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A15–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR RO7247669 
600 mg ARM (IMMEDIATELY REPORTABLE TO THE 
SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.2.3 for reporting instructions).  Adverse events of special interest for the 
RO7247669 600 mg arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
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. 
 
A15–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
RO7247669 600 mg ARM 
A15–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during 
the study or within 4 months after the final dose of RO7247669.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect 
in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 


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allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 6 and 12 months after birth. 
A15–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
4 months after the final dose of RO7247669.  The investigator should report the 
pregnancy on the  paper Clinical Trial Pregnancy Reporting Form and submit the form 
to the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of 
the pregnancy), either by faxing or by scanning and emailing the form using the fax 
number or email address provided to investigators.  Attempts should be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for the Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 6 and 12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A15–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.2.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 


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324/Protocol BO43328, Version 4 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.2.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A15–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to 
study treatment or the female partner of a male patient exposed to study treatment 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.2.2). 
 








Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
  
TABLE A15-4 SCHEDULE OF ACTIVITIES FOR RO7247669 600 mg ARM (cont.) 
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Assessment/ 
Procedure a 
Protocol 
Section 
Screening  
(see 
Appendix 
10) 
Treatment Cycles 
(21-Day Cycles) 
Pre-Surgery 
Surgery 
CLND 
Post-Surgery 
Treatment 
Comp./ 
Discon. b 
Long-
Term 
Follow-
Up 
 
Surgery 
Follow-Up c 
Cycle 1 
Cycle 2 
D 28 
to D 1 
D1 
( 7D after 
randomization) 
D1 
( 1D) 
Wk 6 
( 8D to 
surgery) 
Wk 7 
( 7D) 
Wk 10 
( 20D after 
surgery) 
Wk 13 
Every 
3M 
( 7D) 
6M after 
surgery 
( 7D) 
Blood and plasma 
samples for biomarkers 
 4.5.9.2 
Refer to Section A15–7.  
x  
(only if 
onsite) 
Refer to 
Section  
 A15–7.  
Pre-dose tumor biopsy 
 
x l 
 
 
 
 
 
 
Resected tissue 
 
 
 
x 
 
 
 
 
Tumor biopsy (optional) 
4.5.11 
Perform at the time of unacceptable toxicity, loss of clinical benefit, relapse,  
or at any other time if deemed clinically feasible by the investigator. 
ADA  anti-drug antibody; CLND  complete lymph node dissection; Comp.   completion; CT  computed tomography; D   day; 
Discon.  discontinuation; ECOG  Eastern Cooperative Oncology Group; IMP   investigational medicinal product; M   month; 
MUGA  multiple-gated acquisition; PK  pharmacokinetic; T3  triiodothyronine; T4   thyroxine; TSH  thyroid-stimulating hormone; 
TTE  transthoracic echocardiogram; Wk  week. 
Note:  On treatment days, all assessments and procedures should be performed prior to dosing, unless otherwise specifi ed. 
a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window.  
b Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely , patients who proceed to surgery 
will return to the clinic for a treatment completion/discontinuation visit 6 weeks after surgery  and patients who do not proceed to surgery 
will return to the clinic for a treatment completion/discontinuation visit not more than 30 days after the final dose of study treatment. 
c Patients who proceed to surgery will have the surgery follow-up 6 months after surgery. 
d Assessment may be performed within 24 hours prior to dosing during the treatment period. 
e The disease status assessments at Week 13 should include a mandatory CT scan. 


Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
  
TABLE A15-4 SCHEDULE OF ACTIVITIES FOR RO7247669 600 mg ARM (cont.) 
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f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation 
of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to 
be reported until 135 days after the final dose of study treatment or until initiation of new systemic anti -cancer therapy, whichever occurs 
first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on 
reporting all treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be rela ted to study 
treatment or trial-related procedures until a final outcome can be reported. 
g Regardless of whether they complete the study drug treatment period or discontinue study drug prematurely, patients who proceed to sur gery 
will have their first long-term follow-up visit 3 months after surgery and patients who do not proceed to surgery will have th eir first long-
term follow-up visit 3 months after the final dose of study treatment.  Information on long-term follow-up and new anti-cancer therapy 
(including targeted therapy and immunotherapy) will be collected via telephone calls, patient medical reco rds, and/or clinic visits 
approximately every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study).  If a pa tient requests 
to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator.  If a patient 
withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain information ab out survival 
status only.  For an experimental arm in which all patients discontinued treatment and passed the safety follow-up window, as well as 
approximately 80% of patients discontinued the study, the Sponsor may conclude the arm (the remaining ~20% of patients will b e 
discontinued from the study). 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated.  
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry 
panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments.  
k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a 
local gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration.  
 


Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
 
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330/Protocol BO43328, Version 4 
A15–7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, 
AND BIOMARKER SAMPLES FOR RO7247669 600 mg ARM 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to first infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
30 (  10) minutes after the end 
of RO7247669 infusion 
 RO7247669 PK (serum) 
Day 1 of Cycle 2 
Prior to infusion 
(6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
30 (  10) minutes after the end 
of RO7247669 infusion 
 RO7247669 PK (serum) 
Surgery CLND 
Week 7 
Prior to surgery 
(24 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation 
Week 13 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
Long-term follow-up 
Every 3 months ( 7 days) b 
At visit 
 Biomarkers (blood, plasma) 
Surgery follow-up 
6 months after surgery  
(  7 days) 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Biomarkers (blood, plasma) 
ADA  anti-drug antibody; CLND   complete lymph node dissection; PK   pharmacokinetic. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples may 
not be analyzed if not warranted.  On the basis of emerging biomarker data, the number of 
biomarker samples may be reduced, or sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained   20 days post-surgery. 
b To be collected if visit is conducted on site. 
 


Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
 
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331/Protocol BO43328, Version 4 
A15–8 
REFERENCES 
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Herrscher H and Robert C. Immune checkpoint inhibitors in melanoma in the 
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Huard B, Gaulard P, Faure F, et al. Cellular expression and tissue distribution of the 
human LAG-3-encoded protein, an MHC class II ligand.  Immunogenetics 
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Appendix 15:  Study Details Specific to RO7247669 600 mg Arm 
 
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
332/Protocol BO43328, Version 4 
Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor 
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Appendix 16  
Study Details Specific to RO7247669 600 mg   Tira Arm 
TABLE OF CONTENTS 
A16–1 
Background on RO7247669 600 mg  Tira Arm ...................... 335 
A16–1.1 
Background on RO7247669 ...................................................... 335 
A16–1.2 
Background on Tiragolumab ..................................................... 335 
A16–2 
Rationale for RO7247669 600 mg  Tira Arm .......................... 335 
A16–2.1 
Targeting the PD-1 and LAG-3 Antigens ................................ 335 
A16–2.2 
The TIGIT Pathway .................................................................. 337 
A16–2.3 
Combination Treatment with AntiPD-1/ AntiLAG-3 and 
Anti-TIGIT Agents ................................................................... 338 
A16–2.4 
Clinical Studies of Agents Targeting the PD-1 and LAG-3 
Pathways................................................................................... 338 
A16–2.4.1 
Study NP41300 ........................................................................ 339 
A16–2.5 
Clinical Studies of Tiragolumab ............................................... 340 
A16–2.5.1 
Study GO30103 ........................................................................ 340 
A16–2.5.2 
Study GO40290 ........................................................................ 342 
A16–2.6 
BenefitRisk Assessment ......................................................... 343 
A16–3 
Rationale for Dose and Schedule for RO7247669 
600 mg  Tira Arm ................................................................... 344 
A16–3.1 
Rationale for RO7247669 600 mg Dose and Schedule .............. 344 
A16–3.2 
Rationale for Tiragolumab Dose and Schedule ......................... 344 
A16–4 
Materials and Methods Specific to RO7247669 
600 mg  Tira Arm ................................................................... 345 
A16–4.1 
Treatment in RO7247669 600 mg  Tira Arm ......................... 345 
A16–4.1.1 
Formulation, Packaging, and Handling .................................... 345 
A16–4.1.1.1 
RO7247669 ............................................................................... 345 
A16–4.1.1.2 
Tiragolumab .............................................................................. 345 
A16–4.1.2 
Dosage, Administration, and Compliance ................................ 345 
A16–4.1.2.1 
RO7247669 ............................................................................... 346 
A16–4.1.2.2 
Tiragolumab .............................................................................. 348 
A16–4.2 
Concomitant Therapy for RO7247669 600 mg  Tira Arm ...... 349 
A16–4.2.1 
Permitted Therapy for RO7247669 600 mg  Tira Arm ........... 349 
A16–4.2.2 
Cautionary Therapy for RO7247669 600 mg  Tira Arm ......... 349 
A16–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor- Inhibitors ......................................... 349 
A16–4.2.2.2 
Herbal Therapies ....................................................................... 350 
A16–4.2.3 
Prohibited Therapy for RO7247669 600 mg  Tira Arm .......... 350 
A16–4.3 
Contraception Requirements for RO7247669 600 mg  Tira 
Arm ........................................................................................... 351 
A16–5 
Assessment of Safety for RO7247669 600 mg  Tira Arm ....... 352 
A16–5.1 
Safety Plan for RO7247669 600 mg  Tira Arm ...................... 352 


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A16–5.1.1 
Risks Associated with RO7247669 ........................................... 352 
A16–5.1.1.1 
Infusion-Related Reactions and Anaphylaxis ........................... 352 
A16–5.1.1.2 
Immunogenicity ........................................................................ 353 
A16–5.1.1.3 
Immune-Mediated Adverse Events ........................................... 353 
A16–5.1.2 
Risks Associated with Tiragolumab .......................................... 353 
A16–5.1.2.1 
Infusion-Related Reactions ....................................................... 354 
A16–5.1.2.2 
Immune-Mediated Hepatitis ..................................................... 354 
A16–5.1.2.3 
Immune-Mediated Adverse Events ........................................... 354 
A16–5.1.2.4 
Lymphopenia ............................................................................. 355 
A16–5.1.2.5 
Embryofetal Toxicity ................................................................ 355 
A16–5.1.3 
Risks Associated with Combination Use of RO7247669 and 
Tiragolumab .............................................................................. 355 
A16–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the RO7247669 600 mg  Tira Arm ......................... 356 
A16–5.1.4.1 
Dose Modifications ................................................................... 356 
A16–5.1.4.2 
Treatment Interruption for Toxicities ....................................... 356 
A16–5.1.4.3 
Management Guidelines for Adverse Events ............................ 357 
A16–5.2 
Adverse Events of Special Interest for the RO7247669 600 
mg  Tira Arm (Immediately Reportable to the Sponsor) ......... 359 
A16–5.3 
Reporting Requirements for Pregnancies in the RO7247669 
600 mg  Tira Arm ................................................................... 360 
A16–5.3.1 
Pregnancies in Female Patients ................................................ 360 
A16–5.3.2 
Pregnancies in Female Partners of Male Patients..................... 360 
A16–5.3.3 
Abortions .................................................................................. 361 
A16–5.3.4 
Congenital Anomalies/Birth Defects ......................................... 361 
A16–6 
Schedules of Activities and Sample Collection for 
RO7247669 600 mg  TIRA Arm ............................................. 362 
A16–7 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for RO7247669 600 mg  tira Arm ........... 367 
A16–8 
References ................................................................................. 369 
 
 
 


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A16–1 
BACKGROUND ON RO7247669 600 mg  TIRA ARM 
A16–1.1 
BACKGROUND ON RO7247669 
RO7247669 is a novel, Fc-silent IgG1-based bispecific antibody (bsAb) in 1   1 format 
that incorporates monovalent binding to two immune checkpoint proteins:  PD-1 and 
LAG-3.  RO7247669 is designed to target dysfunctional tumor antigen-specific 
T lymphocytes expressing PD-1 and LAG-3 to establish or re-establish an effective 
anti-tumor immune response in cancer patients.  This may result in improved 
therapeutic responses over currently available therapies.  In addition, RO7247669 is 
engineered to prevent binding to Fc gamma receptors, thus potentially avoiding 
tumor-associated macrophage resistance mechanisms.  Such mechanisms have been 
observed with IgG4-based antiPD-1 antibodies, such as pembrolizumab and nivolumab 
(Arlauckas et al. 2017).  Clinical evaluation of RO7247669 is ongoing in a 
first-in-human, dose-finding study (Study NP41300), as a single agent in cancer 
patients with and without prior CPI exposure.   
Refer to the RO7247669 Investigator’s Brochure for details on nonclinical and other 
planned and ongoing clinical studies. 
A16–1.2 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/kappa monoclonal antibody that binds TIGIT and 
prevents its interaction with CD155 (also known as poliovirus receptor [PVR]).  
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.  This may result in improved meaningful anti-tumor activity when 
tiragolumab is used in combination with other cancer immunotherapies and 
administered with chemotherapy.  The available nonclinical and clinical data provide a 
strong rationale for evaluating the potential clinical benefit of tiragolumab in cancer 
patients. 
Refer to the Tiragolumab Investigator’s Brochure for details on nonclinical and 
clinical studies. 
A16–2 
RATIONALE FOR RO7247669 600 mg  TIRA ARM 
A16–2.1 
TARGETING THE PD-1 AND LAG-3 ANTIGENS 
Cancer immunotherapy agents, particularly immune CPIs, have had a significant 
impact on the treatment of patients with advanced malignancies in recent years.  
However, despite the remarkable clinical efficacy of these therapies, additional 
treatment options targeting immune checkpoints are needed, because the majority of 
patients eventually progress after an initial response or fail to respond to the 
PD-1/PD-L1 checkpoint blockade.  This is believed to be mainly due to primary or 


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secondary resistance mechanisms, immunosuppressive activity of myeloid-derived 
suppressor cells and/or T-regulatory cells (Sharma et al. 2017). 
To overcome resistance mechanisms, additional treatment options and multiple 
combinations with antiPD-L1 are being assessed.  One potential reason for resistance 
to antiPD-L1 therapy is the upregulation of alternative immune checkpoints with 
non-redundant regulatory functions (Sharma et al. 2017).  LAG-3 is one such 
alternative immune checkpoint.  Structurally similar to CD4, LAG-3 is a member of the 
Ig superfamily.  LAG-3 is expressed on activated effector T cells and is constitutively 
expressed on T-regulatory cells and natural killer (NK) cells.  The expression of both 
PD-1 and LAG-3 on tumor infiltrating lymphocytes (TILs) correlates with the degree of 
impairment of effector functions, which is associated with poor prognosis 
(Matsuzaki et al. 2010; Baitsch et al. 2011; Thommen et al. 2015).  Hence, LAG-3 is a 
marker of T-cell dysfunctionality.  LAG-3 also regulates T-cell functions, presumably 
including the function of T-regulatory cells.  In chronic infections and cancer, LAG-3, 
together with PD-1, contributes to T-cellacquired dysfunctionality and to the inability 
of T cells to mount an effective/protective immune response upon interaction with the 
LAG-3 ligand, MHC-II. 
The interaction of LAG-3 with MHC-II inhibits T-cell proliferation, activation, 
cytolytic function, and proinflammatory cytokine production (Goldberg and Drake 
2011).  The effect of LAG-3 expression on T-regulatory cells is controversial.  An early 
report concluded that LAG-3 promotes T-regulatory cell-mediated immune suppression 
(Camisaschi et al. 2010).  However, a more recent report from the same authors found 
that LAG-3 limits T-regulatory cell-mediated immune suppression (Zhang et al. 2017). 
Expression of LAG-3 has been reported across various tumor types, including breast 
cancer, ovarian cancer, non-small cell lung cancer (NSCLC), melanoma, renal cell 
cancer (RCC), prostate cancer, and hepatocellular carcinoma (HCC).  In patients with 
these tumor types, LAG-3 is associated with poor prognosis (Matsuzaki et al. 2010; 
Baitsch et al. 2011; Thommen et al. 2015; He et al. 2016; Norstrom et al. 2016).  
Clinical evaluation of antiLAG-3 agents, as a single-agent and in combination with 
other CPIs, is ongoing in several early phase studies in patients with advanced solid 
tumors (Long et al. 2018).  Preliminary data demonstrate that antiLAG-3 therapy is 
well tolerated, both as a single agent and in combination with antiPD-1 therapies, and 
the safety profiles were consistent with those of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018; Stratton et al. 2018).  RO7247669 therefore has the potential to be a 
therapeutic option for patients with melanoma. 
Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory immune checkpoints on the surface of effector T cells.  LAG-3 is 
frequently co-expressed with PD-1 on TILs, and dual blockade of PD-1 and LAG-3 


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enhances CD8   T-cell effector function and potentiates anti-tumor immunity in 
nonclinical models.  Blockade of these two receptors in mice with colon, fibrosarcoma, 
or ovarian tumors resulted in tumor remission in approximately 80% of animals 
compared with 10% to 40% with blockade of either receptor using a single agent 
(Woo et al. 2012; Huang et al. 2015).  TILs from patients with ovarian cancer showed 
that antigen-specific CD8   T cells co-expressing PD-1 and LAG-3 exhibited greater 
impairment in their ability to respond to cognate antigen stimulation compared with 
CD8  T cells that expressed one checkpoint molecule (Matsuzaki et al. 2010).  
In patients with NSCLC, overexpression of LAG-3 on TILs correlated with 
PD-1/PD-L1 expression and was linked to higher risk of recurrence and poor survival 
outcomes (He et al. 2017). 
A16–2.2 
THE TIGIT PATHWAY 
TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin 
superfamily (Yu et al. 2009).  TIGIT is expressed on the surface of activated T cell and 
NK cell subsets and interacts with high affinity with CD155 (also known as PVR) 
(Yu et al. 2009).  Genetic ablation of TIGIT in T cells in mice results in exacerbated 
T-cell responses in nonclinical models of autoimmune and viral infections, 
demonstrating the role of TIGIT in inhibiting T-cell responses (Joller et al. 2011; 
Johnston et al. 2014).  TIGIT expression is elevated in the tumor microenvironment in 
many human tumors, is concordantly expressed with other checkpoint 
immune-receptors such as PD-1 on the surface of T cells, and is associated with 
impaired T-cell function and anti-tumor immunity (Johnston et al. 2014; 
Manieri et al. 2017).  Activation of TIGIT on T cells and NK cells limits cellular 
proliferation, effector cytokine production, and killing of target tumor cells 
(Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; 
Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors.  It is expressed in most solid 
tumors, such as NSCLC, breast cancer, and melanoma, as well as in hematological 
tumors, such as multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL).  
Fluorescence activated cell sorting analysis of T cells isolated from fresh tumor samples 
revealed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells 
(Johnston et al. 2014; Yadav et al. 2016; Yang 2016; Guillerey et al. 2018).  TIGIT was 
expressed in 30%80% of tumor-infiltrating CD4+ T cells and in 50%80% of 
tumor-infiltrating CD8   T cells (Johnston et al. 2014). 
Therefore, TIGIT is a potential target for therapeutic interventions that aim to restore 
the immune response against the tumor.  Agents that inhibit TIGIT’s interaction with 
PVR may inhibit an important source of tumor-associated immune suppression, thereby 
enhancing the activity of other immune-based therapies.  Nonclinical studies using 
genetically deficient mice and blocking antibodies have revealed a key role for TIGIT in 


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regulating T-cell responses in cancer.  Taken together, these data support the 
hypothesis that anti-TIGIT therapy may reactivate anti-tumor immunity and provide 
clinical benefits to patients with cancer. 
A16–2.3 
COMBINATION TREATMENT WITH ANTIPD-1/ 
ANTILAG-3 AND ANTI-TIGIT AGENTS 
Durable clinical benefit is limited to a minority of patients treated with single-agent 
PD-L1/PD-1 inhibitors.  Therapies targeting the mechanisms of resistance to 
anti-PD-L1/PD-1 therapies are needed to improve outcomes in patients with solid 
cancers.  Resistance to PD-L1/PD-1 blockade may result in the expression of multiple 
co-inhibitory receptors on the surface of effector T cells including TIGIT and LAG-3.  
Nonclinical tumor models have shown that TIGIT selectively suppressed the effector 
function of chronically stimulated CD8  
  T cells, and that inhibiting both TIGIT and 
PD-L1/PD-1 resulted in superior efficacy compared with single-agent treatments 
(Johnston et al. 2014).  Similarly, in-vivo proof-of-concept studies using different 
tumor mouse models have shown PD1-LAG-3 bsAbs to be superior in controlling tumor 
growth and promoting tumor eradication when compared with anti-PD-1 antibodies as 
monotherapy.  Hence, targeting PD-1/LAG-3 and TIGIT with RO7247669 and 
tiragolumab, respectively, may enhance the efficacy of PD-L1/PD-1 blockade across 
different cancer types, including melanoma. 
A16–2.4 
CLINICAL STUDIES OF AGENTS TARGETING THE PD-1 
AND LAG-3 PATHWAYS 
Clinical data are available for early- and late- phase studies that evaluated the safety, 
tolerability, and preliminary anti-tumor activity of agents that target both the PD-1 
and LAG-3 pathways.  Evidence of clinical activity has been reported in some of these 
studies.  Overall, adverse events have been manageable to date, and the safety profiles 
appear similar to those of single-agent CPIs. 
An ongoing Phase I/IIa study is evaluating the safety, tolerability, and clinical activity 
of combination treatment with the antiPD-1 monoclonal antibody nivolumab and the 
antiLAG-3 monoclonal antibody relatlimab in patients with advanced solid tumors.  
Preliminary data suggest that the combination of nivolumab and relatlimab may have 
an increased benefit compared with single-agent antiPD-1.  In a cohort of patients 
who had advanced melanoma who were previously treated with antiPD-1/PD-L1 
agents, the objective response rate (ORR) was 11.5% (n   61) with a disease control rate 
of 49%.  The antiPD-1/PD-L1 treatment combination had an acceptable safety profile 
that was similar to the safety profile of nivolumab monotherapy (Ascierto et al. 2017). 
Relativity-047 is a Phase III study evaluating the combination of nivolumab 
(antiPD-1) and relatlimab (antiLAG-3) versus nivolumab alone in patients with 
untreated advanced melanoma.  This study demonstrated that nivolumab and relatlimab 


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improved progression-free survival (PFS  10.1 months) over nivolumab 
(PFS   4.6 months).  The incidence of Grade 3 or 4 treatment-related adverse events 
was 18.9% in patients that received the nivolumab and relatlimab combination and 
9.7% in patients that received nivolumab alonoe (Tawbi et al. 2022).   
An ongoing Phase I/II study is evaluating the safety, tolerability, and clinical activity 
of combination treatment with the antiPD-1 monoclonal antibody spartalizumab and 
the antiLAG-3 monoclonal antibody LAG525 in patients with advanced solid tumors.  
Preliminary anti-tumor activity was observed during the Phase I dose-escalation 
portion of the study, including durable responses in 2 of 5 patients with triple-negative 
breast cancer (TNBC) and in 2 of 8 patients with mesothelioma.  Analyses of tumor 
biopsies from the TNBC cohort also showed a trend of conversion from an immune-cold 
to an immune-activated phenotype.  Common adverse events, i.e., adverse events 
reported in  10% of patients, included fatigue (18%), diarrhea (15%), and nausea 
(12%).  The incidence of Grade 34 adverse events was 8% for both the combination 
(n  121) and monotherapy (n   119) arms (Hong et al. 2018). 
An ongoing, first-in-human, dose-escalation, and dose-expansion Phase I study is 
evaluating the safety, tolerability, and clinical activity of the antiPD-1/LAG-3 dual 
affinity re-targeting protein (DART®) bsAb MGD013 in patients with advanced solid 
tumors and hematologic malignancies.  During the dose-escalation phase of the study, 
the maximum tolerated dose (MTD) was not reached, and the safety profile was 
consistent with antiPD-1 monotherapy.  During the dose-expansion phase, anti-tumor 
activity was observed in patients with TNBC (n   23; ORR, 4.3%; disease control rate 
[DCR], 39.1%), CPI-naive NSCLC (n  14; ORR, 14.3%; DCR, 64.3%), and epithelial 
ovarian cancer (n  23; ORR, 8.7%; DCR, 52.2%).  Expression of LAG-3 and an IFN- 
gene signature at baseline was associated with objective responses (Luke et al. 2020).  
Clinical studies evaluating MGD013 as monotherapy and in combination with 
antiHER-2 agents are ongoing. 
A16–2.4.1 
Study NP41300 
Study NP41300 is an ongoing, first-in-human, dose-escalation, dose-expansion Phase I 
study to evaluate the safety, pharmacokinetics, and therapeutic activity of the 
antiPD-1/LAG-3 bsAb RO7247669 as a single-agent in patients with locally advanced 
and/or metastatic solid tumors.  Part A, the dose-escalation phase of the study, is 
designed to determine the MTD and/or recommended dose for expansion (RDE) of 
RO7247669.  Part B of the study is designed to evaluate the anti-tumor activity of 
RO7247669 at the MTD or RDE in tumor-specific expansion cohorts. 
As of the data cut-off date, 1 March 2022, RO7247669 was well tolerated in the 
patients enrolled in Part A of the study.  No unexpected safety concern associated with 
RO7247669 was identified.  No dose-limiting toxicities (DLTs) were observed up to the 


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maximum dose tested (2100 mg every 2 weeks [Q2W]), and no MTD was identified.  
The maximum dose of 2100 mg was determined to be the recommended dose for the 
dose-expansion phase (Part B) of Study NP41300.  As of the data cutoff date, 
1 March 2022, 83 patients received treatment in Part B.  
As of the data cut-off date, 1 March 2022, the DCR in Part A of the study was 51.4% 
(18 of 35 evaluable patients), and the ORR was 17.1% (6 of 35 patients).  Among the 
patients treated with the proposed dose of 2100 mg Q2W, 7 of 13 patients had a best 
response of stable disease or better (DCR   53.8%), including 4 patients with a 
confirmed partial response (PR, ORR   30.8%).  Besides the confirmed partial responses 
(cPR) observed at the RDE, there were 2 cPRs at the 600 mg dose level (ORR   50.0%). 
As of the data cut-off date, 1 March 2022, in Part B of the study the DCR was 48.3% 
(28 of 58 patients) and the ORR was 5.2% (3 of 58 patients) among patients of the 
study treated at the RDE of 2100 mq Q2W (Cohorts B1, B2, and B3).  Within patients 
treated with 600 mg Q2W (Cohort B5), the DCR was 40% (4 of 10 patients), and the 
ORR was 10% (1 of 10 patients). Among patients treated with 600 mg Q3W, the DCR 
was 28.6% (2 of 7 patients) and the ORR was 14.3% (1 of 7 patients). 
Refer to the RO7247669 Investigator’s Brochure for additional details on all ongoing 
and planned clinical studies. 
A16–2.5 
CLINICAL STUDIES OF TIRAGOLUMAB 
Tiragolumab is currently under investigation in two ongoing clinical studies in 
patients with solid tumors (Studies GO30103 and GO40290) and in one clinical study 
in patients with hematological malignancies (Study GO41036). 
A16–2.5.1 
Study GO30103 
Study GO30103 is a first-in-human, open-label, multicenter, global, 
dose-escalation/dose-expansion Phase I study.  It was designed to evaluate the safety, 
tolerability, and pharmacokinetics of tiragolumab as a single agent (Phase Ia) and in 
combination with atezolizumab (Phase Ib) in patients with locally advanced, recurrent, 
or metastatic incurable tumors, including urothelial cancer, renal cell cancer, NSCLC, 
head and neck squamous cell carcinoma, esophageal cancer, colorectal cancer (CRC), 
gastric cancer, cholangiocarcinoma, and triple-negative breast cancer. 
As of the clinical cutoff date of 2 December 2020, a total of 236 patients had been 
enrolled in Study GO30103.  Forty-two patients were enrolled in the Phase Ia portion 
of the study to receive single-agent tiragolumab, and 217 patients were enrolled in the 
Phase Ib portion of the study to receive tiragolumab in combination with atezolizumab.  
The latter group included 23 patients who crossed over from the Phase Ia portion of 
the study. 


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The best observed response with tiragolumab monotherapy in the Phase Ia portion was 
prolonged stable disease in 8 of 42 patients, with some patients, including 1 patient 
with CRC, experiencing a decrease in tumor size. 
In the Phase Ib portion, complete response was observed in 4 of 217 patients at 
tiragolumab dose levels of 400 mg (n   3/48) and 600 mg (n   1/104) in combination 
with 1200 mg atezolizumab.  Partial response was observed in 27  of 217 patients at 
tiragolumab dose levels of 30 mg (n   2/13), 400 mg (n  6/48), and 600 mg (n   18/104) 
in combination with 1200 mg atezolizumab, including two patients who crossed over 
from the Phase Ia portion at the 600 mg dose level.  Stable disease was observed in 53 of 
217 patients at tiragolumab dose levels of 2 mg (n  1/8), 8 mg (n  3/12), 30 mg 
(n   2/13), 100 mg (n   3/8), 400 mg (n  12/48), 600 mg (n  25/104), and 1200 mg 
(n  7/24) in combination with 1200 mg atezolizumab, including 8 patients who crossed 
over from the Phase Ia portion of the study (2 patients at 8 mg, 1 patient at 30 mg, 
2 patients at 100 mg, and 3 patients at 400 mg). 
As of 2 December 2020, safety data were available for 235 safety-evaluable patients in 
Study GO30103.  A total of 42 patients were treated in the Phase Ia portion with 
tiragolumab as a single agent (2 mg to 1200 mg), while 216 patients were treated in the 
Phase Ib portion with tiragolumab at dose levels of 2 mg to 1200 mg in combination 
with atezolizumab at 1200 mg, including 23 patients who crossed over from the Phase 
Ia portion to the Phase Ib portion. 
Tiragolumab was tolerated across all administered dose levels both as a single agent and 
in combination with atezolizumab.  The MTD was not reached, and the maximum 
administered dose was 1200 mg.  No DLTs or clear dose-related trends in the incidence 
of adverse events were observed.  Grade   3 adverse events, regardless of attribution to 
the study drug(s), were reported in 16 patients (38.1%) and 113 patients (52.3%) in 
the Phase Ia and Phase Ib portions, respectively.  There were 14 reported deaths in the 
Phase Ia portion of the study, including 12 deaths due to malignant neoplasm 
progression, 1 death due to gastrointestinal hemorrhage in the context of progressive 
disease, and 1 death due to hepatic failure.  The death due to hepatic failure was 
considered by the investigator to be related to study drug.  One hundred eighteen 
deaths were reported in the Phase Ib portion of the study.  This included 111 deaths due 
to progressive disease (31 cases were reported as adverse events during the adverse 
event reporting period and coded as malignant neoplasm progression or neoplasm 
malignant), 2 deaths due to pulmonary embolism, 1 death due to esophageal 
hemorrhage, 1 death due to sepsis, 1 death due to septic shock, 1 death due to 
COVID-19, and 1 death due to upper airway obstruction.  Treatment-related serious 
adverse events were reported in 1 patient in the Phase Ia portion (hepatic failure) and 
in 10 patients (4.6%) in the Phase Ib portion.  No patient discontinued study treatment 
due to adverse events in the Phase Ia portion of Study GO30103.  Adverse events 


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leading to treatment discontinuation were reported in 12 patients in the Phase Ib 
portion of the study, with a Grade 4 cardiac tamponade, a Grade 4 pneumonitis, and 
one event of Grade 2 arthralgia considered by the investigator to be related to the study 
drug(s).  Adverse events of special interest were reported in 5 patients (11.9%) in the 
Phase Ia portion and 82 patients (38.0%) in the Phase Ib portion of the study. 
Overall, tiragolumab as a single agent or in combination with atezolizumab has been 
well tolerated, adverse events have been manageable, and the safety profile has been 
observed to be consistent across different solid tumor indications. 
A16–2.5.2 
Study GO40290 
Study GO40290 is a Phase II, randomized, blinded, placebo-controlled study of 
tiragolumab plus atezolizumab compared with placebo plus atezolizumab in patients 
with previously untreated locally advanced unresectable or metastatic PD-L1positive 
NSCLC (defined as tumor proportion score [TPS]    1%). 
As of the primary clinical cutoff date of 30 June 2019, 135 patients with a PD-L1 
TPS   1% were included in the intent-to-treat (ITT) population and were randomly 
assigned to receive tiragolumab plus atezolizumab (n   67) or placebo plus atezolizumab 
(n  68).  As of the primary analysis, 47.8% of patients in the tiragolumab plus 
atezolizumab group versus 27.9% of patients in the placebo plus atezolizumab group 
were still receiving study treatment in the ITT population.  In the TPS   50% 
population, 65.5% of patients in the tiragolumab plus atezolizumab group versus 
24.1% of patients in the placebo plus atezolizumab group were still receiving 
study treatment. 
In all randomized patients, the combination of tiragolumab plus atezolizumab improved 
the co-primary endpoints of investigator-assessed ORR and progression-free survival 
(PFS) compared to placebo plus atezolizumab, with median follow-up of 5.9 months.  
ORR for tiragolumab plus atezolizumab was 31.3% (95% CI: 19.5, 43.2) compared 
with placebo plus atezolizumab which was 16.2% (95% CI: 6.7, 25.7).  
Investigator-assessed median PFS for tiragolumab plus atezolizumab was 5.4 months 
(95% CI: 4.2 months, not reached) compared with placebo plus atezolizumab which was 
3.6 months (95% CI: 2.7 months, 4.4 months), with a stratified hazard ratio (HR) of 
0.57 (95% CI: 0.37, 0.90).  Investigator-assessed PFS was improved in the tiragolumab 
plus atezolizumab group over the placebo plus atezolizumab group (unstratified 
HR  0.33; 95% CI: 0.15, 0.72; median PFS not reached vs. 3.9 months, respectively). 
As of 2 December 2020, 67 safety-evaluable patients in the tiragolumab plus 
atezolizumab arm in Study GO40290 were treated with a median of 8 doses of 
tiragolumab and atezolizumab (range: 138) for a median of 5.0 months 
(range: 0.0326.0).  In the placebo plus atezolizumab arm, 68 safety-evaluable patients 


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343/Protocol BO43328, Version 4 
were treated with a median of 5 doses of placebo and atezolizumab (range: 137) for a 
median of 2.8 months (range: 0.0326.3). 
As of 30 June 2020, in the Phase II randomized, placebo-controlled Study GO40290, 
a total of 135 safety-evaluable patients were administered either tiragolumab (600 mg 
recommended Phase II/III dose) in combination with atezolizumab or placebo in 
combination with atezolizumab.  The safety profile of tiragolumab plus atezolizumab 
was similar to that of placebo plus atezolizumab- for all-grade adverse events 
(98.5% vs. 97.1%), Grade   3 adverse events (53.7% vs. 50.0%), serious adverse events 
(47.8% vs. 39.7%), and adverse events leading to treatment discontinuation 
(13.4% vs. 11.8%).  Adverse events of special interest were reported in 58.2% of 
patients in the tiragolumab plus atezolizumab arm and in 32.4% of patients in the 
placebo plus atezolizumab arm.  One death due to Epstein-Barr virus (EBV) 
reactivation and possible secondary hemophagocytic lymphohistiocytosis (HLH) was 
reported in this study, which was considered by the investigator to be related to the 
study drugs. 
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse 
events have been manageable, and the safety profile seems to be consistent as reported 
across different solid tumor indications. 
Refer to the Tiragolumab Investigator’s Brochure for additional details on all ongoing 
and planned clinical studies. 
A16–2.6 
BENEFITRISK ASSESSMENT 
The combination of RO7247669 and tiragolumab is currently being tested in this study. 
The combination of atezolizumab and tiragolumab has a favorable emergent benefitrisk 
profile, and early clinical experience with RO7247669 suggest a safety profile 
comparable to that of atezolizumab and other PD-1/PD-L1 blocking antibodies 
(Appendix 12).  The combination of nivolumab (antiPD-1) and relatlimab 
(antiLAG-3) improved PFS over nivolumab alone as first-line therapy in melanoma 
patients in the Phase III Relativity-047 study (Tawbi et al. 2022), which supports the 
expected benefit from RO7247669 (antiPD-1/antiLAG-3 bispecific therapy) in 
combination with tiragolumab.  Taking into account the potentially synergistic 
mechanisms of action of RO7247669 and tiragolumab, as well as their manageable and 
tolerable safety profiles (see Section A16–5), combination treatment with these two 
agents has promise as a potential therapy in solid tumors such as melanoma. 
For the evaluation of the impact of the COVID-19 pandemic on the benefitrisk 
assessment, please refer to Section 1.3. 


Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
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344/Protocol BO43328, Version 4 
A16–3 
RATIONALE FOR DOSE AND SCHEDULE FOR RO7247669 
600 mg  TIRA ARM 
A16–3.1 
RATIONALE FOR RO7247669 600 mg DOSE AND 
SCHEDULE 
RO7247669 will be administered at a fixed dose of 600 mg every 3 weeks (Q3W) 
(600 mg on Day 1 of each 21-day cycle).  A fixed dosing regimen of 600 mg Q3W was 
selected based on available clinical pharmacokinetic, efficacy, and safety data from 
Study NP41300.  During the dose-escalation Part A of the study, RO7247669 was well 
tolerated, and no specific safety concern associated with RO7247669 was identified.  
No DLT up to the highest dose of 2100 mg Q2W was observed, and no MTD was 
identified.  Anti-tumor activity, as measured by radiographic partial responses, was 
observed starting at a dose of 600 mg Q2W.  The pharmacokinetics of RO7247669 were 
dose linear within the dose range tested in Study NP41300.  Greater than 90% 
occupancy of peripheral PD-1 and LAG3 receptors on CD8+  cells was observed at 50 mg 
of RO7247669 and was sustained at all higher doses (unpublished Roche data on file).  
Further modelling of intratumoral PD-1 and LAG3 target engagement using estimated 
target properties was performed.  A dose regimen of 600 mg Q3W was selected for this 
study (BO43328) to ensure that the majority of participants have at least 90% PD-1 
and LAG3 tumor receptor saturation by RO7247669, irrespective of intratumoral 
spatial heterogeneity and intersubject variability.  A dose greater than 600 mg would 
not be expected to result in further clinical activity. 
In study NP41300, persistent anti-drug antibodies (ADAs) formed in approximately 
18% of the total population and the incidence rate was not dose dependent.  An impact 
on exposure was observed at 50, 150 and 300 mg; therefore, 600 mg will be used in 
Study BO43328 to minimize the risk of a loss in exposure due to ADAs.    
In addition, RO7247669 was well tolerated in both the dose-range finding studies and 
Good Laboratory Practice (GLP) monkey toxicology studies up to the highest dose 
evaluated (100 mg/kg).  Toxicology findings were consistent with the findings in 
cynomolgus monkey studies of marketed CPIs.  In the current study (BO43328), the 
safety evaluation of the first 6 patients enrolled in the RO7247669 2100 mg arm was 
completed with no safety signals identified.  
The supporting data for the selected dose can be found in the current RO7247669 
Investigator’s Brochure. 
A16–3.2 
RATIONALE FOR TIRAGOLUMAB DOSE AND SCHEDULE 
Tiragolumab will be administered at a fixed dose of 600 mg IV Q3W (600 mg on Day 1 
of each 21-day cycle). 


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345/Protocol BO43328, Version 4 
The fixed dose of 600 mg IV Q3W was selected on the basis of available clinical 
pharmacokinetic, efficacy, and safety data from the combined Phase Ia/Phase Ib Study 
GO30103 with single-agent tiragolumab or tiragolumab in combination with 
atezolizumab.  In the Phase Ia portion of the study with tiragolumab as a single agent, 
the MTD was not reached, and no DLTs were observed during dose-escalation.  As of 
the clinical cutoff date, anti-drug antibodies (ADAs) to tiragolumab were rare in the 
Phase Ia or Phase Ib portions across all dose levels.  Complete occupancy of peripheral 
TIGIT receptors on CD4   , CD8  , and NK cells was observed beginning at 30 mg of 
tiragolumab in both the Phase Ia and Phase Ib portions of the study and remained 
sustained at all higher doses (unpublished Roche data on file). 
Prolonged stable disease was observed in patients in the Phase Ia portion of the study at 
tiragolumab doses beginning at 400 mg.  In the Phase Ib portion of the study with 
tiragolumab plus atezolizumab, the MTD was not reached.  Anti-tumor activity, as 
measured by radiographic partial responses, was observed across doses for tiragolumab 
beginning at 30 mg and ranging up to 600 mg in combination with 1200 mg 
atezolizumab.  Refer to the Tiragolumab Investigator’s Brochure for additional details. 
A16–4 
MATERIALS AND METHODS SPECIFIC TO RO7247669 
600 mg  TIRA ARM 
A16–4.1 
TREATMENT IN RO7247669 600 mg  TIRA ARM 
A16–4.1.1 
Formulation, Packaging, and Handling 
A16–4.1.1.1 RO7247669 
The RO7247669 drug product will be supplied by the Sponsor as a 50 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of RO7247669, refer to 
the pharmacy manual and the RO7247669 Investigator’s Brochure. 
A16–4.1.1.2 Tiragolumab 
The tiragolumab drug product will be supplied by the Sponsor as a 60 mg/mL 
concentrate for solution for infusion. 
For information on the formulation, packaging, and handling of tiragolumab, refer to 
the pharmacy manual and the Tiragolumab Investigator's Brochure. 
A16–4.1.2 
Dosage, Administration, and Compliance 
Patients in the RO7247669 600 mg   Tira arm will receive treatment for 2 cycles 
(6 weeks) as outlined in Table A16-1 until surgery, or until unacceptable toxicity or 
loss of clinical benefit, whichever occurs first (see Section 3.1.2 for details).  It is 
recommended that treatment be initiated no later than 7 days after randomization. 


Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
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346/Protocol BO43328, Version 4 
Table A16-1 
Treatment Regimen for RO7247669 600 mg   Tira Arm 
Cycle Length 
Dose, Route, and Regimen  
(drugs listed in order of administration) 
21 days 
 RO7247669 600 mg IV on Day 1 of each cycle  
 Tiragolumab 600 mg IV on Day 1 of each cycle 
Tira  tiragolumab. 
  
Refer to the pharmacy manuals for detailed instructions on drug preparation, storage, 
and administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  
No safety data related to overdosing of RO7247669 or tiragolumab are available to date. 
A16–4.1.2.1 RO7247669 
RO7247669 will be administered by IV infusion at a fixed dose of 600 mg on Day 1 of 
each 21-day cycle. 
Administration of RO7247669 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 8.  RO7247669 
infusions will be administered per the instructions outlined in Table A16-2. 


Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
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347/Protocol BO43328, Version 4 
Table A16-2 
Administration of First, Second, and Subsequent 
RO7247669 Infusions 
First and Second Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
first RO7247669 infusion. 
 
Vital signs (respiratory rate, pulse rate, 
blood pressure, pulse oximetry, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
For the first infusion, RO7247669 should 
be infused over 60 (  10) minutes. 
 
After the infusion of RO7247669, the 
patient begins a 60-minute observation 
period. 
 
For the second infusion, RO7247669 
should be infused over 30 (  10) minutes if 
the first infusion was tolerated without an 
IRR. 
 
If clinically indicated, vital signs should 
be measured every 15 (   5) minutes during 
the infusion and at 30 (  10) minutes after 
the infusion.  Record on the eCRF in case 
of abnormalities. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with 
any previous infusion, premedication 
with antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
RO77247669 should be infused over 
30 (  10) minutes if the previous 
infusion was tolerated without an IRR. 
 
If the patient tolerated the previous 
infusion of RO77247669 well without 
infusion-associated adverse events, the 
observation period may be reduced to 
30 minutes. 
 
If the patient experienced an IRR with 
the previous infusion or if clinically 
indicated, vital signs should be measured 
every 15 (  5) minutes during the 
infusion and at 30 (  10) minutes after 
the infusion.  Record on the eCRF in 
case of abnormalities. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
  
For patients who experience a Grade   2 infusion-related reaction (IRR), premedication 
with paracetamol 5001000 mg orally [PO] or IV and diphenhydramine 2550 mg PO 
or IV (or an alternative histamine H1/2 antagonist at an adequate dose) is required prior 
to subsequent infusions.  In case of Grade 3 or 4 IRRs related to study treatment, the 
patient should be permanently discontinued from the study treatment. 
Guidelines for medical management of IRRs for RO7247669 are provided in 
Section  A16–5.1.2.1. 
No dose modification for RO7247669 is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A16–5.1.2.2.  


Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
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348/Protocol BO43328, Version 4 
A16–4.1.2.2 Tiragolumab 
Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 
of each 21-day cycle with a post-infusion observation period as described in Table A16-
3. 
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.  For anaphylaxis precautions, see Appendix 8.  
Tiragolumab infusions will be administered per the instructions outlined in Table A16-
3. 
Table A16-3 
Administration of First and Second Tiragolumab Infusions 
First Infusion 
Second Infusions 
 
No premedication is permitted prior to 
the tiragolumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
pulse oximetry, blood pressure, and 
temperature) should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
60 (  15) minutes. 
 
After the infusion of tiragolumab, the 
patient begins a 60-minute observation 
period. 
 
Record vital signs on the eCRF every 
15 (  5) minutes during the infusion and 
at 30 (  10) minutes after the infusion. 
 
Patients will be informed about the 
possibility of delayed postinfusion 
symptoms and will be instructed to 
contact their study physician if they 
develop such symptoms. 
 
If the patient experienced an IRR with the 
first infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
 
Vital signs should be measured within 
60 minutes prior to the infusion and 
recorded on the eCRF. 
 
Tiragolumab should be infused over 
30 (  10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 (  15) minutes if the patient 
experienced an infusion-related reaction 
with the previous infusion. 
 
Patients should be observed for 
30 minutes after completion of the 
tiragolumab infusion if the previous 
infusion was tolerated without an IRR, or 
for 60 minutes after completion of the 
tiragolumab infusion if the patient 
experienced an IRR with the previous 
infusion. 
 
If clinically indicated, vital signs should 
be recorded on the eCRF every 
15 (  5) minutes during the infusion and 
at 30 (  10) minutes after the infusion. 
eCRF  electronic Case Report Form; IRR  infusion-related reaction. 
  
Guidelines for medical management of IRRs for tiragolumab are provided in Table A16-
4.   


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349/Protocol BO43328, Version 4 
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section  A16–5.1.4.2.  
Tiragolumab treatment may be interrupted for reasons other than toxicity 
(e.g., surgical procedures).  The acceptable length of treatment interruption must be 
based on the investigator’s benefitrisk assessment and in alignment with the protocol 
requirements for the duration of treatment and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
A16–4.2 
CONCOMITANT THERAPY FOR RO7247669 
600 mg  TIRA ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
A16–4.2.1 
Permitted Therapy for RO7247669 600 mg  Tira Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of   1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see Section A16–4.2.3) 
 
Megestrol acetate administered as an appetite stimulant 
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Corticosteroids administered for chronic obstructive pulmonary disease (COPD) or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency.  Other use of corticosteroids may be permitted at the investigator’s 
discretion.  The Medical Monitor is available to advise as needed 
 
Local therapy (e.g., surgery other than complete lymph node dissection [CLND] that 
is not considered to be related to melanoma) 
 
A16–4.2.2 
Cautionary Therapy for RO7247669 600 mg  Tira Arm 
A16–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and Tumor 
Necrosis Factor- Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor- 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 


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350/Protocol BO43328, Version 4 
with RO7247669 and/or tiragolumab.  Therefore, in situations in which systemic 
corticosteroids, immunosuppressive medications, or TNF- inhibitors would be 
routinely administered, alternatives, including antihistamines, should be considered.  
If the alternatives are not feasible, systemic corticosteroids, immunosuppressive 
medications, and TNF- inhibitors may be administered at the discretion of the 
investigator. 
Systemic corticosteroids or immunosuppressive medications, are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with RO7247669 and/or tiragolumab therapy (refer to Appendix 9 for 
details). 
A16–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A16–4.2.2) may be used during the study at the discretion of the 
investigator. 
A16–4.2.3 
Prohibited Therapy for RO7247669 600 mg  Tira Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and 
herbal therapy), whether health authorityapproved or experimental, is prohibited 
for various time periods prior to starting study treatment, depending on the agent 
(see Section 4.4), and during study treatment until surgery, or unacceptable 
toxicity.   
 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
 
Live, attenuated vaccines (e.g., FluMist) are prohibited within 4 weeks prior to 
initiation of study treatment, during treatment with RO7247669 and/or 
tiragolumab, and for 4 months after the last dose of RO7247669 and/or 
tiragolumab. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) are prohibited within 4 weeks or 5 half-lives of the drug (whichever 
is longer) prior to initiation of study treatment and during study treatment 
because these agents could potentially increase the risk for autoimmune conditions 
when given in combination with RO7247669 and/or tiragolumab. 
 


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351/Protocol BO43328, Version 4 
A16–4.3 
CONTRACEPTION REQUIREMENTS FOR RO7247669 
600 mg  TIRA ARM 
Contraception requirements for women and men in the RO7247669 600 mg  Tira arm 
are outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period, for 4 months after the last dose of 
RO7247669, and for 90 days after the last dose of tiragolumab. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (   12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of   1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.  If required per local guidelines or regulations, locally 
recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraception, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant or a 
pregnant female partner, men who are not surgically sterile must remain 
abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year during the treatment period, 
for 4 months after the last dose of RO7247669, and for 90 days after the last 
dose of tiragolumab to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period. 


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352/Protocol BO43328, Version 4 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
preventing drug exposure.  If required per local guidelines or regulations, 
information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
A16–5 
ASSESSMENT OF SAFETY FOR RO7247669 600 mg  TIRA 
ARM 
A16–5.1 
SAFETY PLAN FOR RO7247669 600 mg  TIRA ARM 
The safety plan for patients in this study is based on clinical experience with 
RO7247669 and tiragolumab in completed and ongoing studies.  The anticipated 
important safety risks are outlined below (see Sections  A16–5.1.1, A16–5.1.2, A16–
5.1.3, and A16–5.1.4).  Guidelines for the management of patients who experience 
specific adverse events are provided in Section  A16–5.1.4 and Appendix 9. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.   
Administration of RO7247669 and tiragolumab will be performed in a monitored 
setting in which there is immediate access to trained personnel and adequate equipment 
and medicine to manage potentially serious reactions.  Adverse events will be reported 
as described in Sections 5.25.6. 
A16–5.1.1 
Risks Associated with RO7247669 
Clinical evaluation of RO7247669 is ongoing, and not all risks are known.  As an 
antagonist of PD-1 and LAG-3, RO7247669 is anticipated to enhance T-cell and 
NK-cell proliferation, survival, and function.  Based on the mechanism-of-action of 
RO7247669, the safety profile is anticipated to be similar to other CPIs.  Potential risks 
associated with RO7247669 include the following:  IRRs (including anaphylaxis), 
immunogenicity, and immune-mediated adverse events.  Refer to Section 6 of the 
RO7247669 Investigator’s Brochure for a detailed description of anticipated safety risks 
for RO7247669. 
A16–5.1.1.1 Infusion-Related Reactions and Anaphylaxis 
Administration of therapeutic antibodies may cause IRRs, which may include 
symptoms such as fever, chills, hypotension, shortness of breath, skin rash, headache, 
nausea, and vomiting.  Such reactions typically occur during or shortly after the 
infusion and are predominantly reported following the first infusion.  The incidence 
and severity of IRRs typically decrease with subsequent infusions.  Based on in vitro 


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353/Protocol BO43328, Version 4 
data, the risk of proinflammatory cytokine-mediated IRRs on first administration of 
RO7247669 as single agent is considered low. 
Refer to Section  A16–4.1.2 for detailed guidance on administration of RO7247669 in 
this study.  Refer to Appendix 8 for guidance on anaphylaxis precautions and 
Section A16–5.1.4.3 for guidance on the management of IRRs. 
A16–5.1.1.2 Immunogenicity 
Administration of therapeutic antibodies may cause the formation of anti-drug 
antibodies, which may negatively affect the safety of the therapeutic (e.g., allergic 
reactions, immune complex-mediated diseases). 
A16–5.1.1.3 Immune-Mediated Adverse Events 
The co-stimulatory action of RO7247669, particularly given the LAG-3 modulation, 
might bear the risk of exaggerated immune cell activation that may result in the 
occurrence of enhanced, untoward, immune-mediated adverse events and increased 
cytokine-releasemediated toxicities. 
Toxicities from PD-1 blocking agents can involve any organ or tissue, although some 
immune-mediated adverse events occur much more frequently than others.  The most 
frequently occurring immune-mediated adverse events affect skin, colon, endocrine 
organs, liver, and lungs.  Others are very infrequent but may be very serious, even 
lethal, such as neurological disorders and myocarditis. 
The limited data from recent early phase studies showed that antiLAG-3therapy was 
generally well tolerated as a monotherapy or in combination with antiPD-1 therapies, 
and consistent with the safety profiles of other CPIs (Ascierto et al. 2017; 
Hong et al. 2018). 
In this study, specified immune-mediated adverse events will be considered adverse 
events of special interest and will be captured accordingly (see Section A16–5.2 for the 
list of adverse events of special interest and Section 5.4.2 for reporting instructions). 
Patients with a history of autoimmune disease will be excluded from this study.  
Please see Section 4.1.2 for details. 
A16–5.1.2 
Risks Associated with Tiragolumab 
Infusion-related reactions and immune-mediated hepatitis are identified risks of 
tiragolumab.  Lymphopenia is a potential risk with 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 adverse events).   


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Refer to Appendix 9 of the protocol and the Tiragolumab Investigator’s Brochure for a 
detailed description of anticipated safety risks of tiragolumab. 
A16–5.1.2.1 Infusion-Related Reactions 
Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, 
IRRs associated with hypersensitivity reactions, and/or target-mediated cytokine release 
may occur.  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
IRRs have been reported in patients treated with tiragolumab.  The majority of events 
were mild to moderate and manageable. 
To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab will be 
administered over 60 minutes followed by a 60-minute observation period.  Subsequent 
infusions and observation times may be shortened if the preceding infusion was well 
tolerated.  All infusions will be administered in an appropriate medical setting. 
Refer to Section A16–4.1.2 for detailed guidance on administration of tiragolumab in 
this study.  Please see Appendix 8 for guidance on anaphylaxis precautions and 
Table A16-4 for guidance on the management of IRRs. 
A16–5.1.2.2 Immune-Mediated Hepatitis 
The use of tiragolumab to block the immune inhibitory receptor TIGIT serves to 
increase a baseline T-cell and NK-cell immune response, especially in combination with 
other checkpoint inhibitors.  A disruption in the functioning of immune checkpoint 
molecules may lead to imbalances in immunologic tolerance that results in an 
unchecked immune response, including immune-mediated hepatitis. 
Refer to Appendix 9 for guidance on the management of immune-mediated hepatitis. 
A16–5.1.2.3 Immune-Mediated Adverse Events 
Nonclinical models have suggested a role of TIGIT signaling interruption in 
autoimmunity.  In a knockout model (TIGIT/), loss of TIGIT signaling resulted in 
hyperproliferative T-cell responses and exacerbation of experimental autoimmune 
encephalitis (EAE).  TIGIT/ and wild-type B6 mice were immunized with myelin 
oligodendrocyte glycoprotein peptide in an EAE using suboptimal doses.  In contrast to 
the wild-type B6 mice, the majority of the TIGIT/ mice developed severe EAE 
(Joller et al. 2011). 
Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses 
has demonstrated that development of autoimmune inflammatory conditions is a 
general risk and may therefore be considered a potential risk of tiragolumab.  
Such immune-mediated adverse events have been described for virtually all organ 


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systems and include, but are not limited to, colitis, pneumonitis, endocrinopathies, 
ocular toxicity, pancreatic toxicity, neurologic toxicity, cardiac toxicity, nephritis, 
myositis, and severe cutaneous adverse reactions. 
Patients with a history of autoimmune disease will be excluded from this study 
(see Section 4.1.2). 
In this study, immune-mediated adverse events will be considered adverse events of 
special interest and will be captured accordingly (see Section A16–5.2 for the list of 
adverse events of special interest and Section 5.4.2 for reporting instructions). 
Suggested management guidelines for individual suspected immune-mediated adverse 
events are provided in Appendix 9. 
A16–5.1.2.4 Lymphopenia 
The IgG1 backbone of tiragolumab with intact Fc-effector function may lead to 
ADCC-mediated reduction in lymphocyte count.  Lymphopenia is a potential risk with 
tiragolumab.  Transient decreases in lymphocyte count without clinical sequelae have 
been observed in patients treated with tiragolumab. 
Patients with a lymphocyte count   0.5  109/L (500/L) will be excluded from the study 
(see Section 4.1.1), and complete blood counts will be monitored regularly during the 
study (see Section A16–6). 
A16–5.1.2.5 Embryofetal Toxicity 
Embryofetal toxicity is a potential risk with tiragolumab.  Administration of 
tiragolumab is expected to have adverse effects on pregnancy based on the expression of 
TIGIT on decidual NK and CD8    T cells (Powell et al. 2017; van der Zwan et al. 2018; 
Vento-Tormo et al. 2018), and the expected role of these cells in the recognition and 
response to foreign fetal, placental, and viral antigens at the maternal-fetal interface as 
well as maintenance of maternal-fetal tolerance.  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 
of tiragolumab in pregnant women.  Tiragolumab should not be administered to 
pregnant women. 
Refer to Section 6 of the Tiragolumab Investigator’s Brochure for a detailed description 
of embryofetal toxicity. 
A16–5.1.3 
Risks Associated with Combination Use of RO7247669 and 
Tiragolumab 
The blockade of inhibitory checkpoints leads to increase adaptive T-cell immune 
responses via complementary targets, and the combination targeting multiple 
checkpoints may be associated with heightened immune-mediated toxicity relative to 


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either agent alone.  Such toxicity could manifest as a higher incidence or greater 
severity of autoimmune inflammation events, or potentially the development of HLH 
and MAS.  The following adverse events are potential overlapping toxicities associated 
with combination use of RO7247669 plus tiragolumab:  IRR and immune-mediated 
toxicities, (see Appendix 9 for complete list). 
A16–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the RO7247669 600 mg  Tira Arm 
A16–5.1.4.1 Dose Modifications 
There will be no dose modifications for RO7247669 or tiragolumab in this study.   
A16–5.1.4.2 Treatment Interruption for Toxicities 
Treatment with RO7247669 and tiragolumab may be temporarily suspended in patients 
experiencing toxicity considered to be related to study treatment.  If corticosteroids are 
initiated for treatment of the toxicity, they must be tapered over   1 month 
to   10 mg/day oral prednisone or equivalent before study treatment can be resumed if 
warranted.  In the neoadjuvant setting, the study treatment is limited to a pre-surgery 
window of 6 weeks.  Treatment during this period should not be interrupted, unless a 
patient experiences toxicity.  If toxicity meets criteria for interrupting/withholding 
RO7247669 and tiragolumab, RO7247669 and tiragolumab should be 
interrupted/withheld.  After resolution of the toxicity, subsequent treatment cycles 
should only be considered if the benefit-risk profile is acceptable and if the surgery can 
be conducted within 2 weeks of the planned date.  Otherwise, subsequent treatment 
cycles should be omitted to allow the patient to proceed directly to surgery without 
further delay. 
On the basis of the available characterization of mechanism-of-action, tiragolumab may 
cause adverse events similar to, but independent of, RO7247669.  Tiragolumab may 
also exacerbate the frequency or severity of RO7247669-related adverse events or may 
have non-overlapping toxicities with RO7247669.  Because these scenarios may not be 
distinguishable from each other in the clinical setting, adverse events should generally 
be attributed to both agents, and dose interruptions or treatment discontinuation in 
response to adverse events should be applied to both tiragolumab and RO7247669.  
If RO7247669 is withheld or discontinued, tiragolumab should also be withheld or 
discontinued.  If tiragolumab is withheld or discontinued, RO7247669 should also be 
withheld or discontinued. 


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A16–5.1.4.3 Management Guidelines for Adverse Events 
Guidelines for the management of patients who experience specific adverse events are 
provided in Table A16-4 and Appendix 9. 
For cases in which management guidelines are not covered in Appendix 9, patients 
should be managed and treatments should be withheld or discontinued as deemed 
appropriate by the investigator according to best medical judgment. 
Table A16-4 
Guidelines for Management of Patients Who Experience 
Adverse Events in the RO7247669 600 mg  Tira Arm 
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions 
General guidance 
 For anaphylaxis precautions, see Appendix 8. 
 For severe hypersensitivity reactions, permanently 
discontinue RO7247669 and tiragolumab. 
 For suspected CRS, see Appendix 9 for guidance on 
supportive care. 
 Determine tryptase concentration and IgE titer if 
clinical presentation of IRR suggests an anaphylactic 
or hypersensitivity reaction (hives, obstructive 
shortness of breath, urticaria, other histamine 
associated symptoms) and/or if the first IRR or CRS 
(  Grade 2) is observed at the second infusion.  
If tryptase and/or IgE are elevated, collect a second 
sample for IgE/tryptase analysis at least 48 hours after 
the onset of the reaction to rule out the possibility of 
an anaphylactic reaction.   
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic 
lymphohistiocytosis; IRR  infusion-related reaction; MAS  macrophage activation syndrome. 
 


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Table A16-4 
Guidelines for Management of Patients Who Experience 
Adverse Events in the RO7247669 600 mg  Tira Arm (cont.)  
Event 
Action to Be Taken 
IRRs, anaphylaxis, and hypersensitivity reactions (cont.) 
IRR to RO7247669 and/or 
tiragolumab Grade 1 
 Reduce infusion rate to half the rate being given at the 
time of event onset. 
 After the event has resolved, the investigator should 
wait for 30 minutes while delivering the infusion at 
the reduced rate. 
 If the infusion is tolerated at the reduced rate for 
30 minutes after symptoms have resolved, the infusion 
rate may be increased to the original rate. 
IRR to RO7247669 and/or 
tiragolumab Grade 2 
 Interrupt infusion. 
 Administer aggressive symptomatic treatment 
(e.g., oral or IV antihistamine, anti-pyretic 
medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 After symptoms have resolved to baseline, resume 
infusion at half the rate being given at the time of 
event onset. 
 For subsequent infusions, consider administration of 
oral premedication with antihistamines, antipyretic 
medications, and/or analgesics and monitor closely for 
IRRs. 
IRR to RO7247669 and/or 
tiragolumab, Grade 3 or 4 
 Stop infusion. 
 Administer aggressive symptomatic treatment 
(e.g., oral or IV antihistamine, anti-pyretic 
medication, glucocorticoids, epinephrine, 
bronchodilators, oxygen, IV fluids). 
 Permanently discontinue RO7247669 and tiragolumab 
and contact the Medical Monitor. 
Pulmonary, hepatic, GI, endocrine, 
ocular, immune-mediated myocarditis, 
CRS, pancreatic, dermatologic, 
neurologic, immune-mediated 
meningoencephalitis, renal, myositis, 
HLH, MAS, and systemic immune 
activation 
 Guidelines for the management of these events are 
provided in Appendix 9.   
CRS  cytokine-release syndrome; GI  gastrointestinal; HLH  hemophagocytic 
lymphohistiocytosis; IRR  infusion-related reaction; MAS  macrophage activation syndrome. 
 


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A16–5.2 
ADVERSE EVENTS OF SPECIAL INTEREST FOR THE 
RO7247669 600 mg  TIRA ARM (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.2.3 for reporting instructions).  Adverse events of special interest for the 
RO7247669 600 mg  Tira arm are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7) 
 
Suspected transmission of an infectious agent by the study treatment, as defined 
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 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, IRRs, cytokine-release syndrome, 
influenza-like illness, HLH, and MAS 
 
Nephritis 
 
Ocular toxicities (e.g., uveitis, retinitis, and optic neuritis) 
 
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, or 
toxic epidermal necrolysis) 
 


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360/Protocol BO43328, Version 4 
A16–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN THE 
RO7247669 600 mg  TIRA ARM 
A16–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during 
the study or within 4 months after the last dose of RO7247669 or within 90 days after 
the last dose of tiragolumab.  A paper Clinical Trial Pregnancy Reporting Form should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
e-mailing the form using the fax number or e-mail address provided to investigators.  
Pregnancy should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 6 and 12 months after birth. 
A16–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
4 months after the last dose of RO7247669 or within 90 days after the last dose of 
tiragolumab.  The investigator should report the pregnancy on the paper Clinical Trial 
Pregnancy Reporting Form and submit the form to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and e-mailing the form using the fax number or e-mail address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for the Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information 


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361/Protocol BO43328, Version 4 
on the pregnant partner and the course and outcome of the pregnancy as it becomes 
available. 
Attempts should be made to collect and report infant health information.  When 
permitted by the site, an Authorization for the Use and Disclosure of Infant Health 
Information would need to be signed by one or both parents (as per local regulations) to 
allow for follow-up on the infant.  If the authorization has been signed, the infant's 
health status at birth should be recorded on the Clinical Trial Pregnancy Reporting 
Form.  In addition, the Sponsor may collect follow-up information on the infant's 
health status at 6 and 12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A16–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A16–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to 
study treatment or the female partner of a male patient exposed to study treatment 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.2.2). 










Appendix 16:  Study Details Specific to RO7247669 600 mg  Tira Arm 
  
Table A16-5 
SCHEDULE OF ACTIVITIES FOR RO7247669 600 mg   TIRA ARM (cont.) 
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f After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation 
of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to 
be reported until 135 days after the final dose of study treatment or until initiation of new systemic anti -cancer therapy, whichever occurs 
first.  After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  For details on 
reporting all treatment-related non-serious adverse events that lead to surgical delay, see Section 5.6.  The investigator should follow each 
adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to be related to study 
treatment or trial-related procedures until a final outcome can be reported. 
g Patients who complete the treatment period, regardless of whether they complete the study drug treatment period or discontinue study drug 
prematurely, patients who proceed to surgery will have their first long-term follow-up visit 3 months after surgery and patients who do not 
proceed to surgery will have their first long-term follow-up visit 3 months after the final dose of study treatment.  Information on survival 
follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) will be collected via telephone calls, patient med ical 
records, and/or clinic visits approximately every 3 months until death (unless the patient withdraws consent or the Sponsor t erminates the 
study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the 
investigator.  If a patient withdraws from the study, the study staff may use a public information source (e.g., county recor ds) to obtain 
information about survival status only.  For an experimental arm in which all patients disco ntinued treatment and passed the safety 
follow-up window, as well as approximately 80% of patients discontinued the study, the Sponsor may conclude the arm (the remaining 
~20% of patients will be discontinued from the study). 
h Laboratory tests must be performed within 72 hours prior to dosing during the treatment period.  If screening laboratory assessments were 
performed within 72 hours prior to Day 1 of Cycle 1, they do not have to be repeated.  
i At the pre-surgery visit, adrenocorticotropic hormone, cortisol, S100, and erythrocyte sedimentation rate will be included in the chemistry 
panel. 
j This is only applicable if elevated levels of cardiac enzymes were detected in previous assessments.  
k If periods are missed or delayed before the 6-month follow-up visit, pregnancy testing should be repeated.  This test can be performed by a 
local gynecologist. 
l The Cycle 2 Day 1 on-treatment tissue sample must be collected up to 72 hours prior to drug administration. 
 


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A16–7 
SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, 
AND BIOMARKER SAMPLES FOR RO7247669 
600 mg  TIRA ARM 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to first infusion 
(  6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 (  10) minutes after the end of 
tiragolumab infusion 
 Tiragolumab PK (serum) 
30 (  10) minutes after the end of 
RO7247669 infusion 
 RO7247669 PK (serum) 
Day 1 of Cycle 2 
Prior to infusion 
(  6 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
30 (  10) minutes after the end of 
RO7247669 infusion 
 RO7247669 PK (serum) 
Surgery CLND 
Week 7 
Prior to surgery  
(  24 hr to 0 hr) 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Post-surgery 
Week 10 a 
At visit 
 RO7247669 PK (serum) 
 RO7247669 ADA (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Treatment completion/ 
discontinuation 
Week 13 
At visit 
 RO7247669 ADA (serum) 
 RO7247669 PK (serum) 
 Tiragolumab PK (serum) 
 Tiragolumab ADA (serum) 
 Biomarkers (blood, plasma) 
Long-term follow-up 
Every 3 months 
(  7 days) b 
At visit b 
 Biomarkers (blood, plasma) 
 


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A16-7 SCHEDULE OF PHARMACOKINETIC, IMMUNOGENICITY, AND 
BIOMARKER SAMPLES FOR RO7247669 600 mg  TIRA ARM 
(CONT’D) 
Visit 
Time 
Sample Type 
Surgery follow-up 
6 months after surgery 
(  7 days) 
At visit 
 RO7247669 ADA (serum) 
 RO7247669 PK (serum) 
 Biomarkers (blood, plasma) 
ADA   anti-drug antibody; CLND   complete lymph node dissection; PK   pharmacokinetic; 
Tira   tiragolumab. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples may be 
reduced or sample collection may cease altogether.  Additionally, collected samples may not be 
analyzed if not warranted.  On the basis of emerging biomarker data, the number of biomarker 
samples may be reduced or sample collection may cease altogether. 
a Week 10 biomarker samples must be obtained   20 days post-surgery. 
b To be collected if visit is conducted on site. 


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A16–8 
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Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
370/Protocol BO43328, Version 4 
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Appendix 16:  Study Details Specific to RO7247669 600 mg   Tira Arm 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
371/Protocol BO43328, Version 4 
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2017;2:eaah4569. 
 


  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
372/Protocol BO43328, Version 4 
Appendix 17  
Investigational, Auxiliary, and Non-investigational Medicinal 
Product Designations (for Use in the European Economic Area) 
Table A17-1 
Investigational and Auxiliary Medicinal Product 
Designations for the European Economic Area under 
Clinical Trials Regulation (CTR EU No. 536/2014)  
Product Name 
IMP/AxMP 
Designation 
Marketing Authorization 
Status in EEA  
Used within Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product) 
Authorized 
No 
Tiragolumab 
(RO7092284) 
IMP (test product) 
Unauthorized 
Not applicable 
RO7247669 
IMP (test product) 
Unauthorized 
Not applicable 
Nivolumab 
IMP (comparator) 
Authorized 
Yes 
Ipilimumab 
IMP (comparator) 
Authorized 
Yes 
Prednisone 
AxMP (rescue 
medication) 
Authorized 
Yes 
Methylprednisolone 
AxMP (rescue 
medication) 
Authorized 
Yes 
Dexamethasone 
AxMP (rescue 
medication) 
Authorized 
Yes 
Diphenhydramine 
AxMP (rescue 
medication) 
Authorized 
Yes 
Methimazole 
AxMP (rescue 
medication) 
Authorized 
Yes 
Carbimazole 
AxMP (rescue 
medication) 
Authorized 
Yes 
Insulin 
AxMP (rescue 
medication) 
Authorized 
Yes 
Paracetamol 
AxMP (rescue 
medication) 
Authorized 
Yes 
AxMP  Auxiliary Medicinal Product; EEA  European Economic Area; IMP  investigational medicinal 
product. 
 
 
 


Appendix 17:  Investigational, Auxiliary, and Non-Investigational Medicinal Product 
Designations (for Use in the European Economic Area) 
  
Melanoma Treatment Combinations—F. Hoffmann-La Roche Ltd 
373/Protocol BO43328, Version 4 
Table A17-2 
Investigational and Non‑Investigational Medicinal Product 
Designations for European Economic Area under CTD 
(Clinical Trials Directive 2001/20/EC) 
Product Name 
IMP/NIMP 
Designation 
Marketing Authorization 
Status in EEA  
Used within Marketing 
Authorization 
Atezolizumab 
(RO5541267) 
IMP (test product) 
Authorized 
No 
Tiragolumab 
(RO7092284) 
IMP (test product) 
Unauthorized 
Not applicable 
RO7247669 
IMP (test product) 
Unauthorized 
Not applicable 
Nivolumab 
IMP (comparator) 
Authorized 
Yes 
Ipilimumab 
IMP (comparator) 
Authorized 
Yes 
Prednisone 
NIMP (rescue 
medication) 
Authorized 
Yes 
Methylprednisolone 
NIMP (rescue 
medication) 
Authorized 
Yes 
Dexamethasone 
NIMP(rescue 
medication) 
Authorized 
Yes 
Diphenhydramine 
NIMP(rescue 
medication) 
Authorized 
Yes 
Methimazole 
NIMP (rescue 
medication) 
Authorized 
Yes 
Carbimazole 
NIMP(rescue 
medication) 
Authorized 
Yes 
Insulin 
NIMP (rescue 
medication) 
Authorized 
Yes 
Paracetamol 
NIMP (rescue 
medication) 
Authorized 
Yes 
EEA  European Economic Area; IMP  investigational medicinal product; NIMP  non-investigational 
medicinal product.  
 


Signature Page for Protocol - BO43328 - BM EM0060 - v4 - Global/Core - Published
System identifier: RIM-CLIN-485951
Approval Task
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08-May-2023 20:04:57 GMT+0000