Conditions: Solid Tumors
Keywords: RG6292
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 49
Healthy volunteers: no

Brief summary:
This study will evaluate the safety, tolerability and preliminary anti-tumor activity of RO7296682 in combination with Atezolizumab in participants with advanced solid tumors.

Detailed description:

Arms:
arm 1: Dose-Escalation: Mixed solid tumors participants will receive ascending doses of RO7296682 with a fixed dose of Atezolizumab, every three weeks (Q3W) until either the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) is defined. arm 2: Dose-Expansion: Will start once MTD/RP2D dose of RO7296682 in combination with Atezolizumab is defined in Part I. Participants with selected tumor types will receive a fixed dose of RO7296682 in combination with Atezolizumab. arm 3: Dose-Expansion: Will start once MTD/RP2D dose of RO7296682 in combination with Atezolizumab is defined in Part I and if clinical activity is seen in this trial or in the single agent study (WP41188). Participants with selected tumor types will receive a fixed dose of RO7296682 in combination with Atezolizumab at the dosing regimen established in Part I.

Interventions: intervention 1: RO7296682 intervention 2: Atezolizumab
Intervention descriptions: intervention 1: RO7296682 will be administered as per the schedules specified in the respective arms. intervention 2: Atezolizumab will be administered as per the schedules specified in the respective arms.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
An Open-Label, Multicenter, Phase IB Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary 
Anti-Tumor Activity of RO7296682 in Combination with Atezolizumab 
in Participants with Advanced and/or Metastatic Solid Tumors 
NCT Number: 
NCT04642365 
Document Date: 
Protocol Version 4: 21-Dec-2022 
 
 
 


 
CONFIDENTIAL 
 
The information contained in this document, especially any unpublished data, is the property of 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. 
 
RO7296682 —F. Hoffmann-La Roche Ltd 
Protocol BP42595, Version 4 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, MULTICENTER, PHASE IB 
STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND PRELIMINARY 
ANTI-TUMOR ACTIVITY OF RO7296682 IN 
COMBINATION WITH ATEZOLIZUMAB IN 
PARTICIPANTS WITH ADVANCED AND/OR 
METASTATIC SOLID TUMORS 
PROTOCOL NUMBER: 
BP42595 
VERSION: 
4 
EUDRACT NUMBER: 
2020-003164-82 
IND NUMBER: 
151864 
TEST PRODUCT: 
RO7296682 and atezolizumab 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 20 August 2020 
DATE AMENDED: 
Version 2: 3 March 2021 
Version 3: 16 December 2021 
Version 4: see electronic signature and date 
stamp on the final page of this document 


RO7296682—F. Hoffmann-La Roche Ltd 
2/Protocol BP42595, Version 4 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
AN OPEN-LABEL, MULTICENTER, PHASE IB 
STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND PRELIMINARY 
ANTI-TUMOR ACTIVITY OF RO7296682 IN 
COMBINATION WITH ATEZOLIZUMAB IN 
PARTICIPANTS WITH ADVANCED AND/OR 
METASTATIC SOLID TUMORS 
PROTOCOL NUMBER: 
BP42595 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-003164-82 
IND NUMBER: 
151864 
TEST PRODUCT: 
RO7296682 and atezolizumab 
SPONSOR: 
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 keep the signed original form in your study files, and return a copy to your local 
Site Monitor. 


RO7296682—F. Hoffmann-La Roche Ltd 
3/Protocol BP42595, Version 4 
PROTOCOL AMENDMENT, VERSION 4 
RATIONALE 
Immune-mediated pericardial disorders, immune-mediated myelitis, and facial paresis 
have been defined as new identified risks for atezolizumab. Protocol BP42595 has been 
amended to incorporate these changes (Section 8.3.6 and Appendix 12).  
Furthermore, the management guidelines for infusion-related reactions/cytokine-release 
syndrome (Section 8.3.9.2) and for pulmonary events, hepatic events, gastrointestinal 
events, endocrine events, immune-mediated myocarditis, pancreatic events, 
dermatologic events, neurologic disorders, immune-mediated meningoencephalitis, renal 
events, and immune-mediated myositis (Appendix 12) have been updated.  
The general recommendations for management of any other AEs that may occur but are 
not specifically listed in the organ specific immune-mediated adverse event management 
guidelines in Appendix 12 have been aligned with the Investigator’s Brochure 
(Section 8.3.9.3). 
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol. 
 


RO7296682—F. Hoffmann-La Roche Ltd 
4/Protocol BP42595, Version 4 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 2 
PROTOCOL AMENDMENT, VERSION 4 RATIONALE ....................................... 3 
1. 
PROTOCOL SUMMARY ............................................................... 14 
1.1 
Synopsis .................................................................................. 14 
1.2 
Schematic of Study Design ...................................................... 20 
1.3 
Schedule of Activities ............................................................... 20 
2. 
INTRODUCTION ........................................................................... 26 
2.1 
Study Rationale ....................................................................... 26 
2.2 
Background.............................................................................. 28 
2.3 
Benefit/Risk Assessment ......................................................... 29 
3. 
OBJECTIVES AND ENDPOINTS ................................................. 30 
4. 
STUDY DESIGN ........................................................................... 32 
4.1 
Overall Design ......................................................................... 32 
4.1.1 
Length of the Study .................................................................. 33 
4.1.2 
Dose Escalation Decision Criteria ............................................ 34 
4.1.2.1 
Dose-Limiting Toxicities ........................................................... 36 
4.1.2.2 
Individual Dose Increase for Participants in a Dose-
Escalation Cohort (Part I) ........................................................ 37 
4.1.3 
Stopping Rules Criteria for Dose-Escalation ............................ 38 
4.1.4 
Communication Strategy ......................................................... 38 
4.2 
Scientific Rationale for Study Design ....................................... 39 
4.2.1 
Rationale for Study Population ................................................ 39 
4.2.2 
Rationale for the mCRM-EWOC Design .................................. 40 
4.2.3 
Rationale for Biomarker Assessments ..................................... 40 
4.2.4 
Rationale for Real wOrld PROgnostic Score ........................... 42 
4.2.5 
Rationale for Optional Stool Sample Collection ....................... 42 
4.3 
Justification for Dose ............................................................... 43 
4.3.1 
Rationale for Dosage Selection of Atezolizumab ..................... 43 
4.3.2 
Rationale for Dosage Selection of RO7296682 ....................... 43 
4.3.2.1 
Definition of Optimal Biological Dose ....................................... 44 


RO7296682—F. Hoffmann-La Roche Ltd 
5/Protocol BP42595, Version 4 
4.3.3 
Rationale for the Expansion Dose ........................................... 44 
4.4 
End of Study Definition ............................................................ 45 
5. 
STUDY POPULATION .................................................................. 45 
5.1 
Inclusion Criteria ...................................................................... 45 
5.2 
Exclusion Criteria ..................................................................... 49 
5.3 
Lifestyle Considerations ........................................................... 51 
5.4 
Screen Failures ........................................................................ 51 
5.5 
Recruitment Procedures .......................................................... 52 
6. 
TREATMENTS .............................................................................. 52 
6.1 
Treatments Administered ......................................................... 52 
6.1.1 
RO7296682/Atezolizumab and Infusion Rates ........................ 53 
6.1.2 
Pre-medication prior to Administration of RO7296682 ............. 55 
6.2 
Preparation/Handling/Storage/Accountability........................... 56 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....... 57 
6.3.1 
Method of Treatment Assignment ............................................ 57 
6.4 
Treatment Compliance ............................................................ 58 
6.5 
Concomitant Therapy .............................................................. 58 
6.5.1 
Permitted Therapy ................................................................... 58 
6.5.2 
Prohibited Therapy .................................................................. 59 
6.6 
Dose Modification .................................................................... 59 
6.7 
Treatment after the End of the Study ....................................... 60 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................... 60 
7.1 
Discontinuation of Study Treatment ......................................... 61 
7.1.1 
Temporary Interruption ............................................................ 62 
7.2 
Participant Discontinuation/Withdrawal from the Study ........... 63 
7.3 
Lost to Follow-Up ..................................................................... 63 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................... 64 
8.1 
Efficacy Assessments .............................................................. 64 
8.1.1 
Tumor and Response Evaluations ........................................... 64 
8.1.2 
Photography of Cutaneous Lesions ......................................... 66 
8.2 
Safety Assessments ................................................................ 66 


RO7296682—F. Hoffmann-La Roche Ltd 
6/Protocol BP42595, Version 4 
8.2.1 
Physical Examinations ............................................................. 66 
8.2.2 
Height and Weight ................................................................... 66 
8.2.3 
Vital Signs ................................................................................ 67 
8.2.4 
Electrocardiograms .................................................................. 67 
8.2.5 
Transthoracic Echocardiogram or Multiple-Gate Acquisition 
Scans ....................................................................................... 67 
8.2.6 
Chest X-ray .............................................................................. 68 
8.2.7 
Clinical Safety Laboratory Assessments .................................. 68 
8.2.8 
Medical History (including Smoking History) and 
Demographic Data ................................................................... 69 
8.2.9 
ECOG ...................................................................................... 69 
8.2.10 
Other Non-Safety Assessment(s): Real wOrld PROgnostic 
score ........................................................................................ 69 
8.2.11 
Optional Symptom Questionnaire for Part II Participants ......... 70 
8.3 
Adverse Events and Serious Adverse Events ......................... 71 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information .................................. 71 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ...................................................................................... 72 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events .... 72 
8.3.3.1 
Investigator Follow-Up ............................................................. 72 
8.3.3.2 
Sponsor Follow-Up .................................................................. 72 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events ...................................................................................... 72 
8.3.4.1 
Emergency Medical Contacts .................................................. 73 
8.3.5 
Pregnancy................................................................................ 73 
8.3.6 
Non-Serious Adverse Events of Special Interest ..................... 73 
8.3.7 
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor) .................................................................................. 75 
8.3.8 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as Adverse Events or Serious 
Adverse Events ........................................................................ 75 
8.3.9 
Management of Specific Adverse Events ................................ 75 
8.3.9.1 
Management Guidelines for Skin Toxicity for RO7296682 
and/or atezolizumab ................................................................ 76 


RO7296682—F. Hoffmann-La Roche Ltd 
7/Protocol BP42595, Version 4 
8.3.9.2 
Management Guidelines for Infusion-Related 
Reactions/Cytokine-Release Syndrome for RO7296682 
and/or Atezolizumab ................................................................ 78 
8.3.9.3 
Management Guidelines immune-mediated Adverse 
Events for RO7296682 and/or atezolizumab ........................... 81 
8.4 
Treatment of Overdose ............................................................ 82 
8.5 
Pharmacokinetics .................................................................... 83 
8.6 
Immunogenicity Assessments ................................................. 84 
8.7 
Pharmacodynamics and Biomarkers Analyses ........................ 84 
8.7.1 
Genetic and Genomic Analyses ............................................... 86 
8.7.1.1 
Clinical Genotyping .................................................................. 86 
8.7.1.2 
Whole Genome/Exome/Targeted DNA Analysis ...................... 87 
8.8 
Pharmacodynamics and Biomarker Samples .......................... 87 
8.8.1 
Mandatory Samples ................................................................. 88 
8.8.1.1 
Optional Samples .................................................................... 89 
8.9 
Samples for Research Biosample Repository.......................... 90 
8.9.1 
Overview of the Research Biosample Repository .................... 90 
8.9.2 
Sample Collection .................................................................... 90 
8.9.3 
Leftover of Sample Derivatives such as DNA and RNA ........... 91 
8.10 
Health Economics OR Medical Resource Utilization and 
Health Economics .................................................................... 92 
8.11 
Timing of Study Assessments .................................................. 92 
8.11.1 
Screening and Pre-treatment Assessments............................. 92 
8.11.2 
Assessments during Treatment ............................................... 92 
8.11.3 
Assessments at Study Completion/Early Termination Visit ..... 93 
8.11.4 
Follow-Up Assessments .......................................................... 93 
8.11.5 
Assessments at Unscheduled Visits ........................................ 93 
9. 
STATISTICAL CONSIDERATIONS .............................................. 93 
9.1 
Statistical Hypotheses ............................................................. 93 
9.2 
Sample Size Determination ..................................................... 93 
9.3 
Populations for Analyses ......................................................... 95 
9.4 
Statistical Analyses .................................................................. 95 
9.4.1 
Demographics and Baseline Characteristics ........................... 95 
9.4.2 
Efficacy Analyses ..................................................................... 96 


RO7296682—F. Hoffmann-La Roche Ltd 
8/Protocol BP42595, Version 4 
9.4.3 
Safety Analyses ....................................................................... 97 
9.4.4 
Pharmacokinetic Analyses ....................................................... 98 
9.4.5 
Immunogenicity Analyses ........................................................ 99 
9.4.6 
Pharmacodynamic Analyses .................................................. 100 
9.4.7 
Other Analyses ...................................................................... 100 
9.5 
Interim Analyses .................................................................... 100 
9.6 
Summaries of Conduct of Study ............................................ 102 
10. 
REFERENCES............................................................................ 103 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .................................................................... 106 
 
LIST OF TABLES 
 
Table 1 
Schedule of Activities for all Parts (21-Day Cycle, Q3W) ............ 21 
Table 2 
Pharmacokinetics/Pharmacodynamics for Part I Dose 
Escalation ................................................................................... 23 
Table 3 
Pharmacokinetics/Pharmacodynamics for Part II and Part III 
Dose Expansions ........................................................................ 24 
Table 4 
Objectives and Endpoints ........................................................... 31 
Table 5 
Summary of Treatments Administered ........................................ 53 
Table 6 
Administration of First and Subsequent Atezolizumab 
Infusions...................................................................................... 53 
Table 7 
Administration of First and Subsequent RO7296682 
Infusions...................................................................................... 54 
Table 8 
Pre-medication prior to Treatment with RO7296682 ................... 56 
Table 9 
ECOG Status .............................................................................. 69 
Table 10 
Real wOrld PROgnostic score .................................................... 70 
Table 11 
Management Guidelines for Skin Toxicity ................................... 77 
Table 12 
Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome ...................................................... 79 
Table 13 
Analysis Populations ................................................................... 95 
Table 14 
Efficacy Statistical Analysis Methods .......................................... 96 
Table 15 
Safety Statistical Analysis Methods ............................................ 98 
Table 16 
Gating Criteria I to Open Part III Tumor-specific Cohort per 
Indication................................................................................... 101 
Table 17 
Gating Criteria II to Open Part III Tumor-specific Cohort per 
Indication................................................................................... 101 
Table 18 
Gating Criteria III to Open Part III Tumor-specific Cohort per 
Indication................................................................................... 102 
 


RO7296682—F. Hoffmann-La Roche Ltd 
9/Protocol BP42595, Version 4 
 
LIST OF FIGURES 
Figure 1 
Overview of Study Design ........................................................... 20 
Figure 2 
Overview of Mandatory and Optional Tissue Samples ............... 20 
Figure 3 
Infusion Times of Atezolizumab followed by RO7296682 ........... 55 
 
LIST OF APPENDICES 
 
Appendix 1 
 Regulatory, Ethical, and Study Oversight Considerations ........ 107 
Appendix 2 
 Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting ........................................................... 117 
Appendix 3 
 Procedures for Recording Adverse Events .............................. 125 
Appendix 4 
 Clinical Laboratory Tests ......................................................... 130 
Appendix 5 
 Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................ 133 
Appendix 6 
 Study Details for Part III, NSCLC (Cohort A) ............................ 137 
Appendix 7 
 Study Details for Part III, HNSCC (Cohort B) ........................... 139 
Appendix 8 
 Study Details for Part III, MEL (Cohort C) ................................ 141 
Appendix 9 
 Study Details for Part III, Additional Tumor-Specific 
Cohort(s) Potentially in Comparison with Standard of Care ...... 143 
Appendix 10 
 Details on the Real World Prognostic Score ............................ 144 
Appendix 11 
 Statistics for Combination Therapy Dose-Escalation ............... 147 
Appendix 12 
 Management Guidelines for imAEs with RO7296682 and/or 
Combination Therapy with RO7296682 and Atezolizumab ....... 154 
Appendix 13 
 New Response Evaluation Criteria in Solid Tumors—
Version 1.1 ................................................................................ 177 
Appendix 14 
 Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST).................................................................................. 187 
Appendix 15 
 Cockcroft-Gault Formula/Creatinine Clearance (mL/min) ........ 191 


 
RO7296682—F. Hoffmann-La Roche Ltd 
10/Protocol BP42595, Version 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BML 
Below measurable limit 
C1D1 
Cycle 1 Day 1 
CL 
Clearance 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
CPI 
Checkpoint inhibitor 
COVID-19 
Coronavirus disease 2019 
CR 
Complete response 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
ctDNA 
Circulating tumor DNA 
CTL 
Cytotoxic T lymphocyte 
DCR 
Disease control rate 
DLAE 
Dose-limiting adverse event 
DLT 
Dose-limiting toxicities 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ECOG 
Eastern Cooperative Oncology Group 
EiH 
Entry into human 
EOI 
End of infusion 


 
RO7296682—F. Hoffmann-La Roche Ltd 
11/Protocol BP42595, Version 4 
Abbreviation 
Definition 
EsC 
Esophageal cancer 
EU 
European Union 
EWOC 
Escalation with overdose control 
FDA 
Food and Drug Administration 
FFPE 
Formaldehyde fixed-paraffin-embedded  
FSH 
Follicle-stimulating hormone 
GGT 
Gamma-glutamyl transferase 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HNSCC 
Head and neck squamous cell carcinoma 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICU 
Intensive care unit 
IDO 
Indoleamine-pyrrole 2,3-dioxygenase 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
imAE 
Immune-mediated adverse event 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
iRECIST 
Immune response evaluation criteria in solid tumors 
IUD 
Intrauterine device 
IV 
Intravenous 
IxRS 
Interactive (voice/web) response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoproteins 
LFT 
Liver function test 
LPLV 
Last participant, last visit 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MAS 
Macrophage activation syndrome 
mCRM 
Modified continual reassessment method 


 
RO7296682—F. Hoffmann-La Roche Ltd 
12/Protocol BP42595, Version 4 
Abbreviation 
Definition 
MEL 
Melanoma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple-gated acquisition scan 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing 
NSAESI 
Non-serious adverse event of special interest 
NSCLC 
Non-small cell lung cancer 
OBD 
Optimal biological dose 
ORR 
Objective response rate 
OS 
Overall survival 
OTC 
Over-the-counter 
OvCa 
Ovarian cancer 
PD 
Pharmacodynamic 
PD 
Progressive disease (Appendix 14 only) 
PD-1 
Programmed death-1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin time 
Q3W 
Every 3 weeks 
QRS 
QRS complex 
QT 
QT interval 
QTc 
QT corrected for heart rate 
QTcF 
QT corrected for heart rate using the Fridericia’s 
correction factor 
RBR 
Research biosample repository 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RO 
Receptor occupancy 
ROPRO 
Real wOrld PROgnostic (score) 
RP2D 
Recommended Phase 2 dose 
RR 
RR interval 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Stable disease 


 
RO7296682—F. Hoffmann-La Roche Ltd 
13/Protocol BP42595, Version 4 
Abbreviation 
Definition 
SDEC 
Safety and Dose Escalation Committee 
SoA 
Schedule of activities 
SoC 
Standard of care 
t1/2 
Half-life 
TDO 
Tryptophan 2,3-dioxygenase 
Teff 
T-effector cells 
tmax 
Time of maximum concentration observed 
TME 
Tumor microenvironment 
TNBC 
Triple-negative breast cancer 
Treg 
T-regulatory cell 
TSH 
Thyroid-stimulating hormone 
TTE 
Transthoracic echocardiogram 
UC 
Urothelial carcinoma 
ULN 
Upper limit of normal 
V 
Volume 
Vss 
Volume of distribution at steady-state 
WES 
Whole exome sequencing 
WGS 
Whole genome sequencing 
WOCBP 
Women of childbearing potential 


 
RO7296682—F. Hoffmann-La Roche Ltd 
14/Protocol BP42595, Version 4 
1. 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
PROTOCOL TITLE: 
AN OPEN-LABEL, MULTICENTER, PHASE IB STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS, AND 
PRELIMINARY ANTI-TUMOR ACTIVITY OF RO7296682 IN 
COMBINATION WITH ATEZOLIZUMAB IN PARTICIPANTS WITH 
ADVANCED AND/OR METASTATIC SOLID TUMORS 
SHORT TITLE 
A PHASE IB STUDY TO EVALUATE RO7296682 IN 
COMBINATION WITH ATEZOLIZUMAB IN PARTICIPANTS WITH 
ADVANCED AND/OR METASTATIC SOLID TUMORS 
PROTOCOL NUMBER: 
BP42595 
VERSION: 
4 
TEST PRODUCT: 
RO7296682 
PHASE: 
I 
 
RATIONALE 
Patients with advanced solid tumors have benefitted from recent treatment modalities beyond 
chemotherapy, and in particular, from checkpoint inhibitor (CPI) therapy. However, despite 
recent advances with CPI treatment, many patients are refractory to or acquire resistance to 
current therapies, with response rates varying between 20% and 30% when used as 
monotherapy. There is therefore an urgent unmet medical need to define rational combination 
therapies to overcome resistance mechanisms. Multiple studies exploring transcriptome data 
and/or cell phenotypes have explored the contribution of T-regulatory cell (Treg) tumor infiltration 
to cancer outcome. Tregs suppress antigen-specific anti-tumor immune responses, thus allowing 
for tumor growth. High levels of Tregs are associated with poor prognosis in several human 
cancers. CD25 (the IL-2 receptor alpha chain) is a highly expressed cell surface lineage marker 
of Tregs and is critical for their survival. RO7296682 is a monoclonal antibody (mAb) designed to 
bind selectively to CD25 in order to deplete Tregs, while not interfering with the IL-2 signaling. 
There is accumulating evidence that programmed death-1 (PD-1) is expressed on activated Treg 
cells; thus, the activity of Treg cells could be influenced by PD-1/L1 pathway blockade. 
Combining RO7296682 with atezolizumab (TECENTRIQ®), a mAb that targets the programmed 
death-ligand 1 (PD-L1), may complement the mechanism of action of atezolizumab and result in 
improved anti-tumor activity. This Phase Ib study aims to establish the safety, pharmacokinetics 
(PK) and pharmacodynamics (PD) as well as preliminary anti-tumor activity of RO7296682 in 
combination with atezolizumab in selected solid tumors. 
 


 
RO7296682—F. Hoffmann-La Roche Ltd 
15/Protocol BP42595, Version 4 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
All Parts (Dose Escalation [Part I] and Dose Expansion [Part II and Part III]) 
To evaluate the safety, tolerability, maximum 
tolerated dose (MTD) and/or recommended 
Phase 2 dose (RP2D) (Part I only) of 
RO7296682 when administered in 
combination with atezolizumab. 
 
Nature and frequency of adverse events 
(AEs) with severity determined according 
to NCI CTCAE v5.0 
 
Nature and frequency of dose-limiting 
toxicities (DLTs) in Part I 
Primary (Dose Expansion Part II and Part III) 
To evaluate the preliminary anti-tumor 
activity of RO7296682 when administered in 
combination with atezolizumab. 
 
Objective response rate (ORR) 
according to RECIST v1.1 
Secondary (Dose Escalation, Part I) 
To evaluate the preliminary anti-tumor 
activity of RO7296682 when administered in 
combination with atezolizumab. 
 
ORR according to RECIST v1.1 
Secondary (Dose-Escalation [Part I] and Dose Expansion, Part II and Part III) 
To further characterize the anti-tumor activity 
of RO7296682 when administered in 
combination with atezolizumab. 
 
Disease control rate (DCR) defined as 
response rate (RR) and stable disease 
(SD) 
 
Duration of response (DoR) 
 
Progression-free survival (PFS) 
All according to RECIST v1.1 
 
Overall survival (OS), if data are mature 
at the time of analysis 
To investigate the pharmacokinetic (PK) 
profile of RO7296682 and atezolizumab after 
administration of RO7296682 in combination 
with atezolizumab. 
 
PK profiles and parameters derived for 
RO7296682 and atezolizumab, as 
appropriate, including but not limited to: 
o 
Area under the curve (AUC) 
o 
Minimum (Cmin) and maximum 
(Cmax) concentration 
o 
Time of maximum concentration 
(Tmax) 
o 
Volume of distribution at steady-
state (Vss) 
o 
Half-life (t1/2) 
To characterize the pharmacodynamic (PD) 
effects of RO7296682 in combination with 
atezolizumab on peripheral blood cells 
and/or the tumor microenvironment. 
Correlate RO7296682 exposure and clinical 
endpoints with baseline levels and 
on-treatment changes of blood and tumor 
biomarkers, including but not limited to: 
 
Treatment-induced changes in Treg 
levels in blood and/or tumor 
 
Treatment-induced changes in Teff/Treg 
ratio of blood and tumor 
 


 
RO7296682—F. Hoffmann-La Roche Ltd 
16/Protocol BP42595, Version 4 
OVERALL DESIGN 
STUDY DESIGN 
Study BP42595 is an open-label, multicenter, basket trial to evaluate the anti-tumor activity of 
RO7296682 in combination with atezolizumab over a range of advanced and/or metastatic solid 
tumors. The study includes three parts as described below. 
 
Part I: RO7296682 dose escalation in combination with atezolizumab. 
 
Part II: RO7296682 dose expansion in combination with atezolizumab in participants with 
an
. 
 
Part III: RO7296682 in combination with atezolizumab in tumor-specific expansion cohorts. 
 
TREATMENT GROUPS AND DURATION 
Part I 
To determine the RP2D/MTD, safety, tolerability, PK, and PD profile of escalating doses of 
RO7296682 when administered with a fixed dose of atezolizumab in participants with advanced 
and/or metastatic non-small cell lung cancer (NSCLC), melanoma (MEL), head and neck 
squamous cell carcinoma (HNSCC), esophageal cancer (EsC), triple-negative breast cancer 
(TNBC), and ovarian cancer (OvCa) who have progressed on all standard therapies, are 
intolerant to standard of care (SoC), and/or are non-amenable to SoC, or for whom SoC does 
not exist. The starting dose of RO7296682 will be
 mg and the maximum dose is planned to 
be 
 mg. 
 
Part II 
Part II will commence once the RP2D/MTD of RO7296682 in combination with atezolizumab in 
Part I has been determined. Participants must fulfill the following criteria: 
 
Histologically confirmed advanced and/or metastatic NSCLC, MEL, HNSCC.  
 
 tumor phenotype confirmed centrally based on the most recent archival tumor 
specimen.  
 
Acquired resistance to most recent PD-1/PD-L1 treatment. 
 
Part III 
Part III is exploratory, adaptive in nature, and designed to add or stop expansion cohorts, based 
on emerging data from this study or other RO7296682 studies and based on emerging 
treatment landscapes (e.g., chemotherapy in addition to PD-1/PD-L1 treatment in certain 
indications). Should the emerging treatment landscape warrant adding new combination 
partner(s) as SoC in addition to RO7296682 and atezolizumab, a new cohort exploring the new 
combination in a particular indication will be opened after a protocol amendment. Enrollment in 
one of the three Part III tumor cohorts (namely NSCLC, HNSCC, and MEL) will commence 
according to specific gating criteria. 
 
The IMPs are: 
 
RO7296682 administered via IV infusion as ascending flat doses (every three weeks 
[Q3W]). 
 
Atezolizumab administered via IV infusion at 1200 mg (Q3W). 
 
LENGTH OF STUDY 
The maximum duration of the study for each participant will be up to 31 months, divided as 
follows:  
 
Screening: Days -28 to -1. 
 
Treatment Period: Cycle 1 Day 1 (C1D1) to Month 24 (may be modified if supported by 
emerging data). 
 
End of Treatment Visit: 28 ( 7) days after last dose. 


 
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 
Safety follow-up: 135 ( 30) days after last treatment with RO7296682 in combination with 
atezolizumab. 
 
Survival follow-up: 90 ( 7) days after the safety follow-up visit; then every 3 months 
( 14 days) until death, lost to follow-up, or until study closure by the Sponsor, whichever 
occurs first. 
 
END OF STUDY 
The end of the study is defined as the date of the last participant’s last visit per protocol 
(includes the safety follow-up visit 135 [ 35] days after last dose of study drug) or the date on 
which the last data point from the last participant required for statistical analysis is received (last 
participant, last observation), whichever is the latest date. Because of the exploratory nature of 
this clinical study, its conduct can be discontinued at any time at the discretion of the Sponsor. 
 
INTERNAL MONITORING COMMITTEE 
For Part III (Dose Expansion) of this study, an Internal Monitoring Committee will be used to 
review accumulating clinical data in order to assess subject risk and benefit on an ongoing 
basis. 
 
PARTICIPANT POPULATION 
The participants in this study will be adult male and female participants with advanced and/or 
metastatic solid tumors, who fulfill all eligibility criteria. 
 
KEY INCLUSION CRITERIA 
 
Diagnosis of advanced and/or metastatic solid tumors. Participants whose tumors have 
known sensitizing mutations must have experienced disease progression (during or after 
treatment) or intolerance to treatment with a respective targeted therapy. More detailed 
inclusion criteria for Parts I, II, and III are defined in Section 5.1 of the protocol. 
 
Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1. 
(RECIST v1.1). Previously irradiated lesions must not be counted as target lesions, unless 
there has been demonstrated progression in the lesion and no other target lesions are 
available. 
 
Life expectancy of  12 weeks, as assessed by the Investigator and supported by the Real 
wOrld PROgnostic (ROPRO) score. In case the patient’s score is above the cut-off of 0.7, 
the patient may still be enrolled provided that per the Investigator’s judgment the clinical 
benefits of enrollment will outweigh the risks. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
 
Participants must have progressed on all standard therapies, are intolerant to and/or are 
non-amenable to SoC.  
 
Able to provide the most recent archival tumor tissue samples. If no archival samples are 
available, refer to inclusion criteria for Part I and Part II and appendices for Part III.  
 
Able to provide skin punch biopsy at screening and at C2D8. 
 
For Part II and Part III able to provide a fresh tumor biopsy at screening and C2D8. 
 
Adequate organ functions. 
 
Additional adequate laboratory parameters obtained prior to the first study treatment (C1D1): 
serum albumin; prothrombin time (PT); activated partial thromboplastin time (aPTT). 
 
Participants on therapeutic anticoagulation must be on a stable anticoagulant regimen. 
 
Adequate contraception. 
 
Specific Inclusion Criteria for Parts I, II, and III 
See Section 5.1 of the protocol. 
 


 
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KEY EXCLUSION CRITERIA 
 
Known hypersensitivity to any of the components of RO7296682 and atezolizumab. 
 
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion protein. 
 
Participants who experienced infusion-related reactions (IRRs), skin toxicity, and/or immune-
mediated AEs of Grade  3 in conjunction with previous CPI treatment are excluded (with 
the exception of endocrinopathy managed with replacement therapy or controlled type 1 
diabetes mellitus on a stable insulin regimen). 
 
AEs from any prior anti-cancer therapy that have not resolved to Grade  1 except for 
alopecia, vitiligo, or endocrinopathy managed with replacement therapy, and Grade  2 
peripheral neuropathy. 
 
History or clinical evidence of central nervous system (CNS) primary tumors or metastases 
including leptomeningeal metastases. 
 
Participants with another invasive malignancy in the last two years. 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, may affect the interpretation of 
the results, or may render the patient at high risk from treatment complications 
 
Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.  
 
Severe dyspnea or requiring supplemental oxygen therapy at rest. 
 
Significant cardiovascular disease within 3 months prior to initiation of study treatment, 
unstable arrhythmia, or unstable angina. 
 
Known active bacterial, viral, fungal, mycobacterial, or other pathogens, or any major 
episode of infection. 
 
Positive HIV test at screening. 
 
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
 
Vaccination with live vaccines within 28 days prior to C1D1 or anticipation of need for such a 
vaccine during atezolizumab treatment or within 5 months after the final dose of 
atezolizumab.  
 
Known clinically significant liver disease. 
 
Major surgical procedure or significant traumatic injury within 28 days prior to first 
RO7296682 and atezolizumab infusion, or anticipation of the need for major surgery before 
end of treatment period.  
 
Participants with current or history of wound healing complications and/or participants with 
open wounds until complete resolution. 
 
Prior allogeneic stem cell or solid organ transplantation. 
 
Dementia or altered mental status that would prohibit informed consent. 
 
History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with 
eosinophilia and systemic symptoms.  
 
Active or history of autoimmune disease or immune deficiency. 
 
Prior treatment with CPIs, immunomodulatory agents and/or mAbs, and/or mAb derived 
therapies, or immunostimulatory agents is not allowed. For Part II only: Prior treatment with 
anti-CTLA4 is prohibited. 
 
Prior treatment with a CC chemokine receptor 4 (CCR4)-targeting (e.g., mogamulizumab) or 
a CD25-targeting agent (e.g., basiliximab) is prohibited. Note: patients previously treated 
with single agent RO7296682 in the WP41188 study may be included in this study. 
 
Treatment with standard radiotherapy, any chemotherapeutic agent, targeted therapy, or 
treatment with any other investigational drug within 28 days or 5 half-lives of the drug 
(whichever is shorter), prior to C1D1 is prohibited. 
 
Treatment with systemic immunosuppressive medications. 
 
Radiotherapy within the last 4 weeks before start of study drug treatment. 


 
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NUMBER OF PARTICIPANTS 
The maximum total number of participants in the dose escalation portions of Part I will be 
approximately 60 DLT evaluable participants on a Q3W schedule.  
Approximately 60 CPI-experienced participants with NSCLC, HNSCC, and MEL will be enrolled 
in the expansion cohort in Part II. 
In Part III, each tumor-specific cohort for NSCLC, HNSCC, and MEL may be opened for 
approximately 20 response-evaluable participants. 
 
CONCOMITANT MEDICATIONS 
Use of the following therapies is prohibited during the study and for at least 28 days or 5 half-
lives of the study drug (whichever is shorter), prior to initiation of study treatment, unless 
otherwise specified below: 
 
Investigational or unlicensed/unapproved agents. 
 
Immunotherapy/radio-immunotherapy. 
 
Chemotherapy/targeted therapy. 
 
Radiotherapy (with the exception of limited field palliative radiotherapy). 
 
Biologic agents (e.g., bevacizumab, cetuximab) 
Note: Insulin is allowed. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) 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 
RO7296682/atezolizumab. 
 
Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide. 
 
Live, attenuated vaccines (e.g., Flu – Mist® influenza vaccine) are prohibited at any time 
during the study, and for 5 months following the last dose of study treatment. 
 


 
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1.2 
SCHEMATIC OF STUDY DESIGN 
An overview of the study design is provided in Figure 1 and an overview of mandatory 
and optional tissue samples is provided in Figure 2. 
Figure 1 Overview of Study Design 
 
 
Figure 2 Overview of Mandatory and Optional Tissue Samples 
 
 
 
1.3 
SCHEDULE OF ACTIVITIES 
The schedule of the activities (SoA) for Parts I, II, and III is provided in Table 1. The SoA 
for PK/PD sampling is provided in Table 2 for Part I and in Table 3 for Parts II and III. 


 
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Table 1 
Schedule of Activities for all Parts (21-Day Cycle, Q3W) 
 


 
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Table 1 
Schedule of Activities for all Parts (21-Day Cycle, Q3W) (cont.) 
 
 


 
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Table 2 
Pharmacokinetics/Pharmacodynamics for Part I Dose Escalation 
 


 
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Table 3 
Pharmacokinetics/Pharmacodynamics for Part II and Part III Dose Expansions 
 
 


 
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Footnotes for Table 2 and Table 3 
a 
All blood samples for PK assessments will be collected from an IV line in the opposite arm to the one for drug infusion. All times after EOI 
timepoint are to be taken from the end of infusion. Post dose samples except EOI are to be taken from the time of RO7296682 administration. 
b 
Up to Cycle 5: 
PK and ADA samples should be taken at indicated timepoints.  
Subsequent cycles until 6 months after 1st dose: 
PK and ADA samples will be taken on Day 1 of each cycle. 
Subsequent cycles after first 6 months of treatment: 
PK and ADA samples will be taken only Day 1 at cycle of tumor assessments. 
c 
PK samples will be taken (where feasible) at the time of development of any of the following events, or at the earliest possible convenience 
thereafter: 
* DLT 
* Dose reduction or treatment reduction or interruption due to IRR event ≥ Grade 2 or hypersensitivity  
      - At time of interruption, collect the unscheduled PK sample and clearly record the reason this collection (i.e., due to interruption)   
      - At infusion restart and completion, collect scheduled pre, (mid – where applicable) and post infusion time-points as noted per SoA . Note: 
the re-start time after the dose interruption is taken as the reference timepoint. 
d 
Tryptase and IgE samples will be collected for local analysis at onset of the reaction. If tryptase and/or IgE are elevated, a second sample for 
central IgE/tryptase analysis will be collected approximately 48 hours after onset of the reaction. 
e 
Mandatory fresh tumor biopsies collected at baseline and C2D8 for: 
- Part II and Part III participants only 
Mandatory healthy skin punch biopsies collected at baseline and C2D8 for: 
- All Parts (I, II and III) 
f 
Optional biopsies from pathological and healthy tissue may be taken at the investigator's discretion and with participant's consent at different 
time points. For example, but not limited to Adverse Events, disease progression or long-lasting stable disease in order to characterize the 
immune resistance mechanisms.  
g 
For Part II: please refer to protocol Section 5.1 and 8.8.1 for details on the archival samples and for obtaining a pre-screening Informed consent 
form.  
 


 
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2. 
INTRODUCTION 
RO7296682 is a monoclonal antibody (mAb) designed to bind selectively to CD25 (the 
IL-2 receptor alpha chain) in order to deplete T-regulatory cells (Tregs), while not 
interfering with the IL-2 signaling. Combining RO7296682 with atezolizumab 
(TECENTRIQ®), a mAb that targets the programmed death-ligand 1 (PD-L1), may 
complement the mechanism of action of atezolizumab and result in improved anti-tumor 
activity. 
This Phase Ib study aims to establish the safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) as well as preliminary anti-tumor activity of RO7296682 in 
combination with atezolizumab in selected solid tumors. For details, refer to the 
Investigator’s Brochure. 
2.1 
STUDY RATIONALE 
Patients with advanced solid tumors have benefitted from recent treatment modalities 
beyond chemotherapy, and in particular, from checkpoint inhibitor (CPI) therapy. 
However, despite recent advances with CPI treatment, many patients are refractory to or 
acquire resistance to current therapies, with response rates varying between 20% and 
30% when used as monotherapy (Topalian et al. 2015). There is therefore an urgent 
unmet medical need to define rational combination therapies to overcome resistance 
mechanisms. The mechanisms underlying primary and secondary resistance to various 
anti-tumor agents are numerous and in many cases remain poorly understood. Multiple 
studies exploring transcriptome data and/or cell phenotypes have explored the 
contribution of Treg tumor infiltration to cancer outcome (Cai et al. 2019). 
Anti-CD25/RO7296682, a Treg-depleter agent 
Tregs suppress antigen-specific anti-tumor immune responses, thus allowing for tumor 
growth. CD25 is a highly expressed cell surface lineage marker of Tregs and is critical 
for their survival. In this study, RO7296682, which selectively binds to CD25, will be 
assessed as a Treg-depleting strategy. RO7296682 is designed to mediate FcRIIIa-
dependent, CD25-targeted cell cytotoxicity (also known as antibody-dependent cell 
cytotoxicity) and antibody-dependent cellular phagocytosis (Buettner et al. 2018 and 
Kellner et al. 2017). The Fc region of RO7296682 is afucosylated and therefore 
outcompetes human IgG1 isotypes for binding to FcRIIIa. RO7296682 has low affinity 
to CD25 and relies on avidity for effective binding. This results in preferential binding to 
Tregs, which are CD25 high, while it spares CD25 low expressing cells such as cytotoxic 
T lymphocytes (CTLs). An additional key feature of RO7296682 is that it binds CD25 
while not blocking IL-2 signaling, particularly in activated T-effector cells (Teffs).  


 
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Treatment targeting the PD-1/L1 pathway 
The PD-1/L1 pathway serves as an immune checkpoint to temporarily dampen the 
immune response in states of chronic antigen stimulation such as cancer. PD-L1 is an 
extracellular protein that downregulates immune response through binding to its two 
receptors, programmed death-1 (PD-1) and B7-1. PD-1 is an inhibitory receptor 
expressed on T cells following T-cell activation, and expression is sustained in states of 
chronic stimulation (Blank et al. 2005, Keir et al. 2008). B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells. Binding of PD-L1 to PD-1 and B7-1 
inhibits T cell proliferation and activation, cytokine production and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007, Yang et 
al. 2011). Overexpression of PD-L1 on tumor cells has been reported to impede anti-
tumor immunity, resulting in immune evasion (Blank et al. 2007), and elevated PD-L1 
expression is associated with a worse prognosis. Therefore, interruption of the PD-L1 
pathway represents an attractive strategy for restoring tumor-specific T cells immunity. 
Atezolizumab, which targets the PD-1/L1 pathway, has demonstrated overall survival 
(OS) benefit across various malignancies, including non-small cell lung cancer (NSCLC). 
Treg depletion with PD-L1 pathway blockade 
There is accumulating evidence that PD-1 is expressed on activated Treg cells; thus, the 
activity of Treg cells could be influenced by PD-1/L1 pathway blockade (Wang et al. 
2020, Kamada et al. 2019). Administration of an anti-PD-1/L1 agent may increase 
proliferation and activity of Treg cells, thereby enhancing their suppression activity 
towards CD4+ and CD8+ T cells. Treg cells present in the tumor microenvironment 
(TME) would act as a sink towards IL-2, a key proliferative cytokine needed for the 
expansion of cytotoxic T cells, resulting in a suppressed cytotoxic activity of immune 
effector cells. Combining RO7296682 (a Treg deplete) and atezolizumab should 
therefore help restore cancer cell killing via Teffs, by removing one of the resistance 
mechanisms following the administration of a PD-1/L1 agent.  
In preclinical models, RO7296682 has demonstrated the potential to deplete Tregs and 
therefore enhance T-cell responses against engrafted tumors. In murine tumor models, 
the survival benefit of the combination of RO7296682 with anti-PD-1/L1 was established 
and superior to both antibodies when dosed individually. 
This study investigates the combination of RO7296682 with atezolizumab (anti-PD-L1) 
to couple beneficial modifications of the immune microenvironment via RO7296682 with 
its Treg-depletion activity and via atezolizumab with its immune activation properties. 
The rationale for the study design, including the study population, is provided in 
Section 4.2. 


 
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2.2 
BACKGROUND 
High levels of Tregs are associated with poor prognosis in several human cancers 
(Jenkins et al. 2018). CD25 is a highly expressed cell surface marker of Tregs and 
critical for their survival. RO7296682 preferentially binds to Tregs, while it spares CD25 
low expressing cells such as CTLs. RO7296682, particularly in combination with other 
immune-modifying agents (such as atezolizumab) has the potential to improve anti-
cancer outcomes.  
RO7296682 is currently assessed as a single agent in an entry into human (EiH) Phase I 
study (WP41188) in participants with solid tumors. A summary of the clinical data is 
provided below. 
Clinical Safety Data of RO7296682 in Study WP41188 
As of the clinical cut-off date 10 June 2020, 21 patients had been treated with 
RO7296682 up to a dose of  mg. All 21 patients experienced at least one adverse 
event (AE), the majority of which were Grade 1 or Grade 2 in severity. There were 
14 Grade 3 events reported from 8 patients, of which one was considered related. No 
Grade 4 or Grade 5 event was reported. Preliminary safety data suggest that 
RO7296682 is generally well tolerated with no dose-limiting toxicities (DLTs) observed 
so far in the dose-escalation part of the study. Please refer to the Investigator’s Brochure 
for further details of the safety profile. 
Clinical Pharmacokinetic and Immunogenicity Data of RO7296682 in WP41188 
Preliminary data are available from the dose range 
 mg to  mg and were analyzed 
via non-compartmental analysis. RO7296682 PK was time-independent. No apparent 
target mediated drug disposition could be observed, even at the lowest dose tested. The 
clearance of 0.4 L/d falls within the range of a typical mAb (0.2 L/d to 0.5 L/d), 
approximately 2-fold higher than that of a typical IgG1 antibody in humans (Ryman et al. 
2017). 
Preliminary immunogenicity data showed negative treatment-emergent ADA titers in all 
treated patients. 
Clinical Pharmacodynamics Data of RO7296682 in WP41188 
Preliminary data are available from 16 patients in the dose escalation part of the 
WP41188 study. Relevant peripheral blood Treg depletion (defined as a reduction to or 
below 25% of baseline) was observed in 4 out of 9 patients that received RO7296682 in 
doses ranging from 1 mg to 2 mg.  
A detailed description of the chemistry, pharmacology, and safety of RO7296682 is 
provided in the Investigator’s Brochure.  


 
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2.3 
BENEFIT/RISK ASSESSMENT 
This study evaluates the safety, tolerability, and anti-tumor activity of RO7296682 in 
combination with atezolizumab in participants who have exhausted their standard of care 
(SoC) treatment.  
RO7296682 is hypothesized to provide a significantly improved chance of addressing 
the large unmet medical need that remains for many patients with cancer, including CPI-
naïve and CPI-experienced/resistant patients. Depleting CD25-expressing Tregs without 
affecting the number and function of Teffs, and without interfering with IL-2 signaling, 
has the potential to translate into clinical benefit in patients with cancer. The effects of 
RO7296682 are expected to create an environment that enhances the probability of an 
effective anti-tumor immune response. Available non-clinical data demonstrate that 
RO7296682 or its mouse surrogate are active and induce tumor reduction in different 
tumor mouse models as well as deplete Tregs in peripheral blood and tissues.  
Clinical efficacy of anti-PD-1/L1 mAbs are well established. However, treatment options 
in CPI-experienced patients are still limited and represent an unmet need warranting 
research to understand the mechanisms of resistance and novel combination therapies 
targeting the TME. RO7296682 is hypothesized to address this large unmet medical 
need of CPI-experienced/resistant patients with cancer by depleting CD25-expressing 
Tregs and restoring the immune response to tumor cells. Available nonclinical data in 
mouse demonstrated an enhanced anti-cancer response of the combination therapy 
compared to PD-L1 or RO7296682 treatment alone (see Investigator’s Brochure). Tumor 
types with the highest likelihood of benefit from Treg depletion were selected for this 
study. This was based on in-house analysis (refer to Section 4.2.1 and Section 4.2.2). 
Immune-mediated AEs are a potential risk for Treg depleters, whereas they are 
identified risks associated with atezolizumab treatment (see atezolizumab and 
RO7296682 Investigator’s Brochures). The expected PD effect of RO7296682 is to 
deplete Tregs and convert the immunosuppressive TME into a pro-inflammatory 
phenotype. Since a possible consequence of this mode of action is an increased 
adaptive T-cell immune response, a potential for the exacerbation of immune-mediated 
toxicities when combining RO7296682 with atezolizumab exists.  
The protocol will include the following measures to prevent, minimize, and/or manage 
such toxicities: 
 
Patients with a history of autoimmune disease will be excluded from this study.  
 
Dose-modification guidelines. 
 
Pre-medication guidelines. 
 
Management guidelines for potential RO7296682 and atezolizumab-associated 
risks. 


 
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More detailed information about the known and expected benefits in the context of 
potential risks and expected AEs of RO7296682, is provided in the Investigator’s 
Brochure. 
In the setting of the 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 COVID-19. However, it is unclear whether or how 
systemic cancer therapies such as chemotherapy, targeted therapy, or immunotherapy 
impact the incidence or severity of COVID-19. 
A possible consequence of inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system 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 COVID-19 is altered by cancer immunotherapy. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) 
involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- 
(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 participant develops acute 
SARS-CoV-2 infection while receiving atezolizumab in combination with RO7296682. At 
this time, there is insufficient evidence for causal association between atezolizumab and 
an increased risk of severe outcomes from COVID-19. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with atezolizumab in combination with RO7296682 
and clinical and radiologic features for COVID-19related interstitial pneumonia. Thus, 
Investigators should use their clinical judgment when evaluating and managing 
participants with pulmonary symptoms. 
3. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are provided in Table 4. 
Note: Due to the adaptive nature of Part III, additional cohorts, which are not described 
in this protocol, may be added in the study (see Appendix 6, Appendix 7, Appendix 8, 
and Appendix 9). For a rationale, see Appendix 9.  


 
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Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
All Parts (Dose Escalation [Part I] and Dose Expansion [Part II and Part III]) 
To evaluate the safety, tolerability, 
maximum tolerated dose (MTD) and/or 
recommended Phase 2 dose (RP2D) 
(Part I only) of RO7296682 when 
administered in combination with 
atezolizumab.  
 
Nature and frequency of adverse events 
(AEs) with severity determined according to 
NCI CTCAE v5.0 
 
Nature and frequency of dose-limiting 
toxicities (DLTs) in Part I 
Primary (Dose Expansion Part II and Part III) 
To evaluate the preliminary anti-tumor 
activity of RO7296682 when administered 
in combination with atezolizumab.  
 
Objective response rate (ORR) according to 
RECIST v1.1 
Secondary (Dose Escalation, Part I) 
To evaluate the preliminary anti-tumor 
activity of RO7296682 when administered 
in combination with atezolizumab.  
 
ORR according to RECIST v1.1  
Secondary (Dose-Escalation [Part I] and Dose Expansion [Part II and Part III]) 
To further characterize the anti-tumor 
activity of RO7296682 when administered 
in combination with atezolizumab.  
 
Disease control rate (DCR) defined as 
response rate (RR) and stable disease (SD) 
 
Duration of response (DoR) 
 
Progression-free survival (PFS) 
All according to RECIST v1.1 
 
Overall survival (OS), if data are mature at 
the time of analysis 
To investigate the pharmacokinetic (PK) 
profile of RO7296682 and atezolizumab 
after administration of RO7296682 in 
combination with atezolizumab.  
 
PK profiles and parameters derived for 
RO7296682 and atezolizumab, as 
appropriate, including but not limited to: 
o 
Area under the curve (AUC) 
o 
Minimum (Cmin) and maximum (Cmax) 
concentration 
o 
Time of maximum concentration (Tmax) 
o 
Volume of distribution at steady-state 
(Vss) 
o 
Half-life (t1/2) 
To characterize the pharmacodynamic 
(PD) effects of RO7296682 in combination 
with atezolizumab on peripheral blood 
cells and/or the tumor microenvironment. 
Correlate RO7296682 exposure and clinical 
endpoints with baseline levels and on-treatment 
changes of blood and tumor biomarkers, including 
but not limited to: 
 
Treatment-induced changes in Treg levels in 
blood and/or tumor 
 
Treatment-induced changes in Teff/Treg ratio 
of blood and tumor 


 
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Objectives 
Endpoints 
Exploratory (All Parts) 
To evaluate the anti-drug immune 
response after treatment with RO7296682 
in combination with atezolizumab.  
 
Incidence and titer of anti-drug antibodies 
(ADA) to RO7296682 during the study 
relative to the prevalence of ADA at baseline 
 
Incidence and titer of ADA to atezolizumab 
during the study relative to the prevalence of 
ADA at baseline 
To evaluate the preliminary anti-tumor 
activity of RO7296682 when administered 
in combination with atezolizumab. 
 
ORR 
 
DCR 
 
DoR 
 
PFS 
All according to iRECIST 
To characterize PD effects and duration of 
PD response following the administration 
of RO7296682 in combination with 
atezolizumab. 
 
Changes in number, frequency, activation 
status, and distribution of blood and tumor 
infiltrating lymphocytes (TILs) 
 
Immune contexture (i.e., expression levels of 
inhibitory or activation molecules on immune 
cells) 
 
Changes in circulating tumor DNA (ctDNA) 
levels (Parts II and III) 
To explore biologic markers that might act 
as predictors of safety and/or anti-tumor 
activity of the combination of RO7296682 
and atezolizumab. 
Including, but not limited to de novo occurrence 
and/or change from baseline in:  
 
Soluble molecules (e.g., levels and kinetics of 
inflammatory or inhibitory cytokines). 
 
Immune-phenotypic characteristics (i.e. 
levels of expression on immune cells of 
inhibitory or activation molecules). 
 
Tissue genetic factors (i.e., Teff, Treg, etc. 
gene signatures). 
To explore the effect of Treg depletion in 
the skin immune contexture. 
 
Treatment-induced changes in Treg levels in 
the skin as compared to baseline. 
To explore degree of target binding of 
RO7296682 (in association with PK) via a 
receptor occupancy (RO) assay. 
 
Evaluate RO via ex-vivo assay (Part I only) 
To explore the effect of Treg depletion on 
the gut microbiome. 
 
Treatment-induced changes of the gut 
microbiome as compared to baseline. 
 
4. 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Study BP42595 is an open-label, multicenter, basket trial to evaluate the anti-tumor 
activity of RO7296682 in combination with atezolizumab over a range of advanced 
and/or metastatic solid tumors. The study includes three parts as described below. 


 
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Part I: RO7296682 dose -escalation in combination with atezolizumab 
To determine the recommended Phase 2 dose (RP2D)/maximum tolerated dose (MTD), 
safety, tolerability, PK, and PD profile of escalating doses of RO7296682 when 
administered with a fixed dose of atezolizumab in participants with advanced and/or 
metastatic NSCLC, melanoma (MEL), head and neck squamous cell carcinoma 
(HNSCC), esophageal cancer (EsC), triple-negative breast cancer (TNBC), and ovarian 
cancer (OvCa) who have progressed on all standard therapies, are intolerant to SoC, 
and/or are non-amenable to SoC, or for whom SoC does not exist. The starting dose of 
RO7296682 will be 
 mg and the maximum dose is planned to be 
 mg. 
Part II: RO7296682 dose expansion in combination with atezolizumab in 
participants with an 
 
Part II will commence once the RP2D/MTD of RO7296682 in combination with 
atezolizumab in Part I has been determined. Participants must fulfill the following criteria 
(see Sections 5.1 and 5.2 for details): 
 
Histologically confirmed advanced and/or metastatic NSCLC, MEL, HNSCC.  
 
 confirmed centrally based on the most recent archival 
tumor specimen.  
 
Acquired resistance to most recent PD-1/PD-L1 treatment. 
 
Part III: RO7296682 in combination with atezolizumab in tumor-specific expansion 
cohorts  
Part III is exploratory, adaptive in nature, and designed to add or stop expansion 
cohorts, based on emerging data from this study or other RO7296682 studies (for gating 
criteria, see Section 9.5) and based on emerging treatment landscapes (e.g., 
chemotherapy in addition to PD-1/PD-L1 treatment in certain indications). Should the 
emerging treatment landscape warrant adding new combination partner(s) as SoC in 
addition to RO7296682 and atezolizumab, a new cohort exploring the new combination 
in a particular indication will be opened after a protocol amendment (see Appendix 9).  
Enrollment in one of the pre-defined Part III tumor cohorts (namely NSCLC, HNSCC and 
MEL) may commence (without a protocol amendment) provided the gates described in 
Section 9.5 have been met. 
 
4.1.1 
Length of the Study 
The maximum duration of the study for each participant will be up to 31 months, divided 
as follows:  
 
Screening: Days -28 to -1. 


 
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 
Treatment Period: C1D1 to Month 24 (may be modified if supported by emerging 
data). 
 
End of Treatment Visit: 28 ( 7) days after last dose 
 
Safety follow-up: 135 ( 30) days after last treatment with RO7296682 in 
combination with atezolizumab. 
 
Survival follow-up: 90 ( 7) days after the safety follow-up visit; then every 3 months 
( 14 days) until death, lost to follow-up, or until study closure by the Sponsor, 
whichever occurs first. 
 
4.1.2 
Dose Escalation Decision Criteria  
The decision to escalate will be made by the Safety and Dose Escalation Committee 
(SDEC), as described in Appendix 11. The SDEC is composed of key Sponsor-based 
functional representatives and study investigators (see Section 4.1.4) and will meet 
regularly during Part I. Details on the SDEC are available in the SDEC charter.  
In Part I, a modified continual reassessment method (mCRM) with escalation with 
overdose control (EWOC) will guide the dose escalation to determine the MTD 
(Neuenschwander et al. 2008). The decision to escalate (or not) to the next dose level 
will be made when at least three participants in a cohort will have completed the DLT 
period, following the review of all relevant safety information collected. 
The dose-DLT relationship will be described by a Bayesian two-parameter logistic model 
where the probability of DLT is a function of dose (for further information, see 
Appendix 11). The model will be used: 
 
To estimate the MTD (defined as the dose with the highest probability that the DLT 
rate is within the target interval of 20% to 33%, and a probability less than 25% to be 
associated with a DLT rate superior to 33%). 
 
To recommend a dose for the next cohort complying to pre-specified safety rules 
(e.g., dose increments from one cohort to the next bounded to 200%). These safety 
rules are detailed in Appendix 11. 
 
A minimally informative bivariate normal prior for the parameters of the DLT 
dose-response curve is constructed for this model in order to have a weak impact on the 
final MTD determination. For the dose-toxicity relationship, it is conservatively assumed 
that it would be very unlikely that 15% or higher DLT rates are associated with the first 
dose of RO7296682 in combination with atezolizumab and that a 35% or lower DLT rate 
is associated with maximum planned dose of RO7296682. 
The model will be continuously updated as new participant information becomes 
available, including data collected during the DLT period for the current cohort and data 
collected during the treatment period from the previous cohorts. 


 
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Dose-Escalation Process 
The DLT period starts from the first administration of RO7296682 and atezolizumab and 
ends 7 days after the second administration of RO7296682 and atezolizumab. To 
remain DLT evaluable, a delay in receiving the second dose of maximum 2 days can be 
allowed if agreed by the SDEC.  
The first participant at each dose level must have completed at least 7 days from the first 
dose before the second participant can be treated at this dose level. If the first 
participant experiences a DLT within the first 7 days of treatment, a period of at least 
7 days must also be maintained between the second and third participant. This pattern 
must be maintained for subsequent participants until a period of at least 7 days without a 
DLT has been completed between participants. Once achieved, all subsequent 
participants in a cohort can be enrolled with no fixed observation period between 
participants.  
The design will continue as described, assigning participants to the current maximal 
dose allowed as estimated from all of the DLT data cumulatively, until one of the 
predefined stopping criteria are satisfied (Appendix 11) or the predetermined sample is 
reached, whichever comes first. 
Built-in safety constraints are in place to prevent exposing participants to undue risk of 
toxicity. The dose escalation process will utilize a Bayesian model-based approach 
alongside with clinical judgment to guide dose selection during the study (Section 4.2). 
 
In the absence of a DLT event: 
– 
A dose increment of 200% is allowed (i.e., next dose could be as high as 3-fold 
the previous dose). Indeed, a 3-fold dose increment has been assumed in a 
recent Food and Drug Administration (FDA) oncology review of first-in-human 
studies for immune-activating agents as this is approximately equivalent to half-
log dose increment, which is a common approach for biologics and was also 
the approach observed for the majority of investigational new drugs in the 
dataset for the first few escalation steps (Saber et al. 2017). 
– 
Based on the knowledge from the single agent RO7296682 study (WP41188), 
doses of RO7296682 suggested by the model in this study can be overruled 
(either downward or upward) after consultation with the study investigators, i.e. 
clinical judgment, can override model estimates when selecting the next dose. 
In this instance, the dose increment may be larger than 3-fold but must not 
exceed 6-fold. However, 6-fold increases can only be applied for the dose 
levels up to a dose of 
 mg.   
 
After the first DLT event has been observed: 
– 
The maximum allowed dose increment is reduced to 100% (i.e., up to 2-fold) for 
later cohorts. If there is only 1 accumulated DLT, no DLT in the most recent 2 
cohorts, and provided the current dose is less than 
 mg, it is allowed to 


 
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switch back to a dose increment of 200% (i.e., up to 3-fold). Otherwise, the 
maximum dose increment of 100% (i.e., up to 2-fold) remains. 
– 
In addition, if single agent MTD has been determined in the dose-escalation 
study (WP41188), the upper limit to allow switching back to a dose increment of 
200% (i.e. 3-fold) will be reset to 6-fold lower than single agent MTD and will 
overrule the above- mentioned 
 mg.  
 
After 2 DLTs have been observed, a dose increment of 100% (i.e., 2-fold) must be 
maintained for all subsequent cohorts. 
 
A formal notification of the decision for the next dose will be communicated to all study 
sites by the Sponsor after the SDEC meeting. 
If deemed necessary to further characterize the safety, PK, clinical activity, and/or PD 
profile of RO7296682 in combination with atezolizumab, additional participants (up to 
5 per cohort) may be enrolled at a specific dose level.  
Upon determination of the MTD/RP2D, Part I (Dose Escalation) participants may be 
allowed to escalate to the MTD/RP2D after discussion and agreement between the 
Sponsor and the Investigator, provided the lower dose level was tolerated and the 
individual benefit/risk assessment is positive. 
Part I dose escalation may be halted prior to identification of MTD and upon sufficient 
characterization of RO7296682 in regards to safety, PK, clinical activity, and PD. 
4.1.2.1 
Dose-Limiting Toxicities 
For the purpose of this study, a DLT will be defined as any of the following events 
occurring during the DLT window and not attributable to underlying disease or 
intercurrent illness: 
 
Hematological toxicities defined as: 
– 
– 
 
– 
– 
 
 
– 
  
 
Any non-hematological toxicities Grade  3 except for: 
– 
– 


 
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– 
– 
– 
– 
 
– 
 
– 
 
 
– 
 
 
Additional DLTs not fulfilling the above criteria 
– 
 
  
 
During the dose escalation phase, participants who withdraw before the end of the DLT 
period, and participants who did not receive two doses of RO7296682 in combination 
with atezolizumab for reasons other than DLTs, will be replaced to ensure that at least 
3 DLT evaluable participants have been assessed prior to moving to the next dose level 
(see Section 7 for replacement rules). The DLT will be counted for each dose separately 
and each participant will contribute one single representative data point to the EWOC 
design. 
4.1.2.2 
Individual Dose Increase for Participants in a Dose-Escalation 
Cohort (Part I) 
At the discretion of the Investigator and in agreement with the Sponsor, intra-participant 
dose escalation for individual participants treated at lower RO7296682 doses may be 
considered for treatment at higher doses of RO7296682 than those allocated at the time 
of enrollment, if the doses are considered safe. Thus, after completing at least 9 weeks 
on treatment or after the first tumor assessment, whichever comes first, at one dose 
level with no major safety concerns, a participant may receive a higher RO7296682 dose 
level at the next scheduled cycle within the participant’s dosing schedule, which is at 
least one dose level below the highest currently evaluated dose or up to the MTD and/or 
the RP2D of RO7296682, if reached. If intra-participant dose escalation for an individual 
participant is considered, treatment must be administered as indicated in Section 6.1.1 


 
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as if it was the first administration to the study participant (i.e., 4-hour infusion for the first 
higher dose of RO7296682). 
4.1.3 
Stopping Rules Criteria for Dose-Escalation 
Built-in safety constraints are in place in the dose-escalation process to prevent 
exposing participants to undue risk of toxicity. The mCRM with EWOC will propose to 
stop the dose-escalation under the following circumstances: 
 
 
OR 
 
 
 
 
OR 
 
 
 
 
Due to the exploratory nature of this study, any part of its conduct can be discontinued at 
any time at the discretion of the Sponsor. The Sponsor will notify the Investigators and 
Health Authorities if the study is discontinued or the development program is terminated. 
4.1.4 
Communication Strategy  
Screening starts with the signature of the study Informed Consent Form (ICF). Patients 
should be formally screened in the study interactive (voice/web) response system (IxRS) 
as soon as consented, to allow for the assignment of a participant’s screening ID. A 
participant is considered enrolled into the study when eligibility is confirmed by the 
investigational site and entered in the study IxRS system. 
During the dose escalation (Part I), information will be communicated, as follows: 
 
For all participants, during dose escalation Part I, it is anticipated that the 
Investigator(s) will inform the Sponsor that a participant has been dosed and provide 
a brief summary of the status of the participant in terms of safety and tolerability to 
RO7296682 in combination with atezolizumab.   
 
In the event of a DLT, the Investigator will contact the Sponsor immediately to 
discuss participant status and action taken/to be taken. 
 
The Sponsor will organize SDEC meetings with the Investigators to discuss the 
safety and tolerability of RO7296682 in combination with atezolizumab and the dose 
selected for the next cohort. 


 
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The SDEC meeting will be conducted prior to each dose-escalation, by 
teleconference, in presence of the Investigators, the Medical Monitor, the Sponsor 
Clinical Team, and any other person the Investigators consider necessary to assist 
with the decision. During each teleconference: 
– 
National Cancer Institute common terminology criteria for adverse events (NCI-
CTCAE [v5.0]) toxicities (see Appendix 2) will be discussed along with available 
PK, ADA, and PD data, in addition to safety laboratory results and any other 
available data that may assist the dose-escalation decision process.  
– 
Dose escalation will only proceed to the next dose level if the Investigators and 
the Sponsor are satisfied with the safety profile of the previous cohort and 
agree to move to the next dose level.  
– 
The dose level of RO7296682 will be approved during the SDEC meeting and 
documented in writing. 
 
For Part II ongoing medical data review will be performed by the Sponsor together with 
the investigators. 
 
– 
For Part III (Dose Expansion) accumulating clinical data review will be performed by 
an Internal Monitoring Committee (IMC). For details, see Appendix 1, Section 3.3. 
In addition to these communications, the Sponsor and Investigators will be in regular 
contact throughout the study by email/telephone/fax. 
The Sponsor will be available 24 hours a day to discuss any medical or study-related 
issues that may arise during the conduct of this study. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
4.2.1 
Rationale for Study Population 
Part I: In Part I, dose-escalation participants with advanced and/or metastatic NSCLC, 
MEL, HNSCC, OvCa, TNBC, and EsC tumors will be enrolled. The indication selection 
was based on internal prevalence analyses on FOXP3 expression in order to select 
tumor types that are expected to be most responsive to Treg depletion. For details of the 
analyses, refer to the Investigator’s Brochure. 
Part II: For signal seeking purposes, Part II was designed to include tumor types and 
patient characteristics that are most likely to derive clinical benefit from Treg depletion 
(through RO7296682) and from checkpoint inhibition (through atezolizumab). In-house 
analysis of tumor samples (archival and fresh biopsy) have shown a strong correlation of 
 (as defined by 
) and 
 
. To this end, Part II will include participants with 
NSCLC, MEL, and HNSCC who present with an 
 (see 
Section 5.1, 
 In addition, Part II participants must have experienced initial 
benefit from PD-1/PD-L1 treatment before they ultimately progressed (acquired 
resistance; see Section 5.1). It has been suggested that upon PD-1/PD-L1 treatment 
Tregs express PD-1 at equivalent levels as CD8+ or CD4+ effector/memory T cells, 


 
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thereby enhancing the Treg proliferation and suppressive function (Wang et al 2020, 
Kamada et al 2019). The requirement of initial benefit was incorporated in order to rule 
out primary resistance towards checkpoint inhibition.  
Part III: Part III is designed to further explore signals (i.e., clinical benefit) that were 
generated from this or the single agent WP41188 study and/or based on emerging 
treatment landscapes affecting the SoC in a particular indication (e.g., chemotherapy in 
addition to checkpoint blockade as part of the SoC treatment). Enrollment of participants 
in tumor-specific cohorts may be triggered provided the gating criteria in Section 9.5 
have been met. The tumor-specific cohorts will enable further investigation of clinical 
benefit in a less restrictive population by removing the 
 or acquired 
CPI-resistance criteria required in Part II. In the current protocol, the specifics for the 
NSCLC, HNSCC, and MEL cohorts have been outlined in Appendix 6, Appendix 7 and 
Appendix 8. Should the emerging data suggest that other indications, patient 
characteristics, or drug combinations warrant further investigation, a new cohort will be 
opened through a protocol amendment, addressing also the needs of a potential safety 
run-in/dose escalation phase with additional treatments like SoC chemotherapy 
(Appendix 9). 
4.2.2 
Rationale for the mCRM-EWOC Design 
Part I dose escalation will be carried out according to a mCRM-EWOC design and based 
on the occurrence of DLTs. The mCRM-EWOC design has many favorable 
characteristics: 
 
It adaptively fits a dose DLT response curve by incorporating toxicity data from 
eligible participants among different cohorts, and preclinical or clinical information 
from compounds with similar modes of action via the prior. 
 
The design also locates the MTD more efficiently, without pre-specifying exact dose 
levels for each cohort. Dose selections are made based on the DLT dose response 
curve measured by a 2 parameter logistic model over the dose range, subject to 
clinical judgment and mandated safety constraints that limit the size of dose 
increments. Moreover, the EWOC algorithm highly reduces risks of exposing 
participants to overly toxic doses. Of note, the model provides only the upper limit 
for recommended dose. A dose lower or higher than the model recommended dose 
may be selected based on clinical judgment.  
 
4.2.3 
Rationale for Biomarker Assessments 
According to the mode of action of RO7296682, depletion of Tregs will lead to 
reinvigoration of the anti-tumor immune response in the TME. As such, the goal of the 
biomarker assessments is to confirm the RO7296682 mode of action at the tumor site, 
when administered in combination with atezolizumab, and establish a dose−response 
relationship. 


 
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In-house tumor sample analyses and real world data have shown a strong correlation of 
 and 
. Therefore, archival tumor samples will be collected at 
screening from all participants enrolled in the study and analyzed for immune-phenotype 
and immune contexture in all parts of the study. In order to test the effect of the 
treatment in a patient population that could benefit the most from the therapy, Part II of 
the study will enroll only participants with 
 as assessed by prospectively 
characterizing the tumor immune-phenotype on the archival tissue. 
Treatment-induced intra-tumoral PD changes will be assessed by examining alterations 
in the number, activation/differentiation status, and location of intra-tumoral residing 
immune cells. In particular, a reduction of Tregs and/or an increase in Teff/Treg is 
expected. This will be monitored closely in all samples. Moreover, the expression of 
tumor markers (including but not limited to PD-L1) associated with response to 
RO7296682 will be examined. These changes will be assessed in mandatory, fresh, 
paired tumor biopsy samples collected from participants enrolled in Parts II and III.  
RO7296682 treatment may result in changes in peripheral blood immune cells and 
soluble circulating markers such as cytokines or tumor markers. Hence, in all parts of the 
study, plasma samples will be analyzed with respect to the presence or changes in 
levels of cytokines, inflammation, and soluble tumor markers that may be associated 
with treatment benefits. Moreover, blood samples will be assessed with respect to 
alterations of immune cells in their absolute counts and activation/differentiation status 
as well as their functional capacity following treatment with RO7296682. Receptor 
occupancy (RO) assessments following treatment with RO7296682 in combination with 
atezolizumab will also be undertaken to evaluate the degree of target binding of 
RO7296682 (in association with PK) in Part I only. 
Finally, in order to evaluate the value of circulating tumor DNA (ctDNA) as a response 
predictor to RO7296682 in combination with Atezolizumab, the dynamics of plasma 
ctDNA will be analyzed in relation to tumor size variations and response to treatment. 
Changes in ctDNA level will be assessed in samples collected in Parts II and III of the 
study. 
In order to determine if and by how much RO7296682 in combination with atezolizumab 
affects Treg homeostasis in the immune contexture of healthy tissue, mandatory healthy 
skin punch biopsies will be collected at baseline and on treatment, at the same time 
points as the mandatory tumor biopsies. It is expected that analyses from such healthy 
tissues could provide critical information regarding a differential between numbers of 
activated Treg in the tumor and the non-activated Treg in the healthy tissue.  
If preliminary data suggest that modification of the on-treatment tumor biopsy or healthy 
skin punch biopsy time point would be appropriate, alternative on-treatment biopsy time-
points may be considered.  


 
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Optional tumor and/or healthy tissue biopsies may be taken at any time point and in all 
parts of the study (Parts I-III), for example, due to either skin-related AEs, disease 
progression, or long-lasting stable disease (SD) as per Investigator discretion and if the 
participant consents to these samples being taken to aid the understanding of immune 
resistance or homeostasis mechanisms.  
Finally, all specimens will be used also for research purposes to identify additional 
biomarkers that may be useful to predict and monitor response to RO7296682 in 
combination with atezolizumab and safety, assess PD effects of RO7296682 in 
combination with atezolizumab, and investigate any mechanisms of resistance to 
therapy. Additional biomarkers may be measured if initial data lead to strong scientific 
rationale for these measurements. 
4.2.4 
Rationale for Real wOrld PROgnostic Score 
The Real wOrld PROgnostic (ROPRO) score serves as an objective tool to assess the 
patient’s life expectancy and has been shown to enable prognosis of OS 
homogeneously across solid cancer indications (Becker et al. 2020). The ROPRO score 
consists of routinely collected clinical parameters (listed in Section 8.2.10) reflecting both 
the tumor biology and patient characteristics. It has been shown to strongly outperform 
other risk scores, such as the Royal Marsden Hospital Score. Patients with elevated 
ROPRO scores (upper 10%) had a 7.91-fold (95% confidence interval [CI] 7.45–8.39) 
increased death hazard compared with that of patients with low scores (lower 10%). 
Refer to Appendix 10 for data demonstrating that a poor ROPRO score correlates with 
reduced probability of 12-week survival. 
In this study, the ROPRO score serves to objectively support the Investigator with the 
assessment of the commonly used inclusion criteria “Life expectancy, in the opinion of 
the Investigator, of  12 weeks” (see Section 5.1). Patients who demonstrate a poor 
ROPRO score, should be excluded unless clinical judgment may determine potential 
clinical benefit and thereby the inclusion of the patient in the study. Such decisions will 
be clearly documented.  
4.2.5 
Rationale for Optional Stool Sample Collection 
The gut microbiome has been shown to be a key determinant of immune regulation in 
cancer, in part by influencing T-cell driven anti-tumor responses (Routy et al. 2018). For 
example, antibiotic treatment is associated with poor survival outcomes to anti-PD-1 
therapy in NSCLC, renal cell carcinoma, and urothelial carcinoma (UC) (Elkrief et al. 
2019). Conversely, the risk of colitis with CITs may be predicted on the basis of a 
patient’s pretreatment microbiome (Dubin et al. 2016; Chaput et al. 2017). In addition, 
the role of Tregs in influencing the progression of inflammatory bowel disease and the 
development of colorectal cancer has been established in the literature (van Herk et al. 
2016; Neurath 2020). Thus, heterogeneity in microbiome composition across patients 
may be a relevant driver of safety events, in addition to efficacy.  


 
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This study will examine a participant’s microbiome at baseline and on-treatment in order 
to investigate potential changes by RO7296682 in combination with atezolizumab. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 
Rationale for Dosage Selection of Atezolizumab 
Atezolizumab is approved for the treatment of patients with locally advanced or 
metastatic UC and those with metastatic NSCLC who have disease progression during 
or following platinum-containing chemotherapy at a dose of 1200 mg as an intravenous 
infusion over 60 minutes every 3 weeks (Q3W) until disease progression or 
unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be 
delivered over 30 minutes. 
4.3.2 
Rationale for Dosage Selection of RO7296682 
The starting dose and regimen of RO7296682 in combination with atezolizumab is 
defined as 
 mg administered Q3W by IV administration. The RO7296682 starting 
dose and schedule were selected based on several factors, including non-clinical 
toxicology, exposure and efficacy studies of RO7296682 and clinical experience from 
RO7296682 administered as a single agent in study WP41188: 
Non-clinical toxicology data 
RO7296682 was tested in combination with atezolizumab in a whole blood assay to 
investigate the potential of the combination to trigger systemic cytokine release. When 
compared with single agent RO7296682 in the same assay, 
 
 Therefore, at the starting dose of 
 mg for RO7296682 combined with 
atezolizumab at the dose of 
 mg, 
 
 after the IV administration. In addition, the combination of atezolizumab and 
RO7296682 was tested in mouse models for efficacy assessment. 
 
were reported in these pharmacological models. 
Clinical data from single agent study WP41188 
RO7296682 is being investigated as a single agent in the ongoing WP41188 Phase I 
study. At the time of clinical cutoff date 10 June 2020 (in order to produce validated 
safety outputs), 21 participants had received multiple ascending doses of RO7296682 
up to  mg on a Q3W schedule and had not shown any dose limiting toxicity event. The 
safety profile, PK, and immune-related PD effects in the peripheral blood were analyzed 
to define the starting dose in this study. 
At the time of finalizing the first version of this protocol, the highest cleared dose of 
RO7296682 in the ongoing WP41188 study was  mg 
. Further dose increments 
will be explored in the WP41188 study until MTD or optimal biological dose is reached. 


 
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Based on the clinical experience from study WP41188, the selected RO7296682 starting 
dose of 
 mg is expected to be safe and result in exposure levels that will initiate no or 
minimal PD response, either from a 
 or from a 
 
. Indeed, starting at 
, a consistent PD 
response is observed with a 
 
 
  
Analyzing the RO7296682 PK data at doses from 
 to  mg 
, preliminary 
exposure estimates 
 
 
Given the preliminary data, RO7296682 PK is considered 
 and shows 
 
Given the risk for overlapping toxicities between an anti-CD25 agent and a CPI targeting 
the PD-1/L1 pathway (see Investigator’s Brochure), the proposal of a known safe 
starting dose of RO7296682 
 mg is considered adequate for the initiation of the study.  
4.3.2.1 
Definition of Optimal Biological Dose  
Pharmacokinetic and pharmacodynamic data (i.e., peripheral blood and tumor/skin 
tissues) are being collected to inform on RO7296692 exposure-response relationship in 
order to select the optimal biological dose (OBD) required for RO7296682, which may be 
different from MTD. 
4.3.3 
Rationale for the Expansion Dose 
The RO7296682 dose selected for Part II of BP42595 studying the combination of 
RO7296682 with atezolizumab is 
 mg Q3W. 
This dose was selected based on the integration of all available safety, efficacy, PK, and 
PD data from Study WP41188. While there was neither correlation between drug 
concentration and clinical response (according to RECIST 1.1.) nor AEs (such as 
frequency of total reported, related, immune-mediated, and skin-related AEs), a 
dose-dependent effect on 
 was observed. Consequently, the 
dose recommendation is based on PK/PD modelling with an optimization towards 
 with the least possible effect on 
 in the 
periphery. 
The anti-tumor activity observed in the first 10 response-evaluable participants with an 
, treated with 
 mg RO7296682 (and fixed dose of 
atezolizumab) will be assessed. If the ORR is less than 25%, another RO7296682 dose, 
which previously cleared in Part I may be explored. In this scenario the 
 mg dose 
cohort will be closed and a new Part II dose cohort will be initiated. The Sponsor is 
committed to action based upon emerging data and to aim at optimizing the dose 


 
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selection process in real-time which may include the exploration of other doses with an 
expected improved Benefit-Risk profile. To this end, a total of approximately 60 
participants are planned to be enrolled in Part II. 
4.4 
END OF STUDY DEFINITION 
The end of the study is defined as the date of the last participant’s last visit per protocol 
(includes the safety follow-up visit 135 [ 35] days after last dose of study drug) or the 
date on which the last data point from the last participant required for statistical analysis 
is received (last participant, last observation), whichever is the latest date. 
Because of the exploratory nature of this clinical study, its conduct can be discontinued 
at any time at the discretion of the Sponsor. 
5. 
STUDY POPULATION 
The study population rationale is provided in Section 4.2.1. 
The participants in this study will be adult male and female participants with advanced 
and/or metastatic solid tumors, who fulfill all eligibility criteria. For a high-level overview 
of the cancer types across the study, refer to Section 1.2 or Section 4.1. 
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. 
Signed written informed consent and ability to comply with the study protocol 
according to International Council for Harmonisation (ICH) and local regulations. 
2. 
Age  18 years.  
3. 
Diagnosis of advanced and/or metastatic solid tumors. Participants whose tumors 
have known sensitizing mutations must have experienced disease progression 
(during or after treatment) or intolerance to treatment with a respective targeted 
therapy. More detailed criteria for Parts I, II, and III are defined further below. 
4. 
Measurable disease according to Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1). 
Previously irradiated lesions must not be counted as target lesions, unless there has 
been demonstrated progression in the lesion and no other target lesions are 
available. 
5. 
Life expectancy of 12 weeks, as assessed by the Investigator and supported by 
the ROPRO score. In case the patient’s score is above the cut-off of 0.7, the patient 
may still be enrolled provided that per the Investigator’s judgment the clinical 
benefits of enrollment will outweigh the risks. Please see Section 4.2.4 for rationale. 


 
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6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
7. 
Participants must have progressed on all standard therapies, be intolerant to and/or 
non-amenable to SoC.  
8. 
Able to provide the most recent archival tumor tissue samples (formalin-fixed-
paraffin-embedded [FFPE] blocks preferred; if not available, slides accepted). If no 
archival samples are available, refer to inclusion criteria #19 and #23 for Part I and 
Part II, respectively. For Part III, refer to Appendix 6, Appendix 7 and Appendix 8.  
9. 
Able to provide skin punch biopsy at screening and at C2D8. 
10. For Part II and Part III able to provide a fresh tumor biopsy at screening and C2D8. 
11. Adequate cardiovascular function:  
 
Left ventricular ejection fraction  50%, as determined by multiple-gated 
acquisition scan (MUGA) or transthoracic echocardiogram (TTE). 
 
New York Heart Association (NYHA) Heart Failure Stage  2. 
 
Baseline-corrected QT (QTcF) interval  470 ms. 
 
Resting systolic blood pressure 150 mmHg and diastolic blood pressure 
 100 mmHg (average of  3 readings). 
 
Resting heart rate (HR) between 45 to 100 bpm. 
12. Adequate hematological function:  
 
Neutrophil count of  1.5  109 cells/L (1500/L). 
 
Platelet count of  75  109 /L (75,000/L). 
 
Hemoglobin  9 g/dL (90 g/L, ~ 5.6 mmol/L). 
 
Lymphocyte count of 0.5  109 cells /L (500/L) (borderline lymphocyte values 
can also be confirmed with manual counts if machine count is below limit). 
13. Adequate liver function: 
 
Total bilirubin 1.5 upper limit of normal (ULN; excluding Gilbert syndrome; 
see below). 
 
AST, ALT, and alkaline phosphatase (ALP)  2.5  ULN; with the following 
exceptions:  
o 
Participants with documented liver metastases: AST and ALT  5  ULN. 
o 
Participants with documented liver or bone metastases: ALP  5  ULN. 
o 
GGT  2.5  ULN (in case of liver metastases:  5  ULN) must be 
discussed and agreed with the Sponsor. 
14. Adequate renal function: serum creatinine  1.5  ULN or creatinine clearance by 
Cockcroft-Gault formula  50 mL/min for participants in whom, in the Investigator‘s 
judgment, serum creatinine levels do not adequately reflect renal function. 
15. Additional adequate laboratory parameters obtained prior to the first study treatment 
(C1D1):  
 
Serum albumin  25 g/L (2.5 g/dL). 


 
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 
Prothrombin time (PT) and activated partial thromboplastin time (aPTT) 
 1.5  ULN or  2  ULN for participants with hepatocellular carcinoma. 
16. Participants on therapeutic anticoagulation must be on a stable anticoagulant 
regimen. 
17. A female participant is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies:  
 
Not a woman of childbearing potential (WOCBP). 
 
WOCBP, who:  
o Agree to remain abstinent (refrain from heterosexual intercourse) or use 
highly effective contraceptive methods that result in a failure rate of  1% 
per year during the treatment period and for at least 4 months after the final 
dose of RO7296682 and for 5 months after the final dose of atezolizumab, 
whichever is longer. 
o Examples of contraceptive methods with a failure rate of  1% per year 
include bilateral tubal occlusion, male sterilization, established proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices (IUDs), and copper IUDs. 
 
Have a negative pregnancy test (blood) within the 7 days prior to the first study 
treatment administration.  
Male participants: During the treatment period and for at least 28 days after the last 
dose of RO7296682, agreement to the following: 
 
Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that 
together result in a failure rate of  1% per year, with partners who are WOCBP. 
 
With pregnant female partners, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo. 
 
Refrain from donating sperm during that period. 
Specific Inclusion Criteria for Dose Escalation, Part I 
18. Participants with histologically confirmed advanced and/or metastatic OvCa, TNBC, 
HNSCC, NSCLC, MEL, or EsC. 
19. In the absence of sufficient archival tissue, a fresh biopsy from a safely accessible 
site, per Investigator determination and patient consent, will be requested, providing 
the patient has more than one measurable target lesion.  
Note: if fresh biopsy cannot be obtained, please contact the Medical Monitor. 
Specific Inclusion Criteria for CPI-resistant Participants, Part II 
20. Participants with histologically confirmed advanced and/or metastatic HNSCC, 
NSCLC or MEL. 


 
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21. 
 positivity established using a validated IHC 
method and readout (validated laboratory-developed test). For this purpose, the 
most recent archival sample from a metastatic site (and NOT primary tumor) must 
be obtained. Please see Section 4.2.1 for rationale. 
Note: In the absence of sufficient or appropriate archival tissue the immune-
phenotype must be confirmed using a fresh tumor biopsy, providing the patient has 
more than one measurable target lesion. Please refer to inclusion criteria #23. 
22. For participants to be defined as acquired CPI-resistant, they must have received 
prior treatment with approved or investigational anti-PD-1/L1 (Note: prior treatment 
with anti-CTLA-4 at any time during anti-cancer treatment is prohibited) and meet 
the following requirements: 
 
CPI administration as (neo-) adjuvant therapy is not allowed. 
 
For participants with MEL, no line of chemotherapy is allowed between the 
most recent PD-1/PD-L1 treatment and study treatment. For participants with 
HNSCC and NSCLC, a maximum of 1 line of chemotherapy is allowed between 
the most recent PD-1/PD-L1 treatment and study treatment. 
 
Participants must have experienced Investigator-assessed initial clinical benefit 
(SD or better) from most recent CPI therapy for at least 4 months:  
o 
If a scan within the first 4 months exists and shows progressive disease the 
patient is not eligible (i.e., the scan result cannot be overruled by 
Investigator assessment of clinical benefit).  
o 
Should a subsequent scan for the same line of treatment show clinical 
benefit after initial radiographic progression (i.e., pseudoprogression) the 
patient is eligible. 
23. Able to provide a freshly collected biopsy of a tumor lesion (primary and/or 
metastatic) from a safely accessible site, per Investigator determination and patient 
consent, providing the patient has more than one measurable target lesion. If the 
patient has only one target lesion, the patient will be excluded from study 
participation. The biopsied lesion must not be a target lesion. The following rules 
apply: 
 
Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine 
needle aspirates are not acceptable. 
 
The tumor lesion must not be a metastatic lymph node sample; metastatic 
lymph node is acceptable ONLY when other accessible tumor sites are not 
available for biopsy. 
 
Fresh biopsies must be obtained within 28 days before the first dose at C1D1. 
 
If fresh tissue biopsies cannot be obtained, please contact the Medical Monitor. 
 
For specific inclusion criteria for tumor-specific expansion cohorts, Part III, refer 
to Appendix 6, Appendix 7, and Appendix 8. 


 
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5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Pregnancy, lactation, or breastfeeding.  
2. 
Known hypersensitivity to any of the components of RO7296682 and atezolizumab, 
including but not limited to hypersensitivity to Chinese hamster ovary cell products 
or other recombinant human or humanized antibodies. 
3. 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
4. 
Participants who experienced infusion-related reactions (IRRs), skin toxicity, and/or 
immune-mediated AEs of Grade  3 in conjunction with previous CPI treatment are 
excluded (with the exception of endocrinopathy managed with replacement therapy 
or controlled type 1 diabetes mellitus on a stable insulin regimen).  
5. 
AEs from any prior anti-cancer therapy that have not resolved to Grade 1 except 
for alopecia, vitiligo, or endocrinopathy managed with replacement therapy, and 
Grade  2 peripheral neuropathy.  
Note: Other Grade 2 AEs that are deemed clinically insignificant by treating 
physician are permitted.  
6. 
History or clinical evidence of central nervous system (CNS) primary tumors or 
metastases including leptomeningeal metastases, unless they have been previously 
treated, are asymptomatic, are stable (without evidence of progression by computed 
tomography [CT] or magnetic resonance imaging [MRI] for at least 4 weeks prior to 
the first dose of the study drug), and have had no requirement for steroids or 
enzyme-inducing anticonvulsants in the last 14 days prior to screening.  
Note: Anticonvulsants are permitted if anticonvulsant therapeutic is established for 
 14 days. 
7. 
Participants with another invasive malignancy in the last two years (exceptions are 
non-melanoma skin cancer, cervical carcinoma in situ, good prognosis ductal 
carcinoma in situ of the breast, or prostate carcinoma that is in remission under 
androgen deprivation therapy for  2 years). Other exceptions may apply and 
require discussion between the Investigator and the Sponsor. 
8. 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications. 
9. 
Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed 
consent.  
10. Severe dyspnea or requiring supplemental oxygen therapy at rest.  
11. Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable 
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12. Participants with known active or uncontrolled infection that, in the opinion of the 
Investigator, could impact patient safety, or reactivation of a latent infection, whether 
bacterial, viral (including, but not limited to, hepatitis B, hepatitis C and HIV), fungal, 
mycobacterial (including but not limited to tuberculosis), or other pathogens 
(excluding fungal infections of nail beds) or any major episode of infection requiring 
hospitalization or treatment with IV antibiotics (for IV antibiotics, this pertains to 
completion of last course of antibiotic treatment), or hospitalization for severe 
pneumonia within 28 days of first drug administration. 
13. Positive HIV test at screening. 
14. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
15. Vaccination with live vaccines within 28 days prior to C1D1 or anticipation of need 
for such a vaccine during atezolizumab treatment or within 5 months after the final 
dose of atezolizumab.  
16. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease. 
17. Major surgical procedure or significant traumatic injury within 28 days prior to first 
RO7296682 and atezolizumab infusion, or anticipation of the need for major surgery 
before end of treatment period. After major surgery, participant must wait until 
surgical wounds are fully healed before initiating treatment. 
18. Participants with current or history of wound healing complications and/or 
participants with open wounds until complete resolution. 
19. Prior allogeneic stem cell or solid organ transplantation. 
20. Dementia or altered mental status that would prohibit informed consent. 
21. History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with 
eosinophilia and systemic symptoms.  
22. Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener 
granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 
with the following exceptions: 
 
Participants with a history of autoimmune-mediated hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
 
Participants with controlled type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study.  
 
Participants with controlled eczema, psoriasis, lichen simplex chronicus, or 
vitiligo with dermatologic manifestations only (e.g., participants with psoriatic 
arthritis are excluded) are eligible for the study provided all of following 
conditions are met: 
o Rash must cover  10% of body surface area. 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 


 
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o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months. 
23. Prior treatment with CPIs, immunomodulatory agents and/or mAbs, and/or mAb-
derived therapies, or immunostimulatory agents is not allowed (approved or 
investigational), provided that: 
 
Less than 4 weeks have elapsed between the last dose and the proposed 
C1D1. 
 
Less than 5 half-lives or 28 days (whichever is shorter) have elapsed since prior 
treatments with specific immunomodulators, TLR-agonists, inhibitors of 
IDO/TDO, or agonists (e.g., OX40) and the proposed C1D1. 
24. For Part II only: Prior treatment with anti-CTLA4 is prohibited. 
25. Prior treatment with a CC chemokine receptor 4 (CCR4)-targeting (e.g., 
mogamulizumab) or a CD25-targeting agent (e.g., basiliximab) is prohibited. Note: 
participants previously treated with single agent RO7296682 in the WP41188 study 
may be included in this study.  
26. Treatment with standard radiotherapy, any chemotherapeutic agent, targeted 
therapy, or treatment with any other investigational drug (defined as treatment for 
which there is currently no regulatory authority-approved indication) within 28 days 
or 5 half-lives of the drug (whichever is shorter), prior to C1D1 is prohibited. 
27. Treatment with systemic immunosuppressive medications including, but not limited 
to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor (TNF) agents within 2 weeks prior to C1D1. Participants 
who have received acute and/or low-dose systemic immunosuppressive 
medications (e.g., a one-time dose of dexamethasone for nausea or chronic use of 
 10 mg/day of prednisone or another dose-equivalent corticosteroid) may be 
enrolled in the study. The use of inhaled corticosteroids and mineralocorticoids (e.g. 
fludrocortisone) is allowed.  
28. Radiotherapy within the last 4 weeks before start of study drug treatment, with the 
exception of limited palliative radiotherapy (for which no wash out period is 
required). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Participants will be expected to follow protocol requirements for contraception (see 
Appendix 5), but there are no other lifestyle restrictions during the study. There are no 
study-specific restrictions to meals and dietary requirements. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical 
study, but are not subsequently entered in the study. Patients who fail screening due to 
a ROPRO score above the prescribed threshold will be followed up for survival after the 
date of screen failure.  


 
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The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. In the event 
that a fresh biopsy is taken during the screening period and the participant is not 
enrolled into the study, the FFPE biopsy block can be returned to the site upon site 
request.  
Individuals who fail to meet the criteria for participation (screen failures) may be 
re-screened, with Sponsor approval. In the event re-screening is permitted, invasive 
assessments like biopsies do not have to be repeated. Re-screened participants should 
be assigned a different screening number as compared to that used for the initial 
screening. 
Participants who are re-screened are required to sign a new ICF. 
5.5 
RECRUITMENT PROCEDURES 
An IxRS system will be utilized to manage (pre-) screening and enrollment. 
Participants will be identified using pre-screening enrollment logs, clinical database, and 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
newspaper/radio/social-media advertisements prior to consenting to take part in this 
study.  
6. 
TREATMENTS 
Study treatment is defined as any investigational product or marketed product intended 
to be administered to a study participant according to the study protocol. 
For the purpose of the study, RO7296682 and atezolizumab are considered 
investigational medicinal products (IMPs). All IMPs required for completion of this study 
will be provided by the Sponsor or its designee in compliance with local drug 
management regulations. Pre-medications are considered non-IMPs. 
All study treatment administration will be performed at the study center under 
supervision of site staff. In case of infusion-associated AEs in participants, the signs and 
symptoms should have fully resolved before the participant is discharged. Cases of 
accidental overdose or medication error, along with any associated AEs, should be 
reported as described in Appendix 2, Section 5.2. 
6.1 
TREATMENTS ADMINISTERED 
Administration of RO7296682 and atezolizumab will be performed in a monitored setting, 
such as an intensive care unit (ICU), where there is immediate access to trained 
personnel and adequate equipment and medicine to manage potentially serious 
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The administered treatments are summarized in Table 5. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 6.6 or 
Section 7, respectively. 
For more details, refer to the RO7296682 and atezolizumab Investigator’s Brochures 
and the Pharmacy Manual. 
Table 5 
Summary of Treatments Administered 
Study Treatment 
Name: 
RO7296682 
 
Atezolizumab 
Dose Formulation: 
Solution 
Solution 
Solution 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
 mg/mL 
 mg/mL 
60 mg/mL 
Dose: 
Ascending flat 
doses (Q3W) 
Not applicable 
 mg (Q3W) 
Route of 
Administration: 
IV infusion 
IV infusion 
IV infusion 
Sourcing: 
Provided centrally by the Sponsor 
 
6.1.1 
RO7296682/Atezolizumab and Infusion Rates 
For infusion guidelines of atezolizumab, refer to Table 6 and for infusion guidelines of 
RO7296682, refer to Table 7. 
Table 6 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
Atezolizumab must be administered prior to 
RO7296682. 
 
No pre-medication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
 
Participants who do not receive a full dose 
of atezolizumab should not receive 
RO7296682. 
 
If the participant experienced Grade  2 
IRR with any previous infusion, pre-
medication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
 
Atezolizumab must be administered prior 
to RO7296682. 
 
Vital signs should be measured within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated (i.e., absence of Grade  2 
IRRs), or 60 ( 15) minutes if the patient 
experienced Grade  2 IRRs with the 
previous infusion. 
 
Participant should be observed for at 
least 1 hour before receiving 
RO7296682. 


 
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First Infusion 
Subsequent Infusions 
 
Participant should be observed for at least 
2 hours after the first administration of 
atezolizumab before receiving RO7296682. 
 
Participants 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 participant 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. 
 
Table 7 
Administration of First and Subsequent RO7296682 Infusions 
First Infusion 
Subsequent Infusions 
 
For pre-medication guidelines, refer to 
Table 8. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, and temperature) should 
be measured within 60 min prior to the 
infusion. 
 
RO7296682 should be infused over 
4 h ( 15 min). 
 
If clinically indicated, vital signs should be 
measured every 15 ( 5) min during the 
infusion and at 30 ( 10) min after the 
infusion. 
 
Participants 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 participant experienced Grade  2 
IRR with any previous infusion, refer to 
the pre-medication guidelines in Table 8. 
 
Vital signs should be measured within 
60 min prior to the infusion. 
 
RO7296682 should be infused over 
2 h ( 10 min) if the first infusion was well 
tolerated (i.e., absence of Grade  2 
IRRs). If the 2 h infusion was well-
tolerated, all subsequent infusions may 
be reduced to 60 ( 10) min. If the 
participant experienced Grade  2 IRRs 
the previous infusion duration should be 
maintained until absence of Grade  2 
IRRs is observed.  
 
If the participant experienced an IRR with 
the previous infusion or if clinically 
indicated, vital signs should be measured 
during the infusion and at 30 ( 10) min 
after the infusion. 
 


 
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Figure 3 Infusion Times of Atezolizumab followed by RO7296682 
 
*In case of Grade 2 IRRs, refer to Table 6 and Table 7 for infusion durations.  
  
6.1.2 
Pre-medication prior to Administration of RO7296682 
No pre-medication is foreseen prior to the administration of RO7296682, unless per 
Investigator judgment and based on the participants’ medical history, pre-medication is 
warranted in the best interest of the participant. In case of IRRs, a list of pre-medication 
is provided in Table 8. Pre-medications are captured in a dedicated pre-medication 
eCRF. 
For participants having experienced an IRR-like reaction with a single and isolated 
symptom such as fever, occurring within 24 h after study drug infusion was completed, 
the use of pre-medication such as paracetamol, antihistamines and corticosteroids is not 
foreseen prior to subsequent RO7296682 administrations. Pre-medication of those 
participants at subsequent infusions is at the discretion of the investigator, as is the 


 
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treatment and management at the time of an event. The event will be reported as a 
single AE (e.g. fever). 
Table 8 
Pre-medication prior to Treatment with RO7296682 
First Infusion 
Subsequent Infusions 
Pre-medication with the following can be 
considered at Investigator discretion 
approximately 30 minutes prior to the 
infusion: 
 
Antihistamines (both an 
H1-receptor antagonist and an 
H2-receptor antagonist) and/or 
 
Antipyretics per institutional 
standard and/or 
 
Anti-emetic 
In case of IRR Grade 1 at previous infusion 
Pre-medication with the following is recommended 
approximately 30 minutes prior to the infusion: 
 
Antihistamines (both an H1-receptor antagonist and an 
H2-receptor antagonist) and/or 
 
Antipyretics per institutional standard and/or 
 
Anti-emetic 
In case of IRR Grade 2 at previous infusion pre-medication 
with the following must be administered approximately 
30 minutes prior to the infusion: 
 
Antihistamines (both an H1-receptor antagonist and an 
H2-receptor antagonist) and 
 
Anti-pyretics per institutional standard and/or 
 
Anti-emetic 
In case of IRR Grade 3 at previous infusion, pre-medication 
with the following must be administered approximately 
30 minutes prior to the infusion: 
 
Antihistamines (both an H1-receptor antagonist and an 
H2-receptor antagonist) and 
 
Anti-pyretics per institutional standard and 
 
Hydrocortisone (200 mg IV or equivalent according to 
institutional guidelines) and/or 
 
Anti-emetic 
In case of IRR Grade 4, treatment with RO7296682 and must 
be permanently discontinued and patient discontinued. 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Study drug packaging will be overseen by the Sponsor’s clinical study supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.  


 
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The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations. RO7296682, RO7296682 diluent and 
atezolizumab will be provided by the Sponsor. 
The investigational site will acknowledge receipt of IMPs and 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. 
The study site (i.e., Investigator or authorized personnel [e.g., pharmacist]) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records). Upon arrival of the IMPs at the 
site, site personnel will complete the following: 
 
Check the IMPs for damage. 
 
Verify proper identity, quantity, integrity of seals and temperature conditions. 
 
Report any deviations or product complaints to the Study Monitor upon discovery. 
 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the Pharmacy Manual.  
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any 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 the drug accountability log. 
Refer to the Pharmacy Manual and the RO7296682 and atezolizumab Investigator's 
Brochure for information on IMP formulation, IMP handling, including preparation and 
storage, and accountability. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING 
6.3.1 
Method of Treatment Assignment 
This is an open-label study with no randomization.  


 
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The Sponsor will be responsible for allocation of patient numbers, using an IxRS 
process. The log in information and directions for the IxRS will be provided to each site. 
Participants who fulfill all of the inclusion criteria and none of the exclusion criteria are 
eligible to participate in the study and will be assigned to a treatment group/dose in 
consultation with the Sponsor. 
6.4 
TREATMENT COMPLIANCE 
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule. This individual will write the date 
dispensed and participant number on the study treatment vial label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study. 
6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant 
within 30 days of study screening until the safety follow-up visit must be recorded on the 
Concomitant Medications eCRF along with reason for use, dates of administration 
(including start and end dates) and dosage information (including dose and frequency). 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
All medication administered to manage AEs should be recorded on the Adverse Event 
eCRF. 
6.5.1 
Permitted Therapy 
For pre-medication guidelines, refer to Section 6.1.2. Participants who use oral 
contraceptives with a failure rate of  1% (See Appendix 5), hormone-replacement 
therapy, or other maintenance therapy should continue their use. 
The use of limited field palliative radiotherapy during the course of the study should be 
discussed and agreed by the Investigator on a case-by-case basis with the Medical 
Monitor in order to exclude overall progressive disease. No delay of study treatment 
administration is required although participants should not receive study treatment 
during radiation. 
Systemic corticosteroids and TNF- antagonists may attenuate potential beneficial 
immunologic effects of treatment with RO7296682 in combination with atezolizumab. 
Therefore, in situations in which systemic corticosteroids or TNF-α inhibitors would be 
routinely administered, alternatives (including antihistamines) should be considered. If 
the alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors may be 
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Systemic corticosteroids are recommended, at the discretion of the Investigator, for the 
treatment of specific AEs when associated with RO7296682/atezolizumab therapy (for 
details, refer to Section 8.3.9.1, 8.3.9.2, and 8.3.9.3, and Appendix 12).  
6.5.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study and for at least 28 days or 
5 half-lives of the study drug (whichever is shorter), prior to initiation of study treatment, 
unless otherwise specified below: 
 
Investigational or unlicensed/unapproved agents. 
 
Immunotherapy/radio-immunotherapy. 
 
Chemotherapy / targeted therapy. 
 
Radiotherapy (with the exception of limited field palliative radiotherapy).  
 
Biologic agents (e.g., bevacizumab, cetuximab). 
Note: Insulin is allowed. 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) 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 RO7296682 and/or atezolizumab. 
 
Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide. See Section 6.5.1 for guidelines on 
systemic corticosteroids and TNF-α inhibitors. 
 
Live, attenuated vaccines (e.g., Flu – Mist® influenza vaccine) are prohibited at any 
time during the study, and for 5 months following the last dose of study treatment. 
 
6.6 
DOSE MODIFICATION 
If, in the opinion of the Investigator, a toxicity is considered due solely to one of the study 
treatments, the dose of the other study treatment does not require modification. 
However, in cases potentially related to both drugs, treatment with both RO7296682 and 
atezolizumab should be modified or permanently discontinued as appropriate based on 
the grade of toxicity. Examples of potentially overlapping toxicities that could be related 
to both drugs include immune-mediated toxicities, IRR/CRS, skin toxicity and 
immunogenicity. 
For Part I (Dose-Escalation): 
Dose-Limiting Toxicities (DLTs): Participants who experience toxicities fulfilling the 
definition of a DLT during the DLT assessment period should be discontinued from study 
treatment. Nevertheless, the Investigator, after discussion with the Sponsor, will have 
the option to reduce the dose of RO7296682 to the previous tolerated dose level, if 
participant is deemed to be deriving clinical benefit. No dose modification for 
atezolizumab is allowed. 


 
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For All Parts: 
IMP-related AEs (i.e., attributed to RO7296682 in combination with atezolizumab): AEs 
attributable to IMPs must resolve to  Grade 1 or baseline for non-hematological 
toxicities and  Grade 2 for hematological toxicities before resuming treatment. 
Exceptions may be allowed after a careful potential clinical risk/benefit assessment by 
the Investigator and approval by the Medical Monitor.  
Dose reduction of RO7296682 alone may be allowed with the approval of the Medical 
Monitor. No dose modification for atezolizumab is allowed. 
AEs not attributed to IMPs: A delay of IMP administration for up to two cycles will be 
acceptable to allow for resolution of toxicity to NCI CTCAE Grade  2 for hematological 
toxicities or Grade  1 for non-hematological toxicities. If in the judgment of the 
Investigator, a participant is likely to derive clinical benefit from RO7296682 in 
combination with atezolizumab after a hold of more than 2 cycles, study drug may be re-
started with the approval of the Medical Monitor. 
Liver Function Tests: For participants with documented liver metastasis and elevated 
liver function test (LFT) results at baseline, further elevations of LFT results may not 
require dose interruptions if there are no progressive changes in the ALT and/or AST 
(less than a doubling) and if there are no progressive elevations in total bilirubin or 
international normalized ratio. 
Investigators are encouraged to contact the Sponsor for further guidance if needed. After 
Cycle 1 is completed, RO7296682 dose modifications should be discussed with the 
Sponsor. 
6.7 
TREATMENT AFTER THE END OF THE STUDY 
Currently, the Sponsor does not have any plans to provide RO7296682 or any other 
study treatments to the participants after the end of the study, or when participants 
discontinue or have been withdrawn from the study. The Sponsor will evaluate whether 
to continue providing treatment to participants after the main study is over, 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 
7. 
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 


 
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motivate participants to comply with all the study-specific procedures as outlined in this 
protocol. 
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study. 
7.1 
DISCONTINUATION OF STUDY TREATMENT 
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed see the SoA (Section 1.3). 
Reasons for discontinuation of study treatment (or withdrawal from the study) may 
include, but are not limited to, the following: 
 
Participant withdrawal of consent at any time. 
 
Any toxicity, which is not manageable with dose delays, dose decrease, and 
appropriate treatment 
 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study. 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant. 
 
Pregnancy 
 
Disease progression when there is a consensus that the participant will not benefit 
from further study treatment 
 
Immunoglobulin E (IgE)-mediated hypersensitivity reactions, including anaphylaxis. 
 
Any event that meets stopping criteria defined in Section 4.1.3. 
 
Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for a study completion/early termination visit (see Section 8.11.3) and may undergo 
follow‑up assessments (see Section 8.11.4), unless the participant withdrew consent. 
The primary reason for premature study treatment discontinuation should be 
documented on the appropriate eCRF.  
Treatment beyond Disease Progression 
 
As with other immunotherapies, treatment beyond RECIST v1.1 progression may be 
considered following discussion between the Investigator and the Sponsor. 
 
The criteria below are needed for continuing treatment beyond initial apparent 
progressive disease per RECIST v1.1 (e.g., radiological progression secondary to 
tumor inflammation): 
– 
Absence of clinical deterioration or improvement in clinical symptoms. 
– 
Investigator-assessed potential clinical benefit for the participant. 
– 
The participant is tolerating study drug. 


 
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Participant Replacement Rules 
Participants who discontinue study treatments prematurely may be replaced for the 
following reasons to ensure adequate numbers of evaluable participants: 
 
For all parts: Participants who withdraw from the study prior to the treatment start 
may be replaced. 
 
For Part I: 
– 
Participants who discontinue from the study before the end of the DLT period 
for reasons other than DLTs. 
– 
Participants who did not receive at least two doses of RO7296682 and two 
doses of atezolizumab during the DLT period, for reasons other than DLT. 
 
7.1.1 
Temporary Interruption 
Temporary study drug interruption is an acceptable method to manage AEs related to 
any of the study treatments. 
Before permanently discontinuing the study drugs (regardless of whether initiated by the 
participant, Investigator or Sponsor), an interruption should be considered. Participants 
who have temporarily interrupted study treatment should be considered to restart as 
soon as medically justified in the opinion of the Investigator and after discussion with the 
Medical Monitor. 
Temporary interruption in presence of ongoing clinical benefit: 
If a participant has achieved clinical benefit (i.e., durable disease control with stable 
disease [SD], partial response [PR], or complete response [CR]), as determined by the 
Investigator and the Sponsor after an integrated assessment of radiographic data, 
biopsy result (if available), and clinical status, study treatment may be paused at the 
discretion of the Investigator after documented agreement with the Medical Monitor. 
While the treatment is paused, assessments per SoA (Section 1.3) will be suspended, 
except for tumor assessments. The span of the treatment pause is to be included in the 
calculation of the maximum treatment period duration (24 months from C1D1 to 
discontinuation visit), as per Section 4.1.1. 
Restarting study treatment should be considered as soon as medically justified in the 
opinion of the Investigator. If during the treatment pause, signs of disease progression 
emerge, study treatment may be reintroduced after consultation with the Medical Monitor 
if the study is still open. PK and ADA samples should be collected pre-dose and at the 
end of the infusion (PK only) on the day that the treatment is reintroduced. For the 
remaining samples, the SoA will be followed according to the “Subsequent cycles” 


 
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category (Section 1.3). Additional unscheduled samples may be collected at the 
discretion of the Investigator or upon request from the Sponsor if clinically indicated. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY 
Participants have the right to withdraw voluntarily from the study at any time for any 
reason. In addition, the Investigator has the right to withdraw a participant from the study 
for medical conditions that the Investigator or Sponsor determines, may jeopardize the 
participant’s safety if he/she continues in the study. 
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn. 
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR). 
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons may be replaced as 
described in Section 7. 
For data to be collected at the time of study discontinuation and at safety and follow-up 
visits, and for any further evaluations that need to be completed, see the SoAs 
(Section 1.3). 
Participants will be treated until progressive disease, unacceptable toxicities, or 
withdrawal of consent. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 


 
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 
Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record. 
 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
 
Discontinuation of sites or of study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their time points are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for screening 
or baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the timeframe defined in the SoA. 
Exceptional measures during the COVID-19 pandemic, such as adjustments in study 
visits, may be considered if in the overall best interest of the participant. 
Adjustments may include: 
 
Use of alternative facility for assessments (e.g., local laboratory or imaging centers) 
 
Replacement of a study visit with alternative methods for assessments (such as 
phone contacts or virtual visits to assess safety) 
 
Postponement of a study visit or individual assessments 
 
A robust benefit-risk assessment should be performed by the Investigator and discussed 
with the Medical Monitor. This assessment will be fully documented and any deviations 
to the protocol will be recorded in accordance with the Sponsor’s standard procedure. 
8.1 
EFFICACY ASSESSMENTS 
8.1.1 
Tumor and Response Evaluations 
Tumor response will be evaluated according to both RECIST v1.1 (Appendix 13) and 
immune RECIST (iRECIST, Appendix 14). Tumor lesions will be assessed at screening 
and every 8 weeks ( 7 days) after first dose (i.e., C1D1) -regardless of any treatment 
delays - for the first year, and then every 12 weeks ( 7 days) thereafter until disease 
progression. The visit at which a response assessment shows progressive disease may 
be used as the discontinuation visit. For participants who discontinue treatment for any 
other reason than disease progression: an end of study CT/MRI scan is only to be 
performed if it was done  28 days prior to this day. In addition, a CT/MRI scan to be 
performed at the safety follow-up visit.  


 
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Response will be assessed by the Investigator based on physical examinations and CT 
scans (or MRI) of chest, abdomen, and pelvis as defined in the SoAs (Section 1.3). CT 
scans of the neck should be included, if clinically indicated. Ultrasound and x-rays are 
not acceptable for monitoring target lesions. All measurable disease must be 
documented at screening and re- assessed at each subsequent tumor evaluation. 
A CT or MRI scan (with IV contrast unless contraindicated) of the head must be 
performed at screening to assess CNS metastasis. An MRI scan of the brain is required 
to confirm or refute the diagnosis of CNS metastases at baseline in the event of an 
ambiguous CT scan. Patients with untreated or actively progressing CNS metastases 
are not eligible for the study (see Section 5.2). Stable brain metastases must be 
evaluated at each tumor assessment with the same radiographic procedure as the 
baseline. Patients without brain metastases do not need brain scans for tumor 
assessment unless clinically warranted.  
Consistency of consecutive CT scans (or MRIs) should be ensured during all 
assessments for each participant; the same method of assessment (preferable also by 
same evaluator) and the same technique must be used to evaluate lesions throughout 
the entire study. Use of CT (or MRI) is required for baseline lesions 20 mm and must 
be documented in medical records and used consistently throughout the study. The 
same radiographic procedure used to define measurable disease sites at screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans). 
Tumor measurements should be made by the same Investigator/radiologist for each 
participant during the study to the extent that this is feasible. At the Investigator’s 
discretion, CT scans may be repeated at any time if progressive disease is suspected.  
The data collected for RECIST v1.1 will be used by the Sponsor to programmatically 
calculate time point responses for iRECIST, a recently published set of guidelines 
developed by the RECIST working group in an effort to harmonize immune-based 
response criteria across the academic and industrial cancer immunotherapy field 
(Seymour et al. 2017). 
In the absence of clinical deterioration, any initial assessment of radiological progressive 
disease should be confirmed by a repeat evaluation at the next time point for tumor 
assessment. As with other immunotherapies, treatment beyond RECIST progression 
could be considered after approval of the Sponsor (see Section 7 for details on 
continuing treatment). 
All tumor assessments after baseline may be done within one week of the scheduled 
visit. Confirmation of objective responses (partial response [PR] and complete response 
[CR]) will be done at the next scheduled visit after at least 28 days from the initial 
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8.1.2 
Photography of Cutaneous Lesions 
Cutaneous lesions not evaluable by CT or MRI will be documented by anonymized high-
resolution, color digital photography, including a ruler to estimate lesion size. Cutaneous 
lesions may be considered target lesions if they meet RECIST v1.1 criteria (see 
Appendix 13), otherwise they may be considered non-target lesions. 
Photographs of cutaneous lesions will be taken at screening and on the same day as 
tumor assessment visit or at the first clinic visit following each tumor assessment. 
8.2 
SAFETY ASSESSMENTS 
Planned time-points for all safety assessments are provided in the SoA (Section 1.3). 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest (NSAESI); measurement of protocol-specified safety 
laboratory assessments; measurement of protocol-specified vital signs, 
electrocardiograms (ECGs); and other protocol-specified tests that are deemed critical to 
the safety evaluation of the study. 
8.2.1 
Physical Examinations 
Complete physical exam: A complete physical examination should include an 
examination of head and neck, eyes, ears, nose, and throat; cardiovascular; 
dermatology; musculoskeletal; respiratory; gastrointestinal; genitourinary and 
neurological systems. 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
Targeted (symptom-directed) physical exam: At subsequent visits (or as clinically 
indicated), targeted, symptom-directed physical examinations should be performed. 
Targeted physical examinations should be limited to systems of primary relevance (i.e., 
cardiovascular, respiratory, dermatological, neurologic, and any system that might be 
associated with tumor assessment [e.g., lymph nodes, liver, and spleen and those 
systems associated with symptoms] or potential drug-related toxicity; for details see 
RO7296682 IB and atezolizumab IB). Changes from baseline abnormalities should be 
recorded in participant notes. New or worsened clinically significant abnormalities should 
be recorded as AEs on the Adverse Event eCRF. 
8.2.2 
Height and Weight 
Height and body weight must be measured at the time points indicated in the SoA 
(Section 1.3) and recorded in eCRF. If body weight is assessed three days or less 
before the day of the planned dosing, this value should be used and recorded in the 
eCRF.  


 
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8.2.3 
Vital Signs 
Vital signs will be recorded at the time points specified in the SoA (Section 1.3).  
Vital signs will include measurements of systolic and diastolic blood pressure, respiratory 
rate, HR, and body temperature while the participant is in a sitting or semi-supine 
position.  
Blood oxygen saturation will be measured at baseline by pulse oximetry. 
For vital sign assessments on infusion days, refer to Section 6.1.1. It is not required to 
capture vital signs collected during the infusion in the eCRF unless abnormalities are 
observed. 
8.2.4 
Electrocardiograms 
Triplicate 12-lead ECG measurements will be obtained as outlined in the SoA 
(Section 1.3) using an ECG machine that automatically calculates the HR and measures 
PR interval, QRS complex, QT interval, and QT corrected for HR (QTc) interval.  
At each time point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 5 minutes 
apart. The average of the 3 readings will be used to determine ECG intervals (e.g., PR, 
QRS, and QT). Additional unscheduled ECG assessments should be performed in case 
of abnormalities and if clinical symptoms occur. ECGs for each participant should be 
obtained from the same machine whenever possible. To minimize variability, it is 
important that participants be in a resting position for at least 10 minutes prior to each 
ECG evaluation. ECGs should preferably be performed prior to any scheduled vital sign 
measurements, blood draws, and prior to dosing.  
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory. ECG characteristics, including HR, QRS 
duration, and PR, and QT intervals, will be recorded on the eCRF. Changes in T‑wave 
and U‑wave morphology and overall ECG interpretation will be documented on the 
eCRF. T-wave information will be captured as normal or abnormal, U-wave information 
will be captured in two categories: absent/normal or abnormal. 
8.2.5 
Transthoracic Echocardiogram or Multiple-Gate Acquisition 
Scans 
TTE or MUGA scans will be performed according to the time points specified in 
Section 1.3 and more frequent monitoring should be performed in case of left ventricular 
ejection fraction (LVEF) decline during treatment. This may be further repeated at the 
Investigator’s discretion if there are signs or symptoms of cardiotoxicity. TTE or MUGA 
scans will be used to monitor the cardiac parameters of function (i.e., LVEF). 


 
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8.2.6 
Chest X-ray 
A chest x-ray will be performed at baseline, if the baseline tumor assessment does not 
image the chest/thorax, and as clinically indicated during the study treatment period (see 
Section 1.3). 
8.2.7 
Clinical Safety Laboratory Assessments 
Local Laboratory Assessments 
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of local laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the SoA 
(Section 1.3). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the case report 
form (CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those, which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant's condition. 
Results of clinical laboratory testing will be recorded on the eCRF. 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety. 
Where the clinical significance of abnormal laboratory results at screening is considered 
uncertain, screening laboratory tests may be repeated before randomization to confirm 
eligibility. 
Central Laboratory Assessments 
Central laboratory assessments must be conducted in accordance with Section 1.3. 
Samples will be sent to one or several central laboratories or to the Sponsor for analysis. 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments. 
Based on continuous analysis of the data, any sample type not considered critical for 
safety may be stopped at any time if the data from the samples collected do not produce 
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8.2.8 
Medical History (including Smoking History) and Demographic 
Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, OTC 
drugs, herbal or homeopathic remedies, THC and its derivative, nutritional supplements) 
used by the participant within 30 days prior to the screening visit. 
Demographic data will include age, sex, and self-reported race/ethnicity and will be 
recorded in the eCRF.  
Smoking history will be assessed by verifying if participant is a current smoker, former 
smoker, or has never smoked before. 
8.2.9 
ECOG 
Performance status will be measured using the ECOG Performance Status (PS) Scale 
(Table 9). It is recommended, where possible, that a participant’s performance status will 
be assessed by the same person throughout the study.  
Table 9 
ECOG Status 
Grade 
ECOG Status 
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 house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
Reference: Oken et al. 1982. 
8.2.10 
Other Non-Safety Assessment(s): Real wOrld PROgnostic 
score 
The ROPRO score must be measured at the time point indicated in the SoA 
(Section 1.3) and recorded in a “ROPRO calculator“ (system to be determined). For the 
required parameters, see Table 10. Upon entry, the ROPRO value will be reported to the 
site in order to verify patient eligibility in the study. 


 
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Table 10 Real wOrld PROgnostic score 
ROPRO Assessments 
Parameters 
Demographics 
Sex, age 
Anthropometric 
measurements 
Height, weight 
Smoking 
Smoking status  
Vital signs 
Systolic blood pressure, heart rate, oxygen saturation 
Hematology 
Hemoglobin, platelets, leukocytes, lymphocytes, neutrophils, 
eosinophils, monocytes 
Clinical chemistry 
Urea or blood urea nitrogen, calcium, chloride, glucose, total 
protein, albumin, total bilirubin, ALP, ALT, AST, LDH 
Cancer status 
Number of metastatic sites*, tumor stage 
ECOG performance 
ECOG 
* Number of metastatic sites does not equal the number of total lesions but the number of 
organs, which have tumor lesion(s). For example, a participant with two liver lesions and one 
lung lesion, has two metastatic sites corresponding to two organs that have tumor lesions. 
 
8.2.11 
Optional Symptom Questionnaire for Part II Participants 
Participants in Part II of this trial will be offered an optional questionnaire to collect 
symptoms electronically. The questions have been selected on the basis of expected 
symptoms because of known or potential atezolizumab and RO7296682 adverse drug 
reactions. 
The electronic questionnaire will be self-administered at home at specified time points 
during the study (see Section 1.3). The questionnaire, translated into the local language 
as appropriate, will be completed through use of an app downloaded on the participant’s 
own electronic device. The link to download the app and instructions for completing the 
instruments electronically will be provided by the site staff. If the participant does not 
have access to a device capable of installing the app, a web link for the electronic 
completion of the questionnaire may be provided. The data will be transmitted to a 
centralized database maintained by the electronic device vendor. The data will be 
available for access by appropriate study personnel. 
Participants should be given the following instructions for completing the electronic 
questionnaire at home: 
 
Participants should complete the questionnaire in a quiet area with minimal 
distractions and disruptions. 
 
Participants should answer questions to the best of their ability; there are no right or 
wrong answers. 
 


 
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Participants should not obtain advice or help from others to select responses (e.g., 
family members or friends) when completing the questionnaire. 
Adverse event reports will not be derived from this tool by the Sponsor. In addition, the 
Sponsor will make no attempt to reconcile patient reports of treatment-related symptoms 
with Investigator reports of AEs. Though the Investigator Sites are not expected to 
review the data for AEs, they are encouraged to review and to discuss symptoms to 
keep participant engagement high. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 2. The NSAESI and disease-
related events and/or disease-related outcomes not qualifying as AEs or SAEs are 
discussed in Sections 8.3.6 and 8.3.8. 
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2. 
Procedures used for recording AEs are provided in Appendix 3. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows: 
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other AE should not be reported. 
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the safety follow-up visit, or participant discontinuation, 
whichever occurs first. DLTs will be reported during the DLT assessment window. 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period – that is, after the safety 
follow-up visit. 
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 


 
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time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation timepoints. 
8.3.3 
Follow-Up of Adverse Events and Serious Adverse Events 
8.3.3.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered related to study 
treatment or study-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5. 
8.3.3.2 
Sponsor Follow-Up 
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event 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 
event. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met. 


 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.  
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded 
to investigators as necessary.  
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB, and IEC, see Appendix 2. 
8.3.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day 7 days a week. Details will be available separately. 
8.3.5 
Pregnancy 
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 4 months after the last 
dose of RO7296682/atezolizumab. 
Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 28 days after 
the final dose of RO7296682. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs (Appendix 5). 
8.3.6 
Non-Serious Adverse Events of Special Interest 
NSAEIs 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 Appendix 2 for reporting 
instructions). 


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NSAEIs for this study include the following: 

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or
clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, defined as:
Any organism, virus, or infectious particle (e.g., prion protein transmitting
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is
considered an infectious agent. A transmission of an infectious agent may be
suspected from clinical symptoms or laboratory findings that indicate an infection in
a participant exposed to a medicinal product. This term applies only when a
contamination of the study treatment is suspected.
Atezolizumab-specific NSAESIs: 

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, CRS, hemophagocytic
lymphohistiocytosis (HLH), and macrophage activation system (MAS).

Nephritis.

Myositis.

Myopathies, including rhabdomyolysis.

Ocular toxicities (e.g., uveitis, retinitis, optic neuritis).

Grade  2 cardiac disorders.

Vasculitis.

Autoimmune hemolytic anemia.

Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous,
toxic epidermal necrolysis).

Myelitis

Facial paresis


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8.3.7 
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor) 
During the DLT/dose-limiting AE (DLAE) assessment window, AEs identified as 
DLTs/DLAEs, as defined in Section 4.1.3, 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 
Appendix 2, Section 5 for reporting instructions). 
8.3.8 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events 
Not applicable. 
8.3.9 
Management of Specific Adverse Events 
This section describes the management of specific AEs based on nonclinical toxicology 
and clinical experience of RO7296682 as well the clinical experience with molecules in 
the same class. The most common toxicity expected from RO7296682 are IRRs, 
immune-mediated AEs (imAEs) and skin toxicity. The most common toxicities from CPIs 
(i.e., atezolizumab) are IRRs and imAEs.  
This is the first-in-human evaluation of the combination of RO7296682 and 
atezolizumab, therefore, the actual risk of combined toxicity is unknown. Nonclinical 
toxicology studies have not been conducted with the combination of RO7296682 and 
atezolizumab. Based on nonclinical and/or clinical studies with each molecule as a 
single agent, as well as on molecules with similar mechanisms of action, there is a 
potential for overlapping toxicities in participants treated with RO7296682 in combination 
with atezolizumab. For further details on the identified and potential risks associated with 
RO7296682 treatment, see the Investigator’s Brochure. 
Toxicities associated or possibly associated with RO7296682 treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to determine a possible immunogenic etiology. For 
further details on the potential risks associated with RO7296682 treatment, see the 
Investigator’s Brochure. 
Measures will be taken to ensure the safety of participants in this study, including the 
use of stringent inclusion and exclusion criteria and close monitoring of participants 
during the study. Administration of RO7296682 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 as well as life-threatening conditions 
including intensive care unit. 
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 


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guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020). If a participant develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per Investigator 
judgment. If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines. 
For events in which management guidelines are not covered in this protocol, 
participants should be managed as deemed appropriate by the Investigator according to 
best medical judgment and local medical guidelines. Clinical judgment may be applied, 
and a risk/benefit consideration may suggest deviating from these guidelines. In this 
specific case, decisions on study treatments will be taken by the Investigator upon 
consultation with the Medical Monitor. 
Guidelines for management of specific AEs are provided in Table 11, Table 12,  and 
Appendix 12. 
8.3.9.1 
Management Guidelines for Skin Toxicity for RO7296682 
and/or atezolizumab 
Treatment-emergent rash may be associated with RO7296682 and/or atezolizumab. 
In study WP41188, skin-related AEs were observed in 42% of the patients treated up to 
a dose level of  mg. The majority of cases of rash were mild in severity and self-limited, 
with or without pruritus (see Investigator’s Brochure).  
Participants should be advised to implement particular care of the skin and refer to the 
study staff in case of dermatologic issues especially after biopsy. After biopsy, study 
staff should protect the skin and ensure that prevention of superinfections is applied. 
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 11. 


 
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Table 11 Management Guidelines for Skin Toxicity 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue RO7296682 and/or atezolizumab. 
 Consider treatment with topical corticosteroids and/or other symptomatic therapy 
(e.g., antihistamines). 
 Recommend taking anonymized standard clinical photography  
Dermatologic 
event, Grade 2  
 Hold RO7296682 and/or atezolizumab until resolution to Grade 1 or baseline.  
 Consider participant referral to a dermatologist. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with oral and/or higher-potency topical corticosteroids if event 
does not improve. 
 Recommend taking anonymized standard clinical photography 
Dermatologic 
event, Grade 3  
 Withhold RO7296682 and/or atezolizumab after event onset.a 
 Refer participant to a dermatologist. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, 
increasing dose to 1 to 2 mg/kg/day if event does not improve within 48 to 72 hours. 
 If event resolves to Grade 1 or better, resume RO7296682 and/or atezolizumab. 
 If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before RO7296682 and/or atezolizumab 
can be resumed.  
 If event does not resolve to Grade 1 or better while withholding RO7296682 and/or 
atezolizumab, permanently discontinue RO7296682 and/or atezolizumab and contact 
Medical Monitor.b 
 Recommend taking anonymized standard clinical photography 
Dermatologic 
event, Grade 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact Medical 
Monitor.b 
 Recommend taking anonymized standard clinical photography 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 


 
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8.3.9.2 
Management Guidelines for Infusion-Related 
Reactions/Cytokine-Release Syndrome for RO7296682 and/or 
Atezolizumab 
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, 
predominantly the first infusion. The incidence and severity typically decrease with 
subsequent infusions. 
No premedication is indicated for the administration of Cycle 1 of RO7296682 and/or 
atezolizumab. However, patients who experience an infusion-related reaction (IRR) or cytokine 
release syndrome (CRS) with RO7296682 and/or atezolizumab may receive premedication with 
antihistamines, antipyretic medications, and/or analgesics (e.g., acetaminophen) for subsequent 
infusions. Metamizole (dipyrone) is prohibited in treating RO7296682 and/or atezolizumab-
associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of mAbs and may be reported with 
RO7296682 and/or atezolizumab. These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019). CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 
with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for the medical management of IRRs and CRS are provided in Table 12. 
Severe COVID-19 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 
participant develops suspected CRS during the study, a differential diagnosis should 
include COVID-19, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 
Investigator’s judgment. If a diagnosis of COVID-19 is confirmed, the disease should be 
managed as per local or institutional guidelines. 


 
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Table 12 Management Guidelines for Infusion-Related Reactions and 
Cytokine-Release Syndrome 
Event 
Management 
Grade 1a 
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 participants with significant 
symptoms and/or comorbidities, consider managing as per Grade 2. 
 For subsequent infusions, consider administration of oral pre-medication with 
antihistamines, antipyretic medications, and/or analgesics, and monitor closely for IRRs 
and/or CRS. 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygend 
by nasal cannula 
or blow-by 
 Immediately interrupt infusion. 
 Upon symptom resolution, wait for 30 minutes and then restart infusion at half the rate 
being given at the time of event onset. 
 If symptoms recur, discontinue infusion of this dose. 
 Administer symptomatic treatment.c 
 For hypotension, administer IV fluid bolus as needed. 
 Monitor cardiopulmonary and other organ function closely (in the ICU, if appropriate).  
Administer IV fluids as clinically indicated, and manage constitutional symptoms and 
organ toxicities as per institutional practice. 
 Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms of 
HLH or MAS as described in Appendix 12. 
 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 participant (monitoring in 
the ICU is recommended), permanently discontinue RO7296682 and/or atezolizumab, 
and contact the Medical Monitor. 
 If symptoms resolve to Grade 1 or better for three consecutive days, the next dose of 
RO7296682 and/or atezolizumab may be administered. For subsequent infusions, 
consider administration of oral pre-medication with antihistamines, antipyretic 
medications, and/or analgesics and monitor closely for IRRs and/or CRS. 
 If symptoms do not resolve to Grade 1 or better for three consecutive days, contact the 
Medical Monitor. 


 
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Event 
Management 
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygend 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
 Permanently discontinue RO7296682 and/or atezolizumab 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 Appendix 12. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
 Consider anti-cytokine therapy.e 
 Hospitalize participant until complete resolution of symptoms. If no improvement within 
24 hours, manage as per Grade 4, that is, admit participant to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and vasopressors as 
needed. For participants 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 4a 
Feverb with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or  
Hypoxia requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
 Permanently discontinue RO7296682 and/or atezolizumab and contact Medical the 
Monitor.f 
 Administer symptomatic treatment.c 
 Admit participant 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 Appendix 12. 
 Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 
10 mg every 6 hours). 
 Consider anti-cytokine therapy.e For participants who are refractory to anti-cytokine 
therapy, experimental treatmentsg may be considered at the discretion of the 
Investigator and in consultation with the Medical Monitor. 
 Hospitalize participant until complete resolution of symptoms. 
 


 
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Table 12 Management Guidelines for Infusion-Related Reactions and 
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; CPI  checkpoint inhibitor; CRS  cytokine-release syndrome; CTCAE  Common 
Terminology Criteria for Adverse Events; eCRF  electronic Case Report Form; 
HLH  hemophagocytic lymphohistiocytosis; ICU  intensive care unit; IRR  infusion-related 
reaction; IV  intravenous; MAS  macrophage activation syndrome; NCCN  National Cancer 
Comprehensive Network; NCI  National Cancer Institute. 
Note: 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 for CRS. 
NCI CTCAE v 5.0 should be used when reporting severity of IRRs, CRS, or organ toxicities 
associated with CRS on the Adverse Event eCRF. Organ toxicities associated with CRS 
should not influence overall CRS grading. 
b Fever is defined as temperature  38C not attributable to any other cause. In participants who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no 
longer required when subsequently determining event severity (grade). In this case, the grade 
is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, antipyretic medications, 
analgesics, bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, 
additional treatment may be administered as per institutional practice. 
d Low flow is defined as oxygen delivered at  6 L/min, and high flow is defined as oxygen 
delivered at  6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune CPIs (Rotz et al. 2017; Adashek and Feldman 2019), but data are limited, and the role 
of such treatment in the setting of antibody-associated CRS has not been established. 
f Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the event. Participants can be re-challenged 
with RO7296682 and/or atezolizumab only after approval has been documented by the 
Investigator (or an appropriate delegate) and the Medical Monitor. For subsequent infusions, 
administer oral pre-medication with antihistamines, antipyretic medications, and/or analgesics, 
and monitor closely for IRRs and/or CRS. Pre-medication with corticosteroids and extending 
the infusion time may also be considered after consulting the Medical Monitor and considering 
the benefitrisk ratio. 
g Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
8.3.9.3 
Management Guidelines immune-mediated Adverse Events for 
RO7296682 and/or atezolizumab 
Most imAEs observed with immunomodulatory agents have been mild and self-limiting; 
however, such events should be recognized early and treated promptly to avoid potential 
major complications. Any organ or tissue can be involved, although some imAEs occur 
much more commonly than others. The most frequently occurring imAEs 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 following are general recommendations for management of any other AEs that may occur 
and are not specifically listed in the organ specific imAE toxicity management guidelines in 
Appendix 12.  


 
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 
Participants 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 AEs prior to initiating therapy and throughout treatment and survival follow-up. 
There should be a high level of suspicion that new symptoms are treatment related. 
 
Although management varies according to the organ system affected, in general, 
RO7296682 and/or atezolizumab therapy should be continued with close monitoring 
for Grade 1 toxicities, with the exception of some neurologic toxicities. Corticosteroids 
(initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent) may be administered. 
 
RO7296682 in combination with atezolizumab therapy may be suspended for most 
Grade 2 toxicities, with consideration of resuming when symptoms revert to Grade 1 
or less. Corticosteroids may be administered.  
 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a Grade 3 
event.   
 
Grade 3 toxicities generally warrant suspension of RO7296682 in combination with 
atezolizumab and the initiation of high-dose corticosteroids (prednisone, 1 to 
2 mg/kg/day, or methylprednisolone, 1 to 2 mg/kg/day). Corticosteroids should be 
tapered over the course of over 1 month to 10 mg/day oral prednisone or equivalent, 
before RO7296682 and/or atezolizumab can be resumed. If symptoms do not improve within 
48 to 72 hours of high-dose corticosteroid use, other immunosuppressants may be offered for 
some toxicities. 
 
In general, permanent discontinuation of RO7296682 in combination with 
atezolizumab is recommended with grade 4 toxicities, with the exception of 
endocrinopathies that have been controlled by hormone replacement.  
 
The Investigator should consider the benefitrisk balance for a given participant prior 
to further administration of RO7296682 in combination with atezolizumab. Resumption of 
atezolizumab may be considered in participants who are deriving benefit and have fully 
recovered from the immune-mediated event. The decision to re-challenge participants with 
RO7296682 in combination with atezolizumab 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. 
 
Please refer to the American Society of Clinical Oncology (ASCO) (Puzanov et al. 2017) 
and the European Society for Clinical Oncology (ESMO) clinical practice guidelines for 
management of imAEs (Haanen et al. 2017). 
For organ specific imAE toxicity management guidelines, refer to Appendix 12.  
 
8.4 
TREATMENT OF OVERDOSE 
Study treatment overdose is the accidental administration of a drug in a quantity that is 
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (for further details, 
see Sections 5 and 5.2 of Appendix 2). 


 
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Decisions regarding dose-interruptions or modifications (if applicable) will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant. 
In the event of an overdose, the Investigator should: 
 
Contact the Sponsor’s Medical Monitor immediately. 
 
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved. 
 
Obtain a blood sample for (unscheduled) PK analysis as soon as possible after the 
overdose, if requested by the Medical Monitor (determined on a case-by-case 
basis). 
 
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the CRF. 
 
8.5 
PHARMACOKINETICS 
Mandatory blood samples to evaluate concentrations of study treatment will be collected 
from an IV line from the arm opposite to that used for study treatment administration. 
The date and time of each sample collection will be recorded in the eCRF. RO7296682 
and atezolizumab levels will be analyzed by using validated assays. The PK 
assessments will be performed as outlined in Section 1.3.  
During the course of the study, PK sampling time points may be modified on the basis of 
emerging data to ensure the PK of RO7296682 can be adequately characterized (but 
without increasing overall blood collection volume for PK). Any changes in the timing or 
addition of time points for any planned study assessments must be documented and 
approved by the relevant study team member and then, archived in the Sponsor and site 
study files, but this will not constitute a protocol amendment. The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
Additional PK samples will be taken at the time of treatment discontinuation, if the 
participant experiences an IRR, or if the participant experiences an AE leading to dose 
reduction or delay of RO7296682 administration (see Section 1.3 and Section 6.6 Dose 
Modifications). 
Any residual material from PK samples may be used for ADA analyses and 
characterization, additional study-related exploratory biomarker profiling, identification, 
assay development purposes, and assay validation during the development of study or 
compound-related assays after the mentioned intended uses. 
The PK blood samples will be destroyed within 2 years after the date of final clinical 
study report (CSR). Details on sampling procedures, sample storage, and shipment are 
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8.6 
IMMUNOGENICITY ASSESSMENTS 
Although RO7296682 and atezolizumab are humanized antibodies, there is a risk that 
ADAs against RO7296682 or atezolizumab could develop. This could potentially reduce 
their efficacy and/or potentially result in symptomatic hypersensitivity reactions, in 
particular immune-complex reactions, or both. 
Validated screening, confirmatory, and titer assays will be employed to detect potential 
ADAs against RO7296682 and atezolizumab at multiple time points before, during, and 
after treatment. If required, ADA-positive samples will be further characterized in 
exploratory assays. 
Blood samples for ADA determination will be obtained as specified in the SoA 
(Section 1.3). The date and time of each sample will be recorded in the eCRF. 
Additional ADA samples will be drawn at the time of treatment discontinuation or at the 
safety follow-up visits and in participants who experience a Grade  2 IRR and in 
participants with clinical signs of hypersensitivity reaction, in particular immune-complex 
reactions. In any case, for each collected ADA sample, a corresponding PK sample will 
be collected at the same time point for the determination of the RO7296682 and/or 
atezolizumab concentrations. See Section 1.3 for details. 
Remaining volumes of ADA samples may be used for assay development/validation 
experiments, for compound-related exploratory analyses (e.g. PK or biomarker profiling), 
or to help develop further blood tests, after they are used for the mentioned intended 
uses. 
The ADA blood samples will be destroyed within 2 years after the date of the final CSR.  
Details on sampling procedures, sample storage and shipment are documented in the 
sample documentation. 
8.7 
PHARMACODYNAMICS AND BIOMARKERS ANALYSES 
Samples will be collected at time points specified in Section 1.3 and may be modified or 
reduced based on emerging data. The number of samples will not exceed what is 
described in the SoA. 
The PD outcome measures for this study are: 
 
Whole blood samples: Peripheral blood immune cells will be assessed with respect 
to the changes in the characteristics of lineage 
 
 activation (including but not limited to HLA-DR, 
etc.), differentiation 
 and
changes. These samples will also be used to undertake RO assessments for 
RO7296682. These samples will be taken from all participants enrolled in all parts of 
the study.  


 
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 
Serum and/or plasma samples: PD biomarkers such as cytokines, disease-
monitoring and inflammation markers (including but not limited to
 will be analyzed. Because these 
measurements are also safety measure assessments during any IRRs, they will be 
examined to all participants enrolled in all Parts of the study. In addition, PD plasma 
ctDNA changes will be assessed on samples from participants enrolled in Parts II 
and III of the study. 
 
Archival tissue: For all participants enrolled in all parts of the study, the most recent 
archival tumor material must be provided to allow for immune contexture and for 
immune-phenotyping characterization as described for the fresh biopsies below and 
for the genetic and genomic analyses described in Section 8.7.1.2. In Part II 
specifically, only participants with 
, as assessed by their most recent 
archival tissues, will be eligible for the study (see Section 5.1). Archival tumor 
material will also be used to establish the individual tumor genetic alterations 
expected to be reflected on the ctDNA. 
 
Fresh tumor biopsy: Mandatory fresh tumor biopsy samples must be obtained for all 
participants enrolled in Part II and Part III at baseline and on treatment from a safely 
accessible site and after participant’s consent (see Section 1.3). In Part II 
specifically, the samples collected at baseline will reflect the most recent immune 
phenotype (
) of the participant. Should the immune 
phenotype of the fresh biopsy be other than 
 (as evaluated by the archival 
sample), the particular participant will be assessed in a separate efficacy analysis 
population. Furthermore, in Part II and Part III the samples will be assessed for 
treatment-induced changes in immune cell numbers, lineage and activation 
characteristics, as well as changes in tumor markers such as PD-L1 and expression 
of FcγR, TCR V repertoire. (The analyses will be performed with respect to 
changes in the characteristics of lineage [
 
], activation 
 
differentiation 
 expression of FcγR, TCR 
V repertoire). 
 
Healthy skin punch biopsy: Mandatory fresh skin biopsy samples must be obtained 
at baseline and on treatment for all participants enrolled in all Parts of the study after 
participant’s consent (see Section 1.3). These samples will be assessed for 
treatment-induced changes in immune cell numbers, composition, and functional 
immune cell characteristics. The analyses will be undertaken by 
immunohistochemistry and/or genetic and genomic methods (see Section 8.7). 
 
Residual plasma/serum samples (e.g. from PK and/or PD assessments) may be used 
for retrospective and longitudinal testing of bacterial or viral infection (including SARS-
CoV-2) by serological methods. This testing may be performed for each participant. In 
addition to serving as an important safety measure, these analyses will inform as to any 
association of bacterial or viral infection and response to RO7296682 in combination 
with atezolizumab. In addition, residual blood, serum/plasma, tissue, and stool samples 
may also be used for additional (assay) validation experiments after the specified 


 
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analyses were performed. Details on sampling procedures, sample storage, and 
shipment are given in the Study Flow Chart and Laboratory Manual. 
These samples will be destroyed within 2 years after the date of final CSR unless the 
participant gives specific consent for the remainder of the sample(s) to be stored for 
optional exploratory research within the RBR (see Section 8.9). 
8.7.1 
Genetic and Genomic Analyses 
Whole blood samples for genetics will be taken at the time points mentioned in SoA 
(Section 1.3). These samples will be destroyed no later than 2 years after the date of 
final CSR, unless the participant gives specific consent for the remainder of the residual 
material to be stored for optional potential exploratory research within the RBR (see 
Section 8.9). 
The results of such specimen analysis will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for participants in the future. The specimens will also be 
made available for future biomarker research towards further understanding of 
RO7296682, treatment of related diseases and AEs. 
8.7.1.1 
Clinical Genotyping  
A mandatory clinical genotyping whole blood sample will be taken for DNA extraction 
from every participant. If the sample is missed on Day 1, it can be collected at any other 
scheduled visit. 
The DNA may be used to identify biomarkers that are predictive of response to treatment 
with RO7296682 in combination with atezolizumab, and will help to better understand 
the pathogenesis, course, and outcome of the studied cancer types. Genes associated 
with immunity, including but not limited to KIR, HLA, etc. and how these affect the PK, 
PD, efficacy, or safety of the study treatment will be explored. This may include genome 
sequencing to investigate biomarkers that might predispose the participant for 
drug-associated autoimmunity or to a positive tumor response following study treatment. 
These assessments will be performed if safety or efficacy rationales develop. The 
samples will be destroyed no later than 2 years after the date of final CSR, unless the 
participant gives specific consent for the remainder of the residual material to be stored 
for optional potential exploratory research within the RBR (see Section 8.9). Details on 
sampling procedures, sample storage, and shipment are given in the Study Flow Chart 
and Laboratory Manual.  
Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to the confidentiality standards described in Section 1.4 of Appendix 1. 


 
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8.7.1.2 
Whole Genome/Exome/Targeted DNA Analysis  
Archival tumor tissue, fresh tumor tissue sample, and blood will be provided at the visits 
specified in the SoAs (Section 1.3). These may be sent to one or more laboratories for 
DNA and/or RNA extraction for exploratory research to enable germline or somatic 
mutations via whole genome sequencing (WGS), whole exome sequencing (WES), 
next-generation sequencing (NGS), or other genomic analysis methods on genomic 
biomarkers (including, but not limited to, cancer related genes and biomarkers 
associated with common molecular pathways, or immune-related markers [e.g., TCR 
sequence/TCR Vb, ctDNA], microsatellite instability and tumor mutation burden). 
Genomics is increasingly informing researchers’ understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. 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 of important pathways, guiding the development of new targeted agents. 
Given the complexity and exploratory nature of these analyses, data and analyses will 
not be shared with Investigators or study participants unless required by law. 
Participants will not be identified by name or any other personally identifying information. 
Data arising from all biosamples, including samples for analyses of inherited DNA, will 
be subject to the confidentiality standards described in the sample documentation.  
Transcriptome Analysis  
Tissue biopsy/blood (other matrix possible) will be collected as outlined in the SoA 
(Section 1.3) for RNA extraction and subsequent gene expression profiling to enable: 
 
Identification of PD biomarkers. 
 
Identification of response predictive biomarker. 
 
Assessment of treatment response (PD). 
 
8.8 
PHARMACODYNAMICS AND BIOMARKER SAMPLES 
The samples collected during the study may also be used for research purposes to 
identify biomarkers useful for predicting and monitoring response to RO7296682 in 
combination with atezolizumab, identifying biomarkers useful for predicting and 
monitoring safety, assessing PD effects, and investigating mechanism of therapy 
resistance of RO7296682 in combination with atezolizumab. Additional markers may be 
measured in case a strong scientific rationale develops. 
Samples should be collected as specified in the SoAs (Section 1.3). 
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered critical for safety may be stopped at any time if the 
data from the samples collected do not produce useful information.  


 
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Unless otherwise specified below, samples (including blood, slides, extracts, etc.) will be 
destroyed no later than 2 years after the date of final CSR. For participants who consent 
to the RBR, leftover samples will be transferred to the RBR (Section 8.9). 
Any remaining blood and tissue samples after the specified analyses may also be used 
for additional (assay) validation experiments. Samples may be used for research to 
develop methods, assays, prognostics and/or companion diagnostics related to the drug 
target, disease process, pathways associated with disease state, and/or mechanism of 
action of the study treatment. 
8.8.1 
Mandatory Samples 
The following samples for PD and biomarker research are required and will be collected 
from all participants in all parts of the study: 
 
Whole blood will be collected and assessed with respect to the analyses described 
in Section 8.7 for list of analyses. 
 
Serum and/or plasma will be collected and assessed with respect to the analyses 
described in Section 8.7 for list of analyses. In the event of an AE temporally related 
to study drug administration, additional samples will be collected. 
 
For clinical genotyping, from every participant in the study, a baseline mandatory 
whole blood sample will be taken for DNA extraction and assessed with respect to 
the analyses described in Section 8.7 for list of analyses. If the sample is missed on 
D1, it can be collected at any other scheduled visit. 
 
Archival tumor (for list of analyses, refer to Section 8.7). FFPE archival tumor tissue is to 
be obtained from all participants, if available (if not available, slides are acceptable). In 
the case of unavailable archival sample, a fresh biopsy needs to be provided. Note, in 
Part II, archival tumor tissue from a metastatic site (and NOT primary tumor) is required 
in order to assess the participant’s eligibility; see Section 5.1. Prior to signing the main 
consent form, patients must sign the pre-screening Informed Consent Form in order 
to allow for confirmation of their tumor inflammation phenotype in the archival sample. 
Healthy skin punch biopsy (for detailed list of analyses, refer to Section 8.7). 
The following samples for PD and biomarker research are required and will be collected 
only in Part II and Part III of the study: 
 
Fresh tumor biopsy: (refer to Section 8.7 for analyses description) Samples (each 
time point consisting preferably of at least three core specimens) will be collected on 
two occasions (once at baseline and once during the study treatment period [C2D8]) 
from a safely accessible site and after participant’s consent. Collection of tumor 
biopsies will be guided by ultrasound or CT scan using a 16-gauge needle to 
provide cores of at least 20 mm in length. Bone lesion biopsies, 
bronchoscopy/trans-bronchial biopsies, and cytology fine needle aspirates are not 
acceptable. The baseline and on-treatment biopsies should preferably be taken from 


 
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the same accessible, “non-critical” tumor lesion (metastasis) to ensure 
comparability. The location of each biopsy will be documented in relation to each 
tumor lesion, as determined by imaging. If feasible, on-treatment biopsies may be 
repeated if the initial biopsy did not contain sufficient tumor material for analysis. If 
preliminary data suggest, alternative on-treatment, tumor biopsy time points may be 
considered upon joint agreement between Investigators and the Sponsor. 
 
Healthy skin punch biopsy (refer to Section 8.7 for analyses description). A punch 
biopsy will be collected at baseline and on treatment (C2D8) from healthy skin.  
 
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered critical for safety may be stopped at any time if the 
data from the samples collected does not produce useful information, or at the Sponsor’s 
request. 
The blood and tissue samples will be destroyed within 2 years after the date of final 
closure of the clinical database. Remainder of archival tumor blocks will be returned 
where possible. Other residual tissue material (slides, extracts, on-study blocks, etc.) 
and residual samples (blood, serum, plasma, DNA, RNA) will be destroyed within 2 
years after the final CSR is available unless the participant gives specific consent for the 
remainder of the sample(s) to be stored for optional exploratory research. 
8.8.1.1 
Optional Samples  
Optional tissue biopsies may be taken at any time point and at any part of the study per 
Investigator’s discretion, for example due to skin related AEs, disease progression, or 
long-lasting SD, if the participant consents to these samples being taken to aid the 
understanding of immune resistance or homeostasis mechanisms. At the discretion of 
the Investigator, obtaining a healthy tissue alongside the symptomatic/pathological site 
would be desirable in order to serve as control tissue. In the case of skin-related AEs, 
skin biopsies should be obtained from the sites of symptomatic skin as well as from an 
unaffected site of the skin serving as control tissue for histological- and immuno-
histochemical examination. 
Assessments as well as biological samples, which are not protocol-specified and are 
conducted by the Investigator in response to an AE (e.g., laboratory tests, etc.) can be 
performed at any time during the study and the results may be shared with the Sponsor 
in order to further inform about the safety profile of RO7296682.  
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. A separate signature will be required to 
document a participant’s agreement to allow any remaining samples to be used for 
exploratory research. 
Optional tumor and/or healthy tissue samples will be destroyed within 2 years after the 
date of final closure of the clinical database. 


 
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8.9 
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY 
8.9.1 
Overview of the Research Biosample Repository 
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Samples for the RBR will be collected during C1D1 from participants who give specific 
consent to participate in the optional RBR.  
Collected RBR samples will be used to achieve the following objectives: 
 
To study the association of biomarkers with efficacy or progressive disease. 
 
To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation. 
 
To increase knowledge and understanding of disease biology and drug safety. 
 
To study treatment response, including drug effects and the processes of drug 
absorption and disposition.  
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays. 
 
RBR samples will be stored and used until no longer needed or until they are depleted. 
The RBR storage period will be in accordance with the IRB/EC‑approved ICF and 
applicable laws (e.g., Health Authority requirements). 
 
8.9.2 
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 study treatment, diseases 
or drug safety: 
 
C1D1 RBR samples. 
 
Leftover plasma samples. 
 
Leftover serum samples. 
 
Leftover blood samples. 
 
Leftover tissue (fresh tumor, fresh skin, archival tumor) samples. 
 
Leftover blood samples for DNA extraction. 
 


 
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Optional Stool Samples 
Participants will be given the option of consenting to provide stool samples. Dietary 
intake is a central determinant of changes in the microbiota, which influences the 
immunological responses in the intestine and thereby affects potential AEs during 
immunotherapies. A nutritional assessment will therefore be performed at baseline to 
better correlate the profiles of the microbiota to safety-relevant immune responses.  
Upon consent, participants will be requested to provide optional stool samples at the 
following time points:  
 
At screening, any time prior to C1D1. 
 
On-treatment, every 12 weeks (14 days). 
 
Upon occurrence of colitis, as assessed and confirmed by the Investigator. 
 
Screening stool samples of participants who are not enrolled in the study will be 
destroyed.  
Additional stool samples may be requested at any time point per Investigator’s 
discretion, for example when resuming treatment post colitis. 
For sampling procedures, storage conditions, and shipment instructions, see the sample 
flowchart and additional instruction documents.  
8.9.3 
Leftover of Sample Derivatives such as DNA and RNA  
The samples collected for DNA extraction include, but is not limited to genomic analysis 
and may be sent to one or more laboratories for analysis of germline or somatic 
mutations via WGS, WES, NGS, or other genomic analysis methods. 
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. 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 of important pathways, guiding the development of new targeted agents. 
Samples may be sent to one or more laboratories for analysis for of germline or somatic 
mutations via WGS/WES, or other genomic analysis methods. Genomics is increasingly 
informing researchers’ 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 AEs. 


 
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Participants will not be identified by name or any other personally identifying information. 
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 all samples, dates of consent and sample collection should be recorded on the 
associated RBR page of the eCRF. Details on processes for collection and shipment of 
these samples can be found in separate sample documentation. 
RBR samples will be stored and used until no longer needed or until they are depleted. 
The RBR storage period will be in accordance with the IRB/EC‑approved ICF and 
applicable laws (e.g., Health Authority requirements). 
The repository samples will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1). 
8.10 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
8.11 
TIMING OF STUDY ASSESSMENTS 
8.11.1 
Screening and Pre-treatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Pre-screening ICFs and 
ICFs for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site. 
All screening and pre-treatment assessments (related to entry criteria), must be 
completed and reviewed to confirm that participants meet all eligibility criteria. The 
Investigator will maintain a screening log to record details of all participants screened 
and to confirm eligibility or record reasons for screening failure. 
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 
8.11.2 
Assessments during Treatment 
Under no circumstance will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study. 


 
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All assessments must be performed as per SoAs (Section 1.3). Assessments scheduled 
on the day of study treatment administration should be performed prior to administration 
of study treatment, unless otherwise noted in the SoAs.  
8.11.3 
Assessments at Study Completion/Early Termination Visit 
End of Treatment/Early Discontinuation: Participants who complete the treatment or 
discontinue from the study early, will be asked to return to the clinic 28 (± 7) days after 
the last dose of study drug or last data point. The visit at which a response assessment 
shows progressive disease may be used as the Early Discontinuation visit. Assessments 
should be completed as detailed in the SoA (Section 1.3). 
8.11.4 
Follow-Up Assessments 
Safety Follow-Up/End of Study: Participants who complete the treatment or discontinue 
from the study early, will be asked to return to the clinic 135 (± 30) days after the last 
dose of study drug or last data point determined for an End of Treatment Visit. 
Assessments should be completed as detailed in the SoA (Section 1.3). 
Survival Follow-Up: The sites will provide to the Sponsor (using a designated section of 
the eCRF) with an update on survival status 90 (± 7) days after the Safety Follow-Up 
visit and then every 3 months (± 2 weeks) thereafter up until 24 months post initial 
treatment (or until study closure) for each participant enrolled in the study. Patients who 
screen-failed due to the ROPRO score will also be followed up for survival.  
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3. 
8.11.5 
Assessments at Unscheduled Visits  
For activities that required to be performed in case of an unscheduled visit, refer to the 
SoA (Section 1.3). 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
There is no formal statistical model or pre-planned formal hypothesis testing in this 
study. 
9.2 
SAMPLE SIZE DETERMINATION 
Part I: 
The maximum total number of participants in the dose escalation portions of Part I will 
be approximately 60 DLT-evaluable participants on a Q3W schedule. The exact sample 
size cannot be pre-determined and depends on the number of cohorts needed to reach 


 
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a MTD and/or RP2D. However, the simulations presented in Section 3 of Appendix 11 
show simulated sample sizes in a variety of toxicity scenarios. 
Part II: 
Approximately 60 CPI-experienced participants with NSCLC, HNSCC, and MEL will be 
enrolled in Part II in order to have around 10 participants per indication and aim for at 
least 30 response-evaluable participants with an 
, which is confirmed 
in the fresh baseline biopsy. With around 10 participants per indication, there will be 
sufficient number for decision making to open Part III cohorts (Table 18). Participants 
with MEL, NSCLC and HNSCC which are not amenable to standard treatment, will be 
enrolled in Part II; however, if emerging data suggest alternative indications should be 
pursued, then participants with ovarian, esophageal, TNBC or other indications as 
deemed fit may be considered.  
Part III 
In Part III, each tumor-specific cohort for NSCLC, HNSCC, and MEL may be opened for 
approximately 20 response-evaluable participants given that any of the gating criteria 
defined in Section 9.5 are met based on the corresponding indication in single agent 
dose expansion of WP41188, Part I of this study, or Part II of this study. The futility 
interim analysis will be performed when the first 10 response-evaluable participants have 
mature data in each tumor-specific cohort. The detail of the futility analysis is provided in 
Section 9.5. 
For the CPI-experienced HNSCC cohort in Part III, the sample size of 20 response-
evaluable participants allows to declare futility with a probability of 92% under the 
assumption that the true ORR is 5%, based on the posterior probability for ORR to be 
below 20% with a 70% confidence level.  
For CPI-experienced NSCLC cohort in Part III, the sample size of 20 response-evaluable 
participants allows to declare futility with a probability of 87% chances under the 
assumption that the true ORR is 10%, based on the posterior probability for ORR to be 
below 25% with a 70% confidence level.  
For CPI-experienced MEL cohort in Part III, the sample size of 20 response-evaluable 
participants allows to declare futility with a probability of 83% under the assumption that 
the true ORR is 15%, based on the posterior probability for ORR to be below 30% with a 
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9.3 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined in Table 13. 
Table 13 Analysis Populations 
Analysis 
Population 
Description 
Efficacy 
All participants who received at least one dose of RO7296682 in combination with 
atezolizumab, and who have at least one baseline and one on-study tumor 
assessment. Participants who received at least one dose of 
RO7296682/atezolizumab and discontinued the study because of progression 
before the first on-study tumor assessment will be considered response-
evaluable.  
DLT evaluable 
DLT evaluable participants are those who have completed the DLT period with 
two administrations of RO7296682/atezolizumab without DLT, or participants 
reported with a DLT. This population will be used in the determination of the MTD 
and/or RP2D.  
Safety 
All participants who received at least one dose of study treatment, whether 
prematurely withdrawn from the study or not, will be included in the safety 
analysis.  
Pharmacokinetic 
All participants who have received at least one dose of study treatment and who 
have data from at least one post-dose sample will be included in the PK analysis 
population. Participants will be excluded from the PK analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete which may influence the PK 
analysis. Excluded cases will be documented together with the reason for 
exclusion. All decisions on exclusions from the analysis will be made prior to 
database closure. 
Immunogenicity 
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any treatment. 
Excluded cases will be documented together with the reason for exclusion.  
Pharmacodynamic All participants who had at least one pre-dose and one post-dose PD assessment 
will be included and analyzed according to the treatment they actually received. 
 
9.4 
STATISTICAL ANALYSES 
The data will be analyzed by the Sponsor and/or designated contract research 
organization. Any data analysis carried out independently by the Investigator should be 
submitted to the Sponsor before publication or presentation. The data will be 
summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and PK and 
biomarker measurements. The baseline value of any variable will be defined as the last 
available value prior to the first administration of study drug. 
9.4.1 
Demographics and Baseline Characteristics 
Demography and baseline characteristics (including age, sex, participant disposition, 
previous therapies, and medical history) will be analyzed using descriptive statistics. The 


 
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analysis will be based on the safety analysis population. Data will be summarized by 
dose cohort within each part. 
This is a non-randomized dose escalation and dose expansion study; therefore, 
comparability of treatment groups does not apply. 
9.4.2 
Efficacy Analyses 
The primary and secondary efficacy analyses listed in Table 14 will include all 
participants in the efficacy population with participants grouped according to dose cohort 
(and schedule if applicable) within each study part. 
Table 14 Efficacy Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
According to RECIST Version 1.1 
criteria (Appendix 13) and iRECIST 
(Appendix 14) 
 
Objective response rate 
(ORR) 
 
Disease control rate (DCR) 
 
Duration of response (DoR) 
 
On treatment progression 
free survival (PFS)  
No formal statistical model and no formal hypothesis testing are 
planned in this study. Tumor response data will be reported 
using descriptive statistics. Response data will be listed. 
Participants with missing or no response assessments will be 
classified as not evaluable unless there is documented clinical 
deterioration, in which case participant will be classified as non-
responders. Reasons for the non-evaluability will be 
summarized (e.g., withdrawal of consent, study discontinuation 
because of AE or physician decision). ORR and DCR will be 
summarized by using relative frequencies and 90% confidence 
interval (CI). Duration of response and PFS (on-treatment) will 
be summarized by using time-to-event analyses and Kaplan-
Meier curves. 
 
Overall Survival (OS) (if 
available) 
OS data may be tabulated and summarized using time-to-event 
analyses and Kaplan-Meier curves if data are collected and 
mature.  
Summaries will be carried out by cohort (and schedule if 
applicable) separately for each part.  
 
Objective response rate (ORR) is determined as the rate of participants with an overall 
response of CR or PR. DCR is determined as the rate of participants with an overall 
response of either CR, PR, or SD rate. ORR and DCR will be derived for RECIST v1.1 
and will be based on Investigators’ assessment. Objective response (OR) is defined as a 
CR or PR as determined by the Investigator. For this protocol, confirmation of response 
is required at least 4 weeks after a first response occurred. To classify a response as 
SD, measurements will have to be classified as stable (according to RECIST v1.1) at 
least once after study entry at a minimum of 6 weeks after study entry. Participants with 
missing or no response assessments will be classified as not evaluable unless there is 
documented clinical deterioration, in which case participants will be classified as non-
responders. 
DoR will be calculated for participants who have a best overall response of CR or PR 
and defined as the time from first occurrence of a documented OR until the time of 


 
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documented disease progression or death (death within 30 days from last study 
treatment) from any cause, whichever occurs first. Censoring methods will be the same 
as the one applied for progression-free survival (PFS; on-treatment).  
PFS on treatment will be defined as the time from study treatment initiation (C1D1) to 
the first occurrence of documented disease progression (based on RECIST v1.1 
Investigator’s assessment) or death from any cause, whichever occurs first. For 
participants who do not have documented progressive disease or death (within 30 days 
from last study treatment) during the study, PFS will be censored at the day of the last 
tumor assessment. Participants without any post baseline assessments or with all post-
baseline assessments having unknown result/response but known to be alive at the 
clinical cut off for the analysis will be censored at the date of study treatment initiation 
plus one day. 
Sensitivity analyses of response endpoints (ORR, DCR, DoR, and PFS) may include the 
evaluation of response according to iRECIST and the evaluation of response from an 
independent centralized review.  
OS is defined as the time from the first dose of study treatment to the time of death from 
any cause. Participants who are still alive at the time of analysis will be censored at the 
time of their last study assessment (for active participants) or at the last date known alive 
(for participants in follow-up). 
9.4.3 
Safety Analyses 
Unless otherwise specified, all safety analyses listed in Table 15 will be based on the 
safety population. All safety parameters will be analyzed using descriptive statistics, 
summarized and presented in tables. Data will be summarized by dose and regimen (if 
applicable) within each part.  


 
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Table 15 Safety Statistical Analysis Methods 
Endpoint 
Statistical Analysis Methods 
Adverse events 
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor. 
Adverse events will be summarized by mapped term and appropriate thesaurus 
level. The severity of AEs will be graded according to the NCI CTCAE v5.0. 
Toxicity grade, seriousness, and relationship to study treatment will be 
presented, as well as summaries of deaths, AEs leading to death and premature 
withdrawal from study treatment. A glossary of AEs, medication(s), and 
procedures will be provided. 
Clinical laboratory 
tests 
All clinical laboratory data will be stored in the database in the units in which they 
were reported. Laboratory test values will be presented in International System 
of Units (SI units; Système International d’Unités) by individual listings with 
flagging of abnormal results. 
Vital signs 
Vital signs data will be presented by individual listings with flagging of values 
outside the normal ranges and flagging of abnormalities. In addition, tabular 
summaries will be used, as appropriate. 
ECG data analysis ECG data will be presented by individual listings. In addition, tabular summaries 
will be used, as appropriate. 
Concomitant 
medications 
The original terms recorded on the participant’s eCRF by the Investigator for 
concomitant medications will be standardized by the Sponsor by utilizing a 
mapped term and appropriate drug dictionary level. 
Concomitant medications will be presented in summary tables and listings. 
Nature and 
frequency of DLTs 
DLT events will be presented by individual listings. The MTD will be estimated 
with an mCRM-EWOC using DLT evaluable participants. The MTD estimate will 
be presented along with 90% Credible Intervals.  
 
9.4.4 
Pharmacokinetic Analyses 
Regular PK sampling will be performed in this study to properly characterize the PK of 
RO7296682 and atezolizumab. 
When appropriate, PK parameters will be derived from the serum concentrations of 
RO7296682 using standard non-compartmental methods.  
Individual and mean serum RO7296682 and atezolizumab concentration versus time 
data will be tabulated and plotted by dose levels and/or group, where appropriate. All PK 
parameters will be presented by listings and descriptive summary statistics separately by 
dose levels and/or dosing regimens. 
Parameters may include, for example, area under the curve (AUC), clearance (CL), and 
volume of distribution under steady-state conditions, as appropriate. These parameters 
will be tabulated and summarized (mean, standard deviation, coefficient of variation, 
median, minimum, and maximum). Inter-participant variability and drug accumulation will 
be evaluated. 


 
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For RO7296682, non-linear mixed effect modeling will be used to analyze the 
concentration-time data. Population and individual PK parameters may be estimated, 
and the influence of various covariates (such as age, gender, and body weight) on these 
parameters may be investigated in an exploratory way. Secondary PK parameters (such 
as Cmax and AUC) may be derived from the model for each participant included in the PK 
analysis and will be presented descriptively.  
For atezolizumab, a previously developed population PK model for atezolizumab will be 
used to provide individual parameter estimates using Bayesian feedback methodology. 
Alternatively, PK data may be compared with available historical data. 
Additionally, exploratory analyses on exposure and safety/efficacy relationship may be 
conducted if deemed necessary. The details of the modeling and exploratory analyses 
will be reported in a document separate from the CSR. 
9.4.5 
Immunogenicity Analyses 
Antibodies against RO7296682 and atezolizumab will be evaluated in serum samples 
collected from all participants using appropriate assays. Listings and/or summaries will 
be prepared. Additional analyses may be conducted as appropriate. 
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any treatment 
(Shankar et al. 2014). 
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence during both the treatment and follow-up periods) will be summarized 
by dose levels and/or cohorts as appropriate. 
 
Participants are considered to be ADA positive if they are ADA negative or missing 
data at baseline and develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and the 
titer of one or more post-baseline samples is greater than the titer of the baseline 
sample by a scientifically reasonable margin such as at least 4-fold (treatment-
enhanced ADA response).Treatment-induced ADA response can be further 
categorized in persistent (post-treatment ADA-positive samples over 16 weeks or 
more or the last ADA time point is positive) and transient (only one ADA-positive 
sample or the time between the first and last ADA-positive sample is less than 16 
weeks and the last ADA sample is negative). 
 
Participants are considered to be ADA negative if they are ADA negative or missing 
data at baseline and all post-baseline samples are negative, or if they are ADA 
positive at baseline but do not have any post-baseline samples with a titer that is 
greater than the titer of the baseline sample by a scientifically reasonable margin 
such as at least 4-fold (treatment unaffected). 
 


 
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The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 
9.4.6 
Pharmacodynamic Analyses 
All PD parameters will be presented by listings and descriptive summary statistics 
separately by group or cohorts. Change and percentage of change from baseline will be 
described and evaluated as evidence of response to treatment. 
Part II will evaluate PD effects and preliminary anti-tumor activity of the MTD and/or 
RP2D of RO7296682 in combination with atezolizumab determined in Part I. To assess 
the effect of RO7296682 in combination with atezolizumab on the Treg population in 
blood and tumor tissue, the secondary endpoint is reached if changes of Treg levels in 
blood and tumor tissues, at a dose at which a 
as compared to 
baseline is observed in 50% or the participants or changes in the ratio of CD8+ T cells to 
Tregs in blood and/tumor tissue as compared to baseline, at a dose at which a
 is observed in 50% of the participants. 
9.4.7 
Other Analyses 
Graphical or exploratory analysis will be performed to assess the possible relationship 
between exposure to RO7296682 in combination with atezolizumab and selected 
biomarkers, efficacy, or safety parameters, as appropriate. 
9.5 
INTERIM ANALYSES 
Three different gating criteria are defined, each of which can ungate a tumor-specific 
cohort in Part III (see Section 1.2 for study design). Part III can start when clinical activity 
is seen already in the ongoing single agent dose expansion study WP41188 (but after 
Part I completed), after Part I, or based on Part II. For Part III (dose expansions), the 
pre-planned futility interim analyses will be performed by an IMC (see Section 3.3 of 
Appendix 1). 
Gate based on WP41188 Dose Expansion (RO7296682 single-agent) study 
In order to open tumor-specific cohort(s) in Part III (based on the corresponding 
participants from single agent dose expansion cohort of RO7296682 from WP41188), 
the gating criteria are defined based on the posterior probability for ORR to be greater 
than 15% with a 50% confidence level. See gating criteria in Table 16. Per indication at 
least 2 responders out of a maximum of 16 evaluable tumor-specific participants (or at 
least 3 responders out of maximum 23 etc.) are needed in the Phase I, single agent 
expansion cohort (from study WP41188) to open the respective Part III cohort, provided 
that the MTD/RP2D of RO7296682 in combination with atezolizumab has been 
determined in Part I. As long as there are at least 2 responders, there is no need to wait 
until there are 16 response-evaluable participants. 


 
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Table 16 Gating Criteria I to Open Part III Tumor-specific Cohort per 
Indication 
Number of required CR/PR in 
the WP41188 expansion  
2 
3 
4 
5 
6 
7 
8 
Number of evaluable tumor-
specific participants 
10-16 
17-23 
24-29 
30-36 
37-43 
44-49 
50 
 
Gate based on BP42595 Dose Expansion Part I (Dose Escalation of RO7296682/ 
atezolizumab) 
In order to open a tumor-specific cohort(s) in Part III (based on the corresponding 
participants from the dose-escalation Part I of this study), the additional gating criteria 
are defined based on the posterior probability for ORR to be greater than 20% with a 
50% confidence level. See gating criteria in Table 17. Per indication, at least 2 
responders out of a maximum of 12 evaluable tumor-specific participants (or at least 3 
responders out of maximum 17 etc.) are needed in the Part II to open the respective Part 
III cohort.  
Table 17 Gating Criteria II to Open Part III Tumor-specific Cohort per 
Indication 
Number of required CR/PR 
in BP42595 Part I 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of evaluable tumor-
specific participants 
8-12 
13-17 
18-22 
23-27 28-32 33-37 38-42 43-47 48-50 
 
Gate based on BP42595 Dose Expansion Part II (
, CPI-experienced 
participants treated with RO7296682/atezolizumab) 
In Part II, efficacy will be evaluated in several interim analyses in each indication. The 
interim analyses will take place to open tumor-specific cohorts in Part III when 
5 to 8 evaluable participants have a mature assessment of response in each indication. 
Additional interim analyses may be needed if the gating criteria based on 5 to 8 
evaluable participants are not met and additional participants with a mature assessment 
of response are included. The exact number of participants per indication in Part II is not 
pre-defined. The detailed gating criteria to open tumor-specific cohort in Part III per 
indication are defined based on the posterior probability for ORR to be greater than 20% 
with a 70% confidence level (see gating criteria in Table 18). Per indication, at least 
2 responders out of maximum 8 evaluable tumor-specific participants (or at least 
3 responders out of maximum 12 etc.) are needed in the Part II to un-gate the respective 
Part III cohort.  


 
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Table 18 Gating Criteria III to Open Part III Tumor-specific Cohort per 
Indication 
Number of required CR/PR 
in BP42595 Part II 
2 
3 
4 
5 
6 
7 
8 
9 
Number of evaluable tumor-
specific participants 
5-8 
9-12 
13-17 
18-21 
22-26 
27-30 
31-35 
36-40 
 
Part III Interim Analyses 
In Part III, efficacy will be evaluated in one interim analysis in each opened cohort. This 
futility interim analysis will be assessed after the first 10 response-evaluable participants 
have mature data in each cohort.  
 
For the HNSCC cohort, interim futility will be concluded if less than 1 out of 
10 response-evaluable participants have CR or PR based on the posterior 
probability for ORR to be below 20% with a 90% confidence level or final futility will 
be concluded if less than 3 out of 20 response-evaluable participants have CR or 
PR based on the posterior probability for ORR to be below 20% with a 70% 
confidence level.  
 
For the NSCLC cohort, interim futility will be concluded if less than 1 out of 10 
response-evaluable participants have CR or PR based on the posterior probability 
for ORR to be below 20% with a 90% confidence level or final futility will be 
concluded if less than 4 out of 20 response-evaluable participants have CR or PR 
based on the posterior probability for ORR to be below 25% with a 70% confidence 
level.  
 
For the MEL cohort, interim futility will be concluded if less than 1 out of 10 
response-evaluable participants have CR or PR based on the posterior probability 
for ORR to be below 20% with a 90% confidence level or interim futility will be 
concluded if less than 5 out of 20 response-evaluable participants have CR or PR 
based on the posterior probability for ORR to be below 30% with a 70% confidence 
level.  
 
Recruitment may not be interrupted while waiting for data maturity. These futility rules 
are not binding and may be overruled if other endpoints (e.g., DCR rate, DoR, PFS, or 
OS) show significant improvement over the expected benefit in the population. At any 
time during the study, parts, cohorts, and arms may be closed based on emerging data 
external to the study or operational reasons. 
9.6 
SUMMARIES OF CONDUCT OF STUDY 
All protocol deviations will be listed. 


 
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10. 
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Buettner MJ, Shah SR, Saeui CT, et al. Improving immunotherapy through glycodesign. 
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Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand interacts specifically 
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Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response 
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Haanen JBAG, Carbonnel F, Robert C, et al. Management of Toxicities from 
Immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
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Investigator’s Brochure for atezolizumab. 


 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
This Section includes the following appendices: 
 
Appendix 1: Regulatory, ethical, and study oversight considerations 
 
Appendix 2: Adverse event definitions, follow-up and reporting 
 
Appendix 3: Procedures for recording adverse events  
 
Appendix 4: Clinical laboratory test 
 
Appendix 5: Contraceptive guidance and collection of pregnancy information 
 
Appendix 6: Study details for Part III, NSCLC (Cohort A) 
 
Appendix 7: Study details for Part III, HNSCC (Cohort B) 
 
Appendix 8: Study details for Part III, MEL (Cohort C) 
 
Appendix 9: Study details for Part III, additional tumor-specific cohort(s) 
 
Appendix 10: Details on Real wOrld PROgnostic score 
 
Appendix 11: Statistics for combination therapy dose-escalation 
 
Appendix 12: Management guidelines for imAEs 
 
Appendix 13: New response evaluation criteria in solid tumors, version 1.1 
 
Appendix 14: Modified RECIST v1.1 for immune-based therapeutics (iRECIST) 
 
Appendix 15: Cockcroft-Gault formula/creatinine clearance  
 
 


 
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Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations 
1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
1.1. 
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 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 EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
1.2. 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the ICFs, any information to be given to the participant (e.g. 
advertisements, diaries etc.), 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 participant 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 
(Section 2.3.1 of this Appendix). 
The Investigator should follow the requirements for reporting all AEs to the Sponsor. 
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. 
1.3. 
INFORMED CONSENT 
The Sponsor’s Master ICF (and ancillary sample ICFs such as a Child’s Assent or 
Caregiver's ICF, if applicable) will be provided to each site. If applicable, it will be 
provided in a certified translation of the local language. Participants must be informed 
that their participation is voluntary. Participants or their legally authorized representative 
will be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 


 
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center. The Sponsor or its designee must review and approve any proposed deviations 
from the Sponsor's sample ICFs 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. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative. 
The ICFs must be signed and dated by the participant or the participant’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each participant shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study. 
The ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant to 
take part. The final revised IRB/EC-approved ICFs must be provided to the Sponsor for 
Health Authority submission purposes if required as per local regulations. 
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant or a legally authorized representative may be 
re-consented by signing the most current version of the ICFs or the addendum, in 
accordance with applicable laws and IRB/EC policy. For any updated or revised ICFs, 
the case history or clinical records for each participant shall document the informed 
consent process and that written informed consent was obtained using the 
updated/revised ICFs for continued participation in the study. The study team will 
provide guidance for which participants need to re-consent in the event of an update to 
the ICF. 
A copy of each signed ICF must be provided to the participant or the participant’s legally 
authorized representative. All signed and dated ICFs must remain in each participant’s 
study file or in the site file and must be available for verification by study monitors at any 
time. 
Participants who are re-screened are required to sign a new ICF. 
Consent to Participate in the Research Biosample Repository 
The ICF will contain a separate section that addresses participation in the RBR. The 
Investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of participation in the RBR. Participants will be told that 
they are free to refuse to participate and may withdraw their samples at any time and for 
any reason during the storage period. A separate, specific signature will be required to 
document a participant’s agreement to provide optional RBR samples. Participants who 
decline to participate will not provide a separate signature. 


 
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The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF. 
In the event of death or loss of competence of a participant who is participating in the 
research, the participant's samples and data will continue to be used as part of the RBR. 
For sites in the United States, each ICF may also include participant authorization to 
allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for participant 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. 
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 ICF 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 will not be applicable at that site 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
BP42595 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP42595. Data already generated before time of withdrawal of consent to RBR will still 
be used. 
1.4. 
CONFIDENTIALITY 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  


 
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Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes. 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
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. 
Confidentiality for Research Biosample Repository 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate. 
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant, unless 
permitted or required by law. 
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication. 
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 


 
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Monitoring and Oversight Research Biosample Repository 
Samples collected for the RBR 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 ICF. 
The Sponsor’s monitors and auditors will have direct access to appropriate parts of 
records relating to participant participation in 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 samples. 
1.5. 
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 one year after completion of the study (i.e., LPLV). 
2. 
DATA HANDLING AND RECORD 
2.1. 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
2.1.1. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
2.1.2. 
Clinical Outcome Assessment Data 
Not applicable. 


 
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2.1.3. 
Source Data Records 
Source documents (paper or electronic) are those in which participant 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, COAs (paper or eCOA), 
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, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical study. 
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
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 below. 
To facilitate source data verification, 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 investigational site must also allow 
inspection by applicable Health Authorities. 
2.1.4. 
Use of Computerized Systems 
When clinical observations are entered directly into an investigational 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. 
2.1.5. 
 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on participant 
management. 
2.2. 
RETENTION OF RECORDS 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 


 
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local health authorities, whichever is longer. After that period, the documents may be 
destroyed, subject to local regulations. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
The Sponsor 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. 
2.3. 
STUDY RECORDS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval.  
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study. 
2.3.1. 
Protocol Amendments 
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
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 participants or any non-substantial changes, as 
defined by regulatory requirements. 
2.3.2. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. 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. 
The Sponsor will comply with the requirements for publication of study results. 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. 
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. 


 
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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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. 
2.3.3. 
Dissemination of Clinical Study Data 
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 (for more details, see Section 2.3.5), 
and redacted clinical study reports and other summary reports will be made available 
upon request, provided the requirements of Roche's global policy on data sharing have 
been met.  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following web site:  
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf  
The results of this study may be published or presented at scientific congresses. 
2.3.4. 
 
Management of Study Quality 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks. Details regarding the applied approach for the study will be provided in the 
integrated Risk Based Quality Management Plan. 
2.3.5. 
Site Inspections 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ 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. 
3. 
ADMINISTRATIVE STRUCTURE 
No formal Independent Review Committee, Steering Committee, Data Monitoring 
Committee or Data Safety Monitoring Board are planned for this study at this moment. 
For Part I, Dose-Escalation, as indicated in Protocol Section 4.1.4 “Communication 
Strategy,” the Sponsor will organize a Safety and Dose Escalation Committee (SDEC) 


 
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with the Investigators to discuss the safety and tolerability of RO7296682 in combination 
with atezolizumab and to discuss the dose(s) for the next cohort.  
For Part II: ongoing medical data review will be performed by the Sponsor together with 
the investigators. 
For Part III (Dose Expansions) ongoing medical data review will be performed by an 
Internal Monitoring Committee (IMC). Please see Section 3.3 of this appendix. 
In addition to these communications, the Sponsor and investigators will be in regular 
contact throughout the study by email/telephone/fax, as per normal interactions during 
the conduct of a clinical study, and the Sponsor will arrange regular teleconferences and 
meetings to discuss study status. 
3.1. 
INDEPENDENT REVIEW COMMITTEE (IRC) 
Not applicable, see Section 3.3 of this appendix. 
3.2. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
Not applicable, see Section 3.3 of this appendix. 
3.3. 
INTERNAL MONITORING COMMITTEE (IMC) 
In Part III of this study, an IMC will be used to review accumulating clinical data in order 
to assess subject risk and benefit on an ongoing basis. The IMC activities included, but 
are not limited to, data monitoring at pre-planned interim analyses for safety, efficacy 
and/or futility. At a minimum, the IMC consists of a Statistician, Safety Scientist, Clinical 
Scientist and Clinical Pharmacologist. If required, additional functional representatives 
may be members of an IMC. The IMC will review all accumulating clinical data at regular 
intervals, as defined in the IMC charter.  
At the time of each review, the IMC may recommend that the trial continues as planned, 
the trial stops, additional analyses need to be performed, enrollment be held pending 
further safety evaluations and opening or closing of expansion cohort(s). The IMC may 
also recommend a protocol amendment.  
4. 
STUDY AND SITE CLOSURE 
The Sponsor (or designee) has the right to close the study site or 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 participants. 
 
Participant enrollment is unsatisfactory. 
 


 
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The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
 
Inadequate recruitment of participants by the Investigator. 
 
Discontinuation of further study treatment development. 
 


 
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Appendix 2  
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting 
1. 
DEFINITION OF ADVERSE EVENTS 
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An adverse event can therefore be: 
 
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. 
 
Events Meeting the AE Definition: 
 
Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 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 (see Appendix 3, Section 4). 
 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
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). 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 


 
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Events NOT Meeting the AE Definition: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
2. 
DEFINITION OF SERIOUS ADVERSE EVENTS 
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that at any 
dose: 
 
Results in death.Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(see Appendix 3). 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 


 
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 
Results in persistent or significant disability/incapacity. 
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 
Is a congenital anomaly/birth defect. 
 
Other significant events: 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
3. 
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
The Investigator will then record all relevant AE/SAE information in the CRF. 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF. 
There may be instances when copies of medical records for certain cases are requested 
by Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to 
Sponsor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 


 
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3.1. 
ASSESSMENT OF SEVERITY 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); 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. 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 2 
Adverse Event Severity Grading Scale 
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 livinga 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily 
livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to adverse eventd 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Ref
erence_8.5x11.pdf 
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 
one's self, 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 6 of this Appendix for reporting instructions), per the definition of serious 
adverse event in Section 2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for reporting 
instructions), per the definition of serious adverse event in Section 2. Grade 4 laboratory 
abnormalities would only be reported as SAEs if these meets one or more of the conditions 
outlined in Section 2 (Definition of Serious Adverse Events) of Appendix 2. 
 


 
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3.2. 
ASSESSMENT OF CAUSALITY 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration: 
 
Temporal relationship of event onset to the initiation of study treatment. 
 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment. 
 
Known association of the event with the study treatment or with similar treatments. 
 
Known association of the event with the disease under study. 
 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event. 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
4. 
FOLLOW-UP OF AES AND SAES 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Medical Monitor with a copy of any post-mortem 
findings including histopathology.  
New or updated information will be recorded in the originally completed eCRF. 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
5. 
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 


 
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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. 
 
NSAESI. 
 
Pregnancies (see Section 8.3.5). 
 
DLTs during the DLT assessment window (see Section 4.1.3; see the eCRF 
completion guideline for further guidance). 
 
The Investigator must report new significant follow-up information for these events 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. 
5.1 
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS, NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST AND DOSE-LIMITING TOXICITIES 
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 Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event). 
Events that Occur after Study Treatment Initiation 
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department. 


 
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In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event). 
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system. 
Reporting of Post-Study Adverse Events and Serious Adverse Events 
After the end of the adverse event reporting period (see Section 8.3.1), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival Follow-
Up eCRF.  
In addition, if the Investigator becomes aware of a SAE that is believed to be related to 
prior study treatment, the event should be reported directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the SAE Reporting Form using 
the fax number or email address provided to investigators. 
5.2 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR 
Accidental overdose and medication error (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. 
 
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. 
 
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, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). For RO7296682 and 
atezolizumab, AEs 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. 
 
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.  
 


 
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In addition, all special situations associated with RO7296682 and atezolizumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF and should be recorded as described below: 
 
Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes. 
 
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. 
 
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages. 
6. 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and NSAESI 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: 
Drug 
Document 
RO7296682  
RO7296682 Investigator's Brochure  
Atezolizumab 
Atezolizumab 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. 


 
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Appendix 3  
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 AE term should be recorded in the event field on the Adverse Event eCRF. 
1. 
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
1.1. 
INFUSION-RELATED REACTIONS 
AEs that occur during or after study drug administration and are judged to be related to 
study treatment infusion should be captured as a diagnosis (e.g., “infusion-related 
reaction” and "anaphylactic reaction") on the Adverse Event eCRF. If possible, avoid 
ambiguous terms such as “systemic reaction”. Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF. If a participant 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF. 
1.2. 
OTHER ADVERSE EVENTS 
For AEs other than infusion-related reactions (see Section 1.1), 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. 
2. 
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS 
In general, AEs occurring 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. However, medically significant adverse events occurring 
secondary to an initiating event that are separated in time should be recorded as 
independent events on the Adverse Event eCRF. For example: 


 
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 
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 subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
3. 
PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time-points. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens. If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent AE is one that resolves between participant evaluation time-points and 
subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
4. 
ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
 
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. 
 
Clinically significant in the Investigator’s judgment. 
 
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., alkaline phosphatase and bilirubin 5  the upper limit of normal [ULN] associated 
with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded on the 
Adverse Event eCRF. 


 
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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 if 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.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5. 
ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
 
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. 
 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
6. 
ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST in combination with either an elevated total 
bilirubin or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of potential severe liver injury. 


 
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Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
 
Treatment-emergent ALT or AST  5  ULN value in combination with total 
bilirubin  2  ULN (of which 35% is direct bilirubin). 
 
Treatment-emergent ALT or AST  5  ULN 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 Appendix 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 a non-serious adverse event of special 
interest (see Section 8.3.6). 
7. 
DEATHS 
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5 of Appendix 2) that are 
attributed by the Investigator solely to progression of cancer should be recorded only on 
the Death Attributed to Progressive Disease eCRF. All other on-study deaths, regardless 
of relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5 of Appendix 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"). 
8. 
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”). 


 
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9. 
LACK OF EFFICACY OR WORSENING OF TUMOR 
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 criteria. In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration. However, every effort should be 
made to document progression using objective criteria. If there is any uncertainty as to 
whether an event is due to progressive disease, it should be reported as an adverse 
event. 
10. 
HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a serious adverse event (per the definition of serious adverse event in 
Appendix 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 insertion of access device for study treatment administration). 
 
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 participant has not suffered 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 AE instead: 
– 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 


 
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Appendix 4  
Clinical Laboratory Tests 
The tests detailed in Table 1 will be performed by the local laboratory and the results 
must be captured in source documentation and entered into the eCRF. If local laboratory 
assessments (except for pregnancy test, which must be performed prior to each 
treatment day with results available prior to dosing) are performed  3 days before the 
day of the planned dosing, these values can be used and recorded in the eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 1 
 Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
 
Leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). 
Clinical chemistry 
 
Sodium, potassium, chloride, bicarbonate, glucose, urea or 
blood urea nitrogen, creatinine, creatinine clearance (required 
at screening only, determined by Cockcroft-Gault formula, see 
Appendix 15), total protein, albumin, magnesium, phosphate, 
calcium, bilirubin (total and direct), alkaline phosphatase, ALT, 
AST, GGT, urate, LDH, CRP, ferritin. 
Coagulation 
 
INR or PT, aPTT. 
Viral serology 
 
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis B surface antigen (HBsAg), total hepatitis 
B core antibody (HBcAb), hepatitis C virus (HCV) antibody. 
For participants with positive HCV antibody perform HCV 
RNA test. 
Lipids 
 
Cholesterol, LDL cholesterol, high-density lipoproteins (HDL) 
cholesterol, triglycerides. 
Thyroid hormones 
 
TSH, free T3 (or total T3 for sites where free T3 is not 
performed), free T4. 
Pregnancy test 
 
All women of childbearing potential (including those who have 
had a tubal occlusion/ ligation) will have a blood pregnancy 
test at screening within 7 days before the first dose of study 
treatment on C1D1. Urine or serum pregnancy test performed 
prior to each treatment, with result available prior to dosing. If 
a urine pregnancy test is positive, it must be confirmed by a 
blood pregnancy test. 
 
Serum human chorionic gonadotropin (hCG) pregnancy test 
(as needed for women of childbearing potential). 


 
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Laboratory Assessments 
Parameters 
Urinalysis 
 
Specific gravity. 
 
Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase. 
 
If there is a clinically significant hematuria (confirmed by a 
positive repeated sample and in the absence of other 
explanation, e.g. menses), urine will be sent to the laboratory 
for microscopy. Culture and sensitivity analysis is indicated if 
urinary tract infection is suspected. 
 
Microscopic examination (sediment, red blood cells, white 
blood cells, casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal. 
Auto-antibody panel 
 Anti-nuclear antibody (ANA), circulating anti-neutrophil cytoplasmic 
antibody (cANCA); and perinuclear anti neutrophil cytoplasmic 
antibody (pANCA). In case of positive ANA test, the anti−double-
stranded DNA antibody test to be performed:  
o The auto-antibody panel will be assessed at Screening, pre-
dose Cycles 2 and 3, and every 6 cycles thereafter. In 
participants who develop signs and/or symptoms suggestive of 
auto-immune disease while on treatment, the auto-antibody 
panel (including anti-dsDNA antibody) must be repeated. 
o Patients with confirmed positive serology of at least one of the 
auto-antibody panel during the course of the study should be 
discussed between Sponsor and Investigators, and if judged 
clinically relevant, could be referred to a specialist to exclude an 
underlying auto-immune disease. 
IgE and Tryptase 
 Tryptase and IgE samples will be collected for local analysis if a 
participant experiences a Grade ≥2 IRR, or with clinical signs of 
hypersensitivity reaction. If tryptase and/or IgE are elevated, a 
second sample for central IgE/Tryptase analysis will be collected 
approximately 48 hours after onset of the reaction. 
 
Investigators must document their review of each laboratory safety report. 
Additional Statistical Considerations for Clinical Laboratory Data 
Standard Reference Ranges and Transformation of Data 
Potential analysis considerations for analyzing laboratory data includes the use of 
standard reference ranges and potential transformation of data for specific laboratory 
tests.  
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these parameters, the 
measured laboratory test result will be assessed directly using the Roche standard 
reference range. Certain laboratory parameters will be transformed to Roche’s standard 
reference ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 


 
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that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data. 
Definition of Laboratory Abnormalities 
For all laboratory parameters included in the analysis described above, there exists a 
Roche predefined standard reference range. Laboratory values falling outside this 
standard reference range will be labeled “H” for high or “L” for low in participant listings 
of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for these laboratory parameters. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low. 
 


 
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Appendix 5  
Contraceptive Guidance and Collection of Pregnancy 
Information 
1. 
DEFINITIONS 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements. 
 
Women in the following categories are considered to be Woman of Non-
Childbearing Potential 
a) Pre-menarchal 
b) Pre-menopausal female with one of the following: 
 
Documented hysterectomy. 
 
Documented bilateral salpingectomy. 
 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
c) 
Post-menopausal female 
– 
A post-menopausal state is defined as no menses for  12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
– 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
 
2. 
CONTRACEPTION GUIDANCE 
 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use highly effective method of contraception consistently and correctly as described in 
Table 1 below. 


 
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Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly as described in Table 1 below. 
Table 1 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependenta 
(Failure rate of  1% per year when used consistently and correctly) 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral 
o 
Injectable  
Highly Effective Methods That Are User-Independent 
(Failure rate of  1% per year) 
 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion/ ligation 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
 
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
 
3. 
PREGNANCY TESTING 
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test. 


 
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Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice. 
4. 
COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). This applies only to male participants who receive 
RO7296682 and atezolizumab. 
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant 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. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Female participants who become pregnant 
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 


 
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While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Appendix 2. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. 
5 
ABORTIONS 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), 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 of Appendix 2). 
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as 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 of Appendix 2). 
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form. 
6 
CONGENITAL ANOMALIES/BIRTH DEFECTS 
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant 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). 


 
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Appendix 6  
Study Details for Part III, NSCLC (Cohort A) 
Background and Rationale for Part III, NSCLC Cohort 
Lung cancer remains the leading cause of cancer death in the United States. Treatment 
of advanced-stage or metastatic non-small cell lung cancer (NSCLC) without EGFR 
mutations or ALK rearrangements has undergone significant advancement with the 
development of CPIs against PD-1/PD-L1 e.g., pembrolizumab, nivolumab, 
atezolizumab or durvalumab in the first line setting. Despite the recent advancements, 
patients respond poorly to CPIs and ultimately develop resistance mechanisms resulting 
in disease progression. Removing Tregs is postulated to increase the anti-tumor 
immunity of participants who do not respond to or progress following CPI treatment. 
Should clinical benefit be observed in this or other trials fulfilling the gating criteria 
outlined in section 9.5, a NSCLC-specific cohort will be opened in order to investigate 
the signals further and in a wider population, without restrictions of 
 type 
or a specific prior CPI response pattern (i.e. as in Part II). As outlined in Section 4.2.1 of 
the protocol, given the high FoxP3 content (surrogate marker for Tregs) in this tumor 
type, Treg depletion through RO7296682 is postulated to increase anti-tumor activity in 
combination with anti-PD-L1 (atezolizumab). 
Specific Inclusion Criteria for Part III, NSCLC Cohort 
Participants are eligible to be included in the study only if all of the appropriate inclusion 
criteria listed in protocol Section 5.1 and all of the following criteria apply: 
1. Participants with histologically confirmed advanced and/or metastatic NSCLC 
previously treated with CPI    platinum based chemotherapy, including 
PD-L1/PD-1/CTLA-4 inhibitors (investigational or approved) sequentially or 
concurrently with chemotherapy. 
 
CPI administration as (neo-) adjuvant therapy is not allowed. 
2. Participants whose tumors have known sensitizing mutations must also have 
experienced disease progression (during or after treatment) or intolerance to 
targeted therapy. 
3. Able to provide archival tissue and fresh skin punch biopsy, as per inclusion criteria 
#7 and #8 in protocol Section 5.1, respectively. 
4. Able to provide a freshly collected biopsy of a tumor lesion (primary and/or 
metastatic) from a safely accessible site, per Investigator determination and patient 
consent, providing the patient has more than one measurable target lesion. If the 
patient has only one target lesion, the patient will be excluded from study 


 
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participation. The biopsied lesion must not be a target lesion. The following rules 
apply: 
 
Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine 
needle aspirates are not acceptable. 
 
The tumor lesion must not be a metastatic LN sample; metastatic LN is 
acceptable ONLY when other accessible tumor sites are not available for biopsy. 
 
Fresh biopsies must be obtained within 28 days before the first dose at C1D1. 
 
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Appendix 7  
Study Details for Part III, HNSCC (Cohort B) 
Background and Rationale for Part III, HNSCC Cohort 
Head and neck cancer describes a range of tumors that arise in the head and neck 
region, which includes the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, 
thyroid, and salivary glands. The worldwide incidence of head and neck cancer exceeds 
half a million cases annually. Despite the wide diversity in Head and Neck cancers, the 
majority arise from squamous cell in origin. Subjects with advanced and/or metastatic 
head and neck cancer present a therapeutic challenge. Conventional cytotoxic drugs 
and molecularly targeted compounds have shown some activity in metastatic and 
recurrent HNSCC, yet the prognosis of such patients is poor. Therefore, single agent 
and/or combination therapy together with best supportive care is palliative for these 
patients. 
Should clinical benefit be observed in this or other trials fulfilling the gating criteria 
outlined in Section 9.5, a HNSCC-specific cohort will be opened in order to investigate 
the signals further and in a wider population, without restrictions of 
 type 
or a specific prior CPI response pattern (i.e., as in Part II). As outlined in Section 4.2.1 of 
the protocol, given the high FoxP3 content (surrogate marker for Tregs) in this tumor 
type, Treg depletion through RO7296682 is postulated to increase anti-tumor activity in 
combination with anti-PD-L1 (atezolizumab). 
Specific Inclusion Criteria for Part III, HNSCC Cohort 
Participants are eligible to be included in the study only if all of the appropriate inclusion 
criteria listed in protocol Section 5.1 and all of the following criteria apply: 
1. Participants with histologically confirmed advanced and/or metastatic HNSCC 
previously treated with CPI    platinum based chemotherapy, including PD-L1/PD-
1/CTLA-4 inhibitors (investigational or approved) sequentially or concurrently with 
chemotherapy. 
 
CPI administration as (neo-) adjuvant therapy is not allowed. 
2. Participants whose tumors have known sensitizing mutations must also have 
experienced disease progression (during or after treatment) or intolerance to 
targeted therapy. 
3. Able to provide archival tissue and fresh skin punch biopsy, as per inclusion criteria 
#7 and #8 in protocol Section 5.1, respectively. 


 
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4. Able to provide a freshly collected biopsy of a tumor lesion (primary and/or 
metastatic) from a safely accessible site, per Investigator determination and patient 
consent, providing the patient has more than one measurable target lesion. If the 
patient has only one target lesion, the patient will be excluded from study 
participation. The biopsied lesion must not be a target lesion. The following rules 
apply: 
 
Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine 
needle aspirates are not acceptable. 
 
The tumor lesion must not be a metastatic lymph node sample; metastatic lymph 
node is acceptable ONLY when other accessible tumor sites are not available for 
biopsy. 
 
Fresh biopsies must be obtained within 28 days before the first dose at C1D1. 
 
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Appendix 8  
Study Details for Part III, MEL (Cohort C) 
Background and Rationale for Part III, MEL Cohort 
CPIs represent the current paradigm of treatment options in patients with melanoma. 
However, only a fraction of patients derive durable benefit from CPIs. Ipilimumab was 
the first CPI approved for use in unresectable or metastatic melanoma. Subsequent to 
this, nivolumab was approved in advanced melanoma patients without BRAF mutation. 
The combination of ipilumumab and nivolumab was approved in previously untreated 
patients with unresectable or metastatic melanoma (Robert et al. 2015), although toxicity 
is more prominent with the combination therapy. Despite anti-CTLA4 and PD-1 CPI 
therapies many melanoma patients fail to respond (innate resistance), and more 
worrying, some patients who initially benefited from CPIs acquired resistance over time. 
Consequently, there remains a medical need to develop new combination therapies to 
overcome the resistance mechanisms to immunotherapy. 
Should clinical benefit be observed in this or other trials fulfilling the gating criteria 
outlined in section 9.5, a MEL-specific cohort will be opened in order to investigate the 
signals further and in a wider population, without restrictions of 
 type or a 
specific prior CPI response pattern (i.e. as in Part II). As outlined in Section 4.2.1 of the 
protocol, given the high FoxP3 content (surrogate marker for Tregs) in this tumor type, 
Treg depletion through RO7296682 is postulated to increase anti-tumor activity in 
combination with anti-PD-L1 (atezolizumab). 
Specific Inclusion Criteria for Part III, MEL Cohort 
Participants are eligible to be included in the study only if all of the appropriate inclusion 
criteria listed in protocol Section 5.1 and all of the following criteria apply: 
1. Participants with histologically confirmed advanced and/or metastatic MEL previously 
treated with CPI    platinum based chemotherapy, including PD-L1/PD-1/CTLA-4 
inhibitors (investigational or approved) sequentially or concurrently with 
chemotherapy. 
 
CPI administration as (neo-) adjuvant therapy is not allowed. 
2. Participants whose tumors have known sensitizing mutations must also have 
experienced disease progression (during or after treatment) or intolerance to 
targeted therapy.  
Note: enrollment will be managed so that no more than approximately 10% of 
participants will be participants with ocular (uveal) melanoma. 
3. Able to provide archival tissue and fresh skin punch biopsy, as per inclusion criteria 
#7 and #8 in protocol Section 5.1, respectively. 


 
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4. Able to provide a freshly collected biopsy of a tumor lesion (primary and/or 
metastatic) from a safely accessible site, per Investigator determination and patient 
consent, providing the patient has more than one measurable target lesion. If the 
patient has only one target lesion, the patient will be excluded from study 
participation. The biopsied lesion must not be a target lesion. The following rules 
apply: 
 
Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and cytology fine 
needle aspirates are not acceptable 
 
The tumor lesion must not be a metastatic LN sample; metastatic LN is 
acceptable ONLY when other accessible tumor sites are not available for biopsy 
 
Fresh biopsies must be obtained within 28 days before the first dose at C1D1. 
 
If fresh tissue biopsies cannot be obtained, please contact the Medical Monitor. 


 
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Appendix 9  
Study Details for Part III, Additional Tumor-Specific Cohort(s) 
Potentially in Comparison with Standard of Care 
Background and Rationale for Part III, Additional Tumor-specific Cohort(s) 
New tumor-specific cohorts may be added based on emerging data from this study or 
other RO7296682 studies (see Section 9.5 for gating criteria). The cohort details, 
including but not limited to study objectives, patient eligibility criteria, dosing and 
schedule requirements, statistical hypothesis, etc. will be outlined in a substantial 
protocol amendment. 


 
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Appendix 10  
Details on the Real World Prognostic Score 
In a Real World Data cohort of 122,694 patients, demographic, clinical, routine 
hematology and blood chemistry parameters were analyzed within a Cox proportional 
hazard framework to derive a multivariate prognostic risk model for overall survival 
called the Real World Prognostic score (ROPRO; Becker et al. 2020). In total, ROPRO 
comprised 29 variables (see Table 1), which contributed significantly to overall survival 
across cancer indications. In the largest cohort (advanced non-small-cell lung cancer), 
patients with elevated scores (upper 10%) had a 7.91-fold (95% CI 7.45 to 8.39) 
increased death hazard compared with patients with low scores (lower 10%) 
(P<2.23×10-308). The ROPRO model performance indicators (generalized-r²=0.32, 
C-index=0.747, 3-month-AUC=0.82) strongly outperformed those of the Royal Marsden 
Hospital score (r²=0.03, C-index=0.54, 3-month-AUC=0.58). ROPRO was validated in 
two independent Phase I and Phase III clinical studies. 


 
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Table 1 
ROPRO Variables 
 
Individual patient ROPRO scores (derived by inputting their measurements for each of 
the variables into the formula) ranged from -3.49 to 4.12 and 99% were in between -2.21 
and 2.09.  
As demonstrated in the publication (Becker et al. 2020), increased ROPRO correlates 
with increased risk for early death. In order to identify a cut-off value of the ROPRO 
above, which the risk of early death (within 12 weeks of study entry) is particularly high, 
the study will proceeded as follows:  
Four Roche-internal clinical Phase I studies were retrospectively analyzed. In all studies, 
higher ROPRO was associated with increased hazard of death. Different ROPRO 
cut-offs were applied and compared to the proportion of patients who died within 


 
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12 weeks in the low and high risk patient groups (as defined by the respective ROPRO 
cutoff). The F-measure (F1) was used, which is the harmonic mean of the precision 
(probability to die within 12 weeks when the patient is excluded) and recall (probability to 
be excluded when the patient dies within 12 weeks), to define the optimal ROPRO 
cutoff. F1 was chosen in order to get a good tradeoff between excluding high-risk 
patients who will not benefit from the trial and should not undergo unnecessary 
procedural burden (low false negatives and thus high recall) and not excluding too many 
patients at the same time that will benefit from the trial (low number of false positives 
and thus high precision). The F1 measure for different ROPRO cutoffs is shown in 
Figure 1. The maximum F1 is reached for a ROPRO cut-off of 0.7. 
Figure 1  Different potential ROPRO cut-offs and F1 measure. Maximizing 
F1 results in a ROPRO cut-off of 0.7. 
Reference:  
Becker T, Weberpals J, Jegg AM, et al. An enhanced prognostic score for overall 
survival of patients with cancer derived from a large real world cohort. Annals of 
Oncology. 2020. https://doi.org/10.1016/j.annonc.2020.07.013. 


 
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Appendix 11  
Statistics for Combination Therapy Dose-Escalation 
1. COMBINATION THERAPY DOSE ESCALATION 
This appendix provides details of the design that will guide the dose-escalation of 
RO7296682 in combination with atezolizumab and its operating characteristics through 
simulations. All analyses were performed using the R statistical software version 3.5.3 
(2019-03-11; R Core Team, 2017). 
2.  RATIONALE FOR MODEL-BASED DESIGN 
The modified continuous reassessment method (mCRM) design uses a statistical model 
that actively seeks a dose level close to the maximum tolerated dose (MTD) by using 
toxicity data from all enrolled evaluable participants to compute a precise dose-toxicity 
curve. It locates the MTD efficiently and minimizes the number of participants treated at 
possibly pharmacological inactive dose levels. Such model-based designs have been 
successfully applied in many Phase 1 dose-escalation studies (Schöffski et al. 2004; 
Le Tourneau et al. 2009; Neuenschwander et al. 2008). The simulations in this appendix 
investigate the operating characteristics of the design as implemented for this study. 
In this design, the MTD is defined as the dose maximizing the posterior probability that 
the dose-limiting toxicity (DLT) rate π (MTD) ϵ [0.2, 0.33] while keeping the probability of 
overdose {p(MTD)  0.33}  0.25. 
3. STATISTICAL MODEL 
A two-parameter logistic model will be used to fit the dose-toxicity relationship. The 
probability of DLT at dose dj, p(dj) is defined as (1) 
 
where 
 
and d* is the reference dose (in this case d*  
 mg) 


 
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The model (1) thus can be rewritten as (2): 
 
where  and  are the parameters to be estimated and assumed to follow a 
bivariate normal distribution. 
3.1 GENERAL MODEL SETTING 
3.1.1 Dose Grid 
The following dose grid has been used: 
From 
 by 
; from 
, by ; from 
 by 
. 
3.1.2 
Maximum Dose Increments 
The following rules for selecting the maximum allowed dose increment will be applied. 
 
Maximum Dose Increments relative to DLT: 
 
In absence of a DLT a dose increment of 200% is allowed (i.e., next dose could be 
as high as 3-fold the previous dose) 
 
After the first DLT has been observed, the maximum allowed dose increment is 
reduced to 100% (i.e. up to 2-fold) for later cohorts. If there is only 1 accumulated 
DLT, no DLT in the most recent 2 cohorts, and provided the current dose is less 
than 
 mg, it is allowed to switch back to a dose increment of 200% (i.e. up to 
3-fold). Otherwise, the maximum dose increment of 100% (i.e. up to 2-fold) remains.  
o In addition, based on the emerging data from the single agent dose-
escalation study (WP41188), the upper limit to allow switching back to a 
dose increment of 200% (i.e. 3-fold) will be reset to 6-fold lower than single 
agent MTD.  
 
After 2 accumulated DLTs have been observed, a dose increment of 100% (i.e. 
2-fold) must be maintained for all subsequent cohorts.  
 
3.1.3 
Stopping Rules 
The algorithm will recommend ending the dose-escalation if any of the following criteria 
applies: 
 
Enough information on MTD: 
At least a minimum of 12 participants evaluated and at least 6 participants have been 
accrued near the MTD dose (where near means differing from the MTD by at most 10%) 


 
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and the posterior probability that the MTD dose lies within the target toxicity interval is 
above 50% OR 
 
Maximum dose is safe: 
at least 6 subjects have been observed at the maximum dose or near (differing from the 
maximum dose by at most 10%) and it is at least 50% likely that the probability of a DLT 
for the maximum dose is below 0.2. OR 
 
Maximum number of participants: 
The maximum sample size of 60 DLT evaluable participants has been reached. 
3.2 MODEL PRIOR 
A minimally informative bivariate normal prior for the parameters of the DLT dose 
response curve (, ) is constructed in order to have a weak impact on the final MTD 
determination (Neuenschwander et al. 2008). 
This minimally informative prior “neutral” component will be constructed based on the 
assumed not toxic and toxic dose levels. It is conservatively assumed that it would be 
unlikely (less than 10%confidence) that a 15% or higher DLT rates are associated with 
the first dose (
 mg) of RO7296682 in combination with atezolizumab and that it would 
be very unlikely (less than 10% confidence) that a 35% or lower DLT rate are associated 
with the dose of 
 mg.  
The parameters of the minimally informative prior are listed below (3):   
 
where  and  are the parameters of the bivariate normal distribution. 
The prior distribution used to determine the dose-escalation decision for this study is 
shown in Figure 2. 


 
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Figure 2 Minimally Informative Prior 
 
 
3.3  
MODEL PERFORMANCE EVALUATION 
To illustrate how the design will perform, different escalation scenarios were explored 
and the corresponding results are tabulated in Table 1. Each column represents four 
different situations: which dose would the model recommend, after seeing no DLTs in 
previous cohorts and when 0, 1, 2, or 3 DLTs are observed in the current cohort. The 
evaluation is based on cohort size  3, where stop indicates that the model would stop 
escalating and the study would be halted. 
In general, if there are no observed DLTs, the model will suggest to escalate close to 
what the maximum increments allow, while in presence of one DLT the increments are 
more limited (see Table 1). With 2 or 3 DLTs, the model always recommends to 
de-escalate or STOP. Therefore, the results show that the design will adequately adapt 
the dose in the presence of observed DLTs. 


 
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Table 1 
Dose Escalation Mock Runs 
Dose 
Level 
Dose 
(mg) 
Next Dose  
(% Increment)  
if no DLT 
Next Dose  
(% Increment) 
if 1 DLT 
Next Dose  
(% Increment)  
if 2 DLTs 
Next Dose  
(% Increment)  
if 3 DLTs 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
4. SIMULATION STUDY 
A simulation study is conducted to evaluate the operating characteristics for the chosen 
design parameters (priors, reference dose, and stopping rule) under various 
dose-toxicity scenarios. The different scenarios have been selected in order to cover a 
wide range of dose-toxicity possibilities and to be able to quantify the risk and benefit, 
should these scenarios actually occur. 
4.1 DOSE-TOXICITY SCENARIOS 
In these simulations, the starting dose of 
 mg is assumed. Various dose-toxicity 
scenarios have been selected in order to cover a wide range of dose-toxicity possibilities 
and to be able to quantify the risk and benefit under different possible dose-toxicity 
relationships. Scenarios 1 and 7 reflects the toxicity if the compound was to behave very 
toxic. Scenarios 5 and 6 reflects toxicity of this compound if it is very safe. The other 
scenarios (2, 3, and 4) are intermediate scenarios. The dose-toxicity curves and target 
dose intervals are shown in Figure 3. 




 
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Table 2 
Summary for Simulation of Study Results 
Scenario True Target 
Dose Rage 
Overall N of 
Participants* 
Overall N of 
Weeks* 
N Participants 
Treated above 
Target Toxicity* 
Proportions of 
DLTs per  
Trials* 
Doses 
Selected as 
MTD* 
1 
2 
3 
4 
5 
6 
7 
* median (10% quantile, 90% quantile) 
3 participants per cohort in simulation but it is not limited to 3 in real study. 
9 weeks for each multiple participant cohort. 
 
5. REFERENCES 
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. 
J Natl Cancer Inst. 2009;101(10):708-20. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008;27:2420-39. 
R Core Team. 2017. R: A language and environment for statistical computing. Vienna, 
Austria: R Foundation for Statistical Computing. Available from: https://www.R-
project.org/. 
Schöffski P, Riggert S, Fumoleau P, et al. Phase I trial of intravenous aviscumine 
(rViscumin) in patients with solid tumors: a study of the European Organization for 
Research and Treatment of Cancer New Drug Development Group. Ann Oncol. 
2004;15:1816-24. 


 
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Appendix 12  
Management Guidelines for imAEs with RO7296682 and/or 
Combination Therapy with RO7296682 and Atezolizumab 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening dyspnea, cough, chest pain, fever, 
dyspnea, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates. Participants will be 
assessed for pulmonary signs and symptoms throughout the study and will also have CT 
scans of the chest performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. COVID-19 evaluation should be performed per institutional guidelines where 
relevant. Management guidelines for pulmonary events are provided in Table 1. 


 
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Table 1 
Management Guidelines for Pulmonary Events, Including 
Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 Continue RO7296682 and/or atezolizumab and monitor closely. 
 Re-evaluate on serial imaging. 
 Consider participant referral to pulmonary specialist. 
Pulmonary 
event, Grade 2 
 Withhold after event onset. a 
 Refer participant to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
 Initiate treatment with corticosteroids equivalent to 1 to 2 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact Medical Monitor.c, d 
 For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. c 
 Oral or IV broad-spectrum antibiotics should be administered in parallel to 
the immunosuppressive treatment. 
 Bronchoscopy or BAL with or without transbronchial biopsy is recommended. 
 Initiate treatment with corticosteroids equivalent to 1 to 2 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
BAL  Bronchoscopic alveolar lavage. 
a 
 RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682.and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 


 
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HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment. Management guidelines for hepatic events are provided in Table 2. 
Participants 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 participants with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
 Continue RO7296682 and/or atezolizumab. 
 Monitor LFTs until values resolve to within normal limits or to baseline values.  
Hepatic event, 
Grade 2 
All events: 
 Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Initiate treatment with corticosteroids equivalent to 1 to 2 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume RO7296682 and/or 
atezolizumab.b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 


 
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Event 
Management 
Hepatic event, 
Grade 3 or 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor.c 
 Consider participant referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury. 
 Initiate treatment with corticosteroids equivalent to 1 to 2 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
If event resolves to Grade 1 or better, taper corticosteroids over 1 month. 
LFT  Liver function test. 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor.  
 
GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  


 
RO7296682—F. Hoffmann-La Roche Ltd 
158/Protocol BP42595, Version 4 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 Continue RO7296682 and/or atezolizumab. 
 Initiate symptomatic treatment. 
 Endoscopy is recommended if symptoms persist for  7 days. 
 Monitor closely. 
Diarrhea or 
colitis, Grade 2 
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Initiate symptomatic treatment. 
 If strong clinical suspicion for immune-mediated colitis, start empiric IV steroids while 
waiting for definitive diagnosis. 
 Participant referral to GI specialist is recommended. 
 For recurrent events or events that persist  5 days, initiate treatment with 
corticosteroids equivalent to 12 mg/kg/day oral prednisone. If the event does not 
improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or atezolizumab 
and contact the Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or atezolizumab 
and contact the Medical Monitor. c 


 
RO7296682—F. Hoffmann-La Roche Ltd 
159/Protocol BP42595, Version 4 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. c 
 Refer participant 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 RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 
ENDOCRINE EVENTS 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders may 
be associated with the administration of RO7296682 and/or atezolizumab. Management 
guidelines for endocrine events are provided in Table 4. 
Participants with unexplained symptoms such as headache, fatigue, myalgias, 
impotence, constipation, or mental status changes should be investigated for the 
presence of thyroid, pituitary, or adrenal endocrinopathies. The participant 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. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
160/Protocol BP42595, Version 4 
Table 4 
Management Guidelines for Endocrine Events 
Event 
Management 
Grade 1 hypothyroidism 
 Continue RO7296682 and/or atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH weekly. 
Grade 2 hypothyroidism 
 Consider withholding RO7296682 and/or atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Consider participant referral to endocrinologist. 
 Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Grade 3 and 4 hypothyroidism 
 Withhold RO7296682 and/or atezolizumab. 
 Initiate treatment with thyroid replacement hormone. 
 Monitor TSH closely. 
 Refer participant to endocrinologist. 
 Admit participant to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
 Resume RO7296682 and/or atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
Grade 1 hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 
 Continue RO7296682 and/or atezolizumab. 
 Monitor TSH every 4 weeks. 
 Consider participant referral to endocrinologist. 
TSH  0.1 mU/L: 
 Follow guidelines for Grade 2 hyperthyroidism. 
 Consider participant referral to endocrinologist. 
Grade 2 hyperthyroidism 
 Consider withholding RO7296682 and/or atezolizumab. 
 Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
 Consider participant referral to endocrinologist. 
 Resume RO7296682 and/or atezolizumab when symptoms are 
controlled and thyroid function is improving. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
161/Protocol BP42595, Version 4 
Event 
Management 
Grade 3 and 4 hyperthyroidism 
 Withhold RO7296682 and/or atezolizumab. 
 Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed. 
 Refer participant to endocrinologist. 
 Resume RO7296682 and/or atezolizumab when symptoms are 
controlled and thyroid function is improving. 
 Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor for life-threatening immune-
mediated hyperthyroidism. c 
Symptomatic adrenal 
insufficiency, Grade 2 to 4  
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant to endocrinologist. 
 Perform appropriate imaging. 
 Initiate treatment with corticosteroids equivalent to 1 to 
2 mg/kg/day IV methylprednisolone and convert to 1 to 
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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better or participant is 
not stable on replacement therapy while withholding 
RO7296682 and/or atezolizumab, permanently discontinue 
RO7296682 and/or atezolizumab and contact the Medical 
Monitor. c 
Hyperglycemia, Grade 1 or 2  
 Continue RO7296682 and/or atezolizumab. 
 Investigate for diabetes. If participant has Type 1 diabetes, treat 
as a Grade 3 event. If participant does not have Type 1 diabetes, 
treat as per institutional guidelines. 
 Monitor for glucose control. 
Hyperglycemia, Grade 3 or 4 
 Withhold RO7296682 and/or atezolizumab. 
 Initiate treatment with insulin. 
 Monitor for glucose control. 
 Resume RO7296682 and/or atezolizumab when symptoms 
resolve and glucose levels are stable. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
162/Protocol BP42595, Version 4 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), Grade 
2 or 3  
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 1 to 
2 mg/kg/day IV methylprednisolone and convert to 1 to 
2 mg/kg/day oral prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
 If event resolves to Grade 1 or better, resume RO7296682 
and/or atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
RO7296682 and/or atezolizumab, permanently discontinue 
RO7296682 and/or atezolizumab and contact the Medical 
Monitor. c 
 For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), Grade 
4  
 Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor. c 
 Refer participant to endocrinologist. 
 Perform brain MRI (pituitary protocol). 
 Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement. 
 Initiate hormone replacement if clinically indicated. 
MRI  Magnetic resonance imaging; TSH  Thyroid-stimulating hormone. 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 
OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in Table 5. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
163/Protocol BP42595, Version 4 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 Continue RO7296682 and/or atezolizumab. 
 Participant 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 RO7296682 and/or atezolizumab after event onset. a 
 Participant 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 RO7296682 and/or atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 and/or 
atezolizumab, permanently discontinue RO7296682 and/or atezolizumab and 
contact Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact Medical 
Monitor. c 
 Refer participant 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 RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 


 
RO7296682—F. Hoffmann-La Roche Ltd 
164/Protocol BP42595, Version 4 
IMMUNE-MEDIATED CARDIAC EVENTS 
Management guidelines for cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any participant 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 
participant who reports a recent history of gastrointestinal illness), ischemic events, 
underlying arrhythmias, exacerbation of preexisting cardiac conditions, or progression of 
malignancy. 
All participants 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. 
Participants with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
IMMUNE-MEDIATED PERICARDIAL DISORDERS 
Immune-mediated pericarditis should be suspected in any participant 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 
participant presenting with chest pain associated with dyspnea or hemodynamic instability.  
Participants 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 participants 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. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
165/Protocol BP42595, Version 4 
Participants with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, 
in the absence of an identified alternate etiology, should be treated according to the guidelines in 
Table 6. Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a detailed 
cardiac evaluation to determine the etiology and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 
2-4 
 
Immune-mediated 
pericardial disorders, 
Grades 2 to 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. 
 Refer participant to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
ECMO  Extracorporeal membrane oxygenation; IV  intravenous; VAD  Ventricular assist 
device. 
 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis. 
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests. Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 7. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
166/Protocol BP42595, Version 4 
Table 7 
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 RO7296682 and/or atezolizumab. 
 Monitor amylase and lipase weekly. 
 For prolonged elevation (e.g.,  3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase  2.05.0  ULN: 
 Treat as a Grade 3 event. 
Amylase and/or 
lipase elevation, 
Grade 3 or 4 
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 
Immune-
mediated 
pancreatitis, 
Grade 2 or 3 
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 
 For recurrent events, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c  


 
RO7296682—F. Hoffmann-La Roche Ltd 
167/Protocol BP42595, Version 4 
Event 
Management 
Immune-
mediated 
pancreatitis, 
Grade 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor.c 
 Refer participant 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; IV  intravenous. 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self-limited, with or without pruritus. 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 8. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
168/Protocol BP42595, Version 4 
Table 8 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 Continue RO7296682 and/or atezolizumab. 
 Consider treatment with topical corticosteroids and/or other symptomatic therapy 
(e.g., antihistamines). 
Dermatologic 
event, Grade 2  
 Continue RO7296682 and/or atezolizumab. 
 Consider patient referral to dermatologist. 
 Initiate treatment with topical corticosteroids. 
 Consider treatment with higher-potency topical corticosteroids if event does not 
improve. 
Dermatologic 
event, Grade 3  
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Refer participant to dermatologist. 
 Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, 
increasing dose to 12 mg/kg/day if event does not improve within 4872 hours. 
 If event resolves to Grade 1 or better, resume RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or atezolizumab 
and contact the Medical Monitor. c 
Dermatologic 
event, Grade 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor.c 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 
NEUROLOGIC DISORDERS 
Participants may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies. Management guidelines for neurologic disorders are provided in 
Table 9, with specific guidelines for myelitis provided in Table 10. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
169/Protocol BP42595, Version 4 
Table 9 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-
mediated 
neuropathy, 
Grade 1 
 Continue RO7296682 and/or atezolizumab. 
 Investigate etiology. 
 Any cranial nerve disorder (including facial paresis) should be managed as per Grade 2 
management guidelines below. 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 2  
 Withhold RO7296682 and/or atezolizumab after event onset. a 
 Investigate etiology. 
 Initiate treatment as per institutional guidelines. 
 For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume RO7296682 and/or 
atezolizumab. b 
– 
If event does not resolve to Grade 1 or better while withholding 
RO7296682 and/or atezolizumab, permanently discontinue RO7296682 
and/or atezolizumab and contact the Medical Monitor. c 
 For facial paresis: 
– 
If event resolves fully, resume atezolizumab b 
– 
If event does not resolve fully while withholding RO7296682 and/or 
atezolizumab, permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor. c 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact Medical 
Monitor. c  
 Refer participant to neurologist. 
 Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. c 
 Refer participant to neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider initiation of corticosteroids equivalent to 1 to 2 mg/kg/day oral or IV 
prednisone. 
a RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 


 
RO7296682—F. Hoffmann-La Roche Ltd 
170/Protocol BP42595, Version 4 
Table 10 
Management Guidelines for Immune-Mediated Myelitis  
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
 
Continue RO7296682 and/or atezolizumab unless symptoms 
worsen or do not improve. 
 
Investigate etiology and refer participant to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
 
Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor.  
 
Investigate etiology and refer participant to a neurologist. 
 
Rule out infection. 
 
Initiate treatment with corticosteroids equivalent to 1 to 
2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
 
Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor. 
 
Refer participant to a neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any participant 
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 participants 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. 
Participants with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 11. 


 
RO7296682—F. Hoffmann-La Roche Ltd 
171/Protocol BP42595, Version 4 
Table 11 Management Guidelines for Immune-Mediated 
Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
 Permanently discontinue RO7296682 and/or atezolizumab and 
contact the Medical Monitor. 
 Refer participant to neurologist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
RENAL EVENTS 
Eligible participants must have adequate renal function. Renal function, including serum 
creatinine, should be monitored throughout study treatment. Participants with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs). Refer the participant to a renal specialist if 
clinically indicated. A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Participants with signs and symptoms of nephritis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 12. 


 
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Table 12 Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue RO7296682 and/or atezolizumab. 
 Monitor kidney function, including creatinine, closely until values resolve to 
within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold RO7296682 and/or atezolizumab for up to 12 weeks after event 
onset. a 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor.  
 Refer participant 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 RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the Investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or atezolizumab may be considered in participants who are 
deriving benefit and have fully recovered from the immune-mediated event. Participants can be 
re-challenged with RO7296682 and/or atezolizumab only after approval has been documented 
by the Investigator (or an appropriate delegate) and the Medical Monitor. 
 


 
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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. 
Participants with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 13. 
Table 13 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
 Continue RO7296682 and/or atezolizumab. 
 Refer participant to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, Grade 2 
 Withhold RO7296682 and/or atezolizumab after event onset a and contact the 
Medical Monitor. 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact the Medical Monitor. c 


 
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Event 
Management 
Immune-
mediated 
myositis, Grade 3 
 Withhold RO7296682 and/or atezolizumab after event onset a and contact 
Medical Monitor. 
 Refer participant 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 RO7296682 and/or 
atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding RO7296682 
and/or atezolizumab, permanently discontinue RO7296682 and/or 
atezolizumab and contact Medical Monitor. c 
 For recurrent events, treat as a Grade 4 event. Permanently discontinue 
RO7296682 and/or atezolizumab and contact the Medical Monitor. c 
Immune-
mediated 
myositis, Grade 4 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. c 
 Refer participant 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 RO7296682 and/or atezolizumab may be withheld for a longer period (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The acceptable length of the extended period must be agreed 
upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before RO7296682 and/or atezolizumab can be resumed. 
c Resumption of RO7296682 and/or may be considered in participants who are deriving benefit 
and have fully recovered from the immune-mediated event. Participants can be re-challenged 
with RO7296682 and/or atezolizumab only after approval has been documented by the 
Investigator (or an appropriate delegate) and the Medical Monitor. 
 


 
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS).  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.  
Participants with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014). A participant 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 interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms. 
 
Participants with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. (2016). A febrile participant 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). 
 


 
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Participants with suspected HLH or MAS should be treated according to the guidelines in 
Table 14. 
Table 14 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
 Permanently discontinue RO7296682 and/or atezolizumab and contact the 
Medical Monitor. 
 Consider participant 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. 
 
REFERENCES 
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. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2020 [updated 06 April 
2020;]. Available from: https://www.uptodate.com/contents/clinical-features-and-
diagnosis-of-hemophagocytic-lymphohistiocytosis. 
Ravelli A, Minoia F, Davi S, et al. 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89. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood. 2015;125:2908-14.  


 
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Appendix 13  
New Response Evaluation Criteria in Solid Tumors—Version 1.1 
1. 
MEASURABILITY OF TUMOR AT BASELINE 
1.1 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:  
1.1.1 
Measurable 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 of:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm).  
 
10 mm caliper measurement by clinical exam (lesions, which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
 
20 mm by chest x-ray.  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be not greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. See also Section 2.2 on “Baseline 
documentation of target and non-target lesions” for information on lymph node 
measurement.  
1.1.2 Non-measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with 10 to  15 mm short axis) 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 
masses/abdominal organomegaly identiﬁed by physical exam that are not measurable 
by reproducible imaging techniques.  


 
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1.1.3 Special Considerations Regarding Lesion Measurability  
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:  
Bone lesions: 
 
Bone scan, positron emission tomography scan, or plain ﬁlms are not considered 
adequate imaging techniques to measure 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 as 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 as malignant lesions (neither measurable nor non-measurable) because 
they are, by deﬁnition, simple cysts.  
 
“Cystic lesions” thought to represent cystic metastases, can be considered as 
measurable lesions if they meet the deﬁnition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions.  
 
Lesions with previous 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.  
 
1.2 
TARGET LESIONS: SPECIFICATIONS BY METHODS OF 
MEASUREMENTS  
1.2.1 
Measurement of 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.  
1.2.2 Method of Assessment  
The same method of assessment and the same technique should be used to 
characterize each identiﬁed and reported lesion at baseline and during study. Imaging 
based evaluation should always be the preferred option.  


 
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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superﬁcial and 10 mm diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is suggested.  
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint, 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. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has deﬁned measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable.  
If before enrollment, it is known that a participant is unable to undergo CT scans with 
intravenous contrast because of allergy or renal insufficiency, the decision as to whether 
a non-contrast CT or MRI (without intravenous contrast) will be used to evaluate the 
participant at baseline and during study, should be guided by the tumor type under 
investigation and the anatomic location of the disease. For participants 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, anatomic location of the disease and should be 
optimized to allow for comparison to the previous studies if possible. Each case should 
be discussed with the radiologist to determine if a substitution of these other approaches 
is possible and, if not, the participant should be considered not evaluable from that point 
forward. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  
2.2.2 TUMOR RESPONSE EVALUATION 
2.1. 
ASSESSMENT OF OVERALL TUMOR BURDEN AND 
MEASURABLE DISEASE  
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. Measurable disease is deﬁned by the presence of at least one 
measurable lesion (as detailed in Section 1.1.1). 


 
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2.2. 
BASELINE DOCUMENTATION 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 2 lesions per organ) representative of 
all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline. 
This means in instances where participants have only one or 2 organ sites involved, a 
maximum of 2 (one site) and 4 lesions (2 sites), respectively, will be recorded. Other 
lesions (albeit measurable) in that organ will be recorded as non-measurable lesions 
(even if size is 10 mm by CT scan). 
Target lesions should be selected based on their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
reproducible in 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, which can be measured reproducibly should be selected. 
Lymph nodes merit special mention because they are normal anatomical structures, 
which may be visible by imaging even if not involved by tumor. As noted in Section 1.1.1, 
pathological node, which 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. 
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan 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, which is reported as being 20 mm  30 mm has 
a short axis of 20 mm and qualiﬁes as a malignant, measurable node. In this example, 
20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis 10 mm but  15 mm) should be considered non-target lesions.  
Nodes that have a short axis  10 mm are considered non-pathological and should not 
be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
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All other lesions (or sites of disease) including pathological lymph nodes should be 
identiﬁed as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, “absent,” or in rare 
cases “unequivocal progression” (see also Section 2.3.4). 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the case report form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).  
2.3. 
RESPONSE CRITERIA 
This section provides the deﬁnitions of the criteria used to determine objective tumor 
response for target lesions.  
2.3.1. 
Evaluation of Target Lesions  
 
Complete response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis 
to  10 mm. 
 
Partial response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
 
Progressive disease: At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study including baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.  
 
2.3.2. 
Special Notes on the Assessment of Target Lesions 
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 nodes regress to below 10 mm on study. This means 
that when lymph nodes are included as target lesions, the “sum” of lesions 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.  
Target lesions that become *too small to measure”: while on study, all lesions (nodal and 
non-nodal) 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 which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 


 
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and may report them as being “too small to measure.” When this occurs, it is important 
that a value be recorded on the case report form: 
 
If it is the opinion of the radiologist that the lesion has probably 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 BML (below measurable limit) should 
be ticked (Note: It is less probable 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 BML should also be 
ticked).  
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and in that case BML should not be ticked (BML is 
equivalent to a less than sign ). 
Lesions that split or coalesce on treatment: when non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. 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 maximal 
longest diameter for the “coalesced lesion.”  
2.3.3. 
Evaluation of Non-target Lesions  
This section provides the deﬁnitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points speciﬁed in the protocol.  
Complete response (CR): Disappearance of all non-target lesions (and, if applicable, 
normalization of tumor marker level). All lymph nodes must be non-pathological in size 
( 10 mm short axis). 
Non-CR/non-progressive disease: Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
Progressive disease: Unequivocal progression (see Section 2.3.4) of existing non-target 
lesions. The appearance of one or more new lesions is also considered progression.  


 
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2.3.4. 
Special Notes on Assessment of Progression of Non-target 
Disease  
When the participant also has measurable disease: In this setting, to achieve 
“unequivocal progression” based on the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in 
presence of SD or PR in target disease, 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 based on change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.  
When the participant has only non-measurable disease: This circumstance arises in 
some phase III studies when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this 
instance there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden. Because worsening in non-target 
disease cannot be easily quantiﬁed (by deﬁnition: if all lesions are truly non-measurable), 
a useful test that can be applied when assessing participants for unequivocal 
progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare progressive disease for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in “volume” (which is equivalent to a 
20% increase diameter in a measurable lesion). Examples include an increase in a 
pleural effusion from “trace” to “large,” an increase in lymphangitic disease from 
localized to widespread, or may be described in protocols as “sufficient to require a 
change in therapy.” If “unequivocal progression” is seen, the participant should be 
considered to have had overall progressive disease at that point. While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial.  
2.3.5. 
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: i.e., 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 participant’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.  


 
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A lesion identiﬁed during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans conﬁrm 
there is deﬁnitely a new lesion, then progression should be declared using the date of 
the initial scan.  
2.4 
EVALUATION OF RESPONSE  
2.4.1 
Time-Point Response (Overall Response) 
It is assumed that at each protocol-speciﬁed time point, a response assessment occurs. 
A summary of the overall response status calculation at each time point for participants 
who have measurable disease at baseline is provided in Table 1.  
When participants have non-measurable (therefore non-target) disease only, Table 2 is 
to be used. 
Table 1 
 Time-Point Response—Target (with/without non-target) Lesions 
 
 


 
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Table 2 
Time-Point Response—Non-Target Lesions only 
 
 
2.4.2 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the participant is 
not evaluable at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response. This would be most likely 
to happen in the case of progressive disease.  
For example, if a participant had a baseline sum of 50 mm with 3 measured lesions and 
during study only 2 lesions were assessed, but those gave a sum of 80 mm, the 
participant will have achieved progressive disease status, regardless of the contribution 
of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” because the participant is 
not evaluable. Similarly, if one or more non-target lesions are indicated as “not 
assessed,” the response for non-target lesions should be “Unable to Assess” (except 
where there is clear progression). Overall response would be “Unable to Assess” if either 
the target response or the non-target response is “Unable to Assess” (except where this 
is clear evidence of progression) as this equates with the case being not evaluable at 
that time point. 


 
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Table 3 
Best Overall Response when Confirmation is Required 
 
 
2 
Special Notes on Response Assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size ( 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that participants with CR may not have a total sum of ‘zero’ on the 
case report form (CRF).  
Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic deterioration 
is not a descriptor of an objective response: it is a reason for stopping study therapy. 
The objective response status of such participants is to be determined by evaluation of 
target and non-target disease as shown in Table 1, Table 2, and Table 3.  
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. In studies 
where participants with advanced disease are eligible (ie, primary disease still or partially 
present), the primary tumor should be also captured under target or non-target lesions 
as appropriate. This is to avoid wrong assessments of complete overall response by 
statistical programs while the primary is still present but not evaluable. 
References 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 


 
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Appendix 14  
Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST) 
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. These include modified RECIST v1.1 for immune-based therapeutics 
(iRECIST; Seymour et al. 2017), which was developed by the RECIST working group in 
an effort to create a common set of criteria that the cancer immunotherapy 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 based on 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 
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 13) 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 1. Once a lesion has been categorized as a target, non-target, or new lesion, it 
will remain classified as such. 


 
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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. 
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. 
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 axis 


 
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of a lymph node is  10 mm, the lymph node should not be considered pathological and 
should not be considered a new lesion. A lymph node can subsequently become 
measurable, when the short axis is 15 mm. 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 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; PD  Progressive disease; RECIST v1.1  Response Evaluation Criteria 
in Solid Tumors, Version 1. 
 
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 Seymour et al. 2017. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
Hodi FS, Ballinger M, Lyons B, et al. Immune-modified response evaluation criteria in 
solid tumors (imRECIST): refining guidelines to assess the clinical benefit of 
cancer immunotherapy. J Clin Oncol. 2018;36:850-8. 


 
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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 15  
Cockcroft-Gault Formula/Creatinine Clearance (mL/min) 
Creatinine clearance (ml/min) for males 
 
(140 – age years  x body weight kg) 
Creatinine Clearance =  
________________________________________________________ 
 
(72)    x    (serum creatinine mg/dL) 
 
Creatinine Clearance (ml/min) for females: 
 
(140 – age years  x body weight kg) 
Creatinine Clearance =  
__________________________________________________________ x 0.85 (if female) 
 
(72)    x    (serum creatinine mg/dL) 


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