Clinical trial NCT03539484
Conditions: Solid Tumors
Sponsor: Hoffmann-La Roche
Start date: 2018-07-04; Completion date: 2019-07-22
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study was to determine the maximum-tolerated dose (MTD) and/or the optimal biological dose (OBD) as well as the optimal schedule for intravenous (IV) and subcutaneous (SC) administrations of RO7172508 as monotherapy, with or without obinutuzumab pre-treatment, in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA)-positive solid tumors who have progressed on standard of care (SOC) treatment, are intolerant to SOC, and/or are non-amenable to SOC. This study was conducted in two parts. Part I of the study consisted of an IV single participant cohort/multiple-ascending dose-escalation to evaluate the safety of RO7172508. Part II was a multiple participant cohort/multiple-ascending dose-escalation to define the MTD and/or OBD of RO7172508 administered as single agent, IV and/or SC, in participants with tumors that are expressing high as well as moderate/low-CEA. The study switched from Part I to Part II when the maximum planned dose for Part I was reached or the occurrence of a RO7172508-related Grade \>= 2 adverse event (AE) or dose-limiting toxicity (DLT) was observed, whichever comes first. The Sponsor may decide to switch from Part I to Part II in the absence of an observed RO7172508-related Grade \>= 2 toxicity or prior to maximum planned dose for Part I.

Detailed description:

Arms: arm 1: Part I was a multiple-ascending dose-escalation in single participant cohorts. RO7172508 was administered intravenously once every 3 weeks (Q3W). The starting dose of RO7172508 was 65 microgram (mcg) and the maximum dose explored was 1.6 milligram (mg). arm 2: Multiple ascending dose-escalation of IV-administered RO7172508 in multiple participant cohorts: The starting-dose for the initiation of the IV dose-escalation was determined by Part I and RO7172508 was initially given Q3W. Dose-escalation was undertaken based on safety until determination of the MTD or the highest safe dose if MTD is not reached. If on-target toxicity was reported in the first cycle of treatment, fractionated dosing may be implemented for the first cycle to improve tolerability. arm 3: Multiple ascending dose-escalation of SC-administered RO7172508 in multiple participant cohorts. These will be initiated once the IV schedule has shown RO7172508 preliminary clinical activity or the MTD has been established and is equal to or above 2 mg. The starting-dose and regimen once a week or once every 3 weeks (QW or Q3W) for SC administration will be proposed based on the evaluation of the safety and PK data observed following IV administration but will not exceed the highest safe dose tested in the IV Q3W dose escalation; a minimum dose of 2 mg is defined for a single SC administration. In addition, the QW SC starting-dose will not exceed one third of the IV MTD or of the highest safe IV dose tested. Dose escalation will continue based on safety until determination of the MTD or the planned maximum dose of 400 mg. If on-target toxicity is reported in the first cycle of treatment, fractionated dosing may be implemented for the first cycle to improve tolerability.
Interventions: intervention 1: RO7172508 intervention 2: Obinutuzumab intervention 3: Tocilizumab
Intervention descriptions: intervention 1: RO7172508 was administered at a dose and as per the schedule specified in the respective arms. intervention 2: In the event obinutuzumab treatment is implemented, obinutuzumab will be administered either on Day-7 or on Day-7 and Day-6. If obinutuzumab is given only on one day, then the schedule for Day-7 should be followed including an end of infusion sample. intervention 3: Tocilizumab was administered if required, for the management of severe CRS (cytokine release syndrome)

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: 
A First-in-Human, Open-Label, Multicenter, Dose-Escalation Phase I 
Clinical Study of Single-Agent RO7172508 in Patients With Locally 
Advanced and/or Metastatic CEA-Positive Solid Tumors 
NCT Number: NCT03539484 
Document Dates: Protocol Version 4: 26-December-2018 


FINAL PROTOCOL APPROVAL
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.
RO7172508—F. Hoffmann-La Roche Ltd
Protocol BP40092, Version 4
PROTOCOL
TITLE:
A FIRST-IN-HUMAN, OPEN-LABEL, 
MULTICENTER, DOSE-ESCALATION PHASE I 
CLINICAL STUDY OF SINGLE-AGENT RO7172508
IN PATIENTS WITH LOCALLY ADVANCED AND/OR 
METASTATIC CEA-POSITIVE SOLID TUMORS
PROTOCOL NUMBER:
BP40092
VERSION:
4
EUDRACT NUMBER:
2017-003834-10
IND NUMBER:
140737
TEST PRODUCT:
RO7172508 and obinutuzumab
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 18 Dec 2017
DATE AMENDED:
Version 2:  20 Apr 2018
Version 3:  6 Nov 2018
Version 4:  See electronic date stamp below
 
26-Dec-2018 12:08:00
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7172508—F. Hoffmann-La Roche Ltd
2/Protocol BP40092, Version 4
PROTOCOL ACCEPTANCE FORM
TITLE:
A FIRST-IN-HUMAN, OPEN-LABEL, 
MULTICENTER, DOSE-ESCALATION PHASE I 
CLINICAL STUDY OF SINGLE-AGENT RO7172508
IN PATIENTS WITH LOCALLY ADVANCED AND/OR 
METASTATIC CEA-POSITIVE SOLID TUMORS
PROTOCOL NUMBER:
BP40092
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-003834-10
IND NUMBER:
140737
TEST PRODUCT:
RO7172508 and obinutuzumab 
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 
Study Monitor.


RO7172508—F. Hoffmann-La Roche Ltd
3/Protocol BP40092, Version 4
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE
Since the changes made under Protocol BP40092 version 3 and Protocol BP40092 
version 4 followed each other in quick succession and Protocol BP40092 version 3 was 
not submitted to any ethics committees or regulatory authorities, the rationale of Protocol 
BP40092 version 3 has been kept and aggregated with the rationale of Protocol 
BP40092 version 4. Therefore, the changes made throughout this protocol reflect those 
changes made under both Protocol BP40092 version 3 and version 4. 
Protocol BP40092 version 3 and Protocol BP40092 version 4 have been amended for 
the following reasons:
Major Changes
1. Addition of obinutuzumab pretreatment 
Rationale: Previous studies with T-cell bispecifics against CEA (cibisatamab 
[RO6958688, CEA-TCB]) have shown that significant proportions of patients may 
develop anti-drug antibodies (ADAs). ADA formation can lead to loss of exposure, in 
addition to potential safety events by unintended activation of peripheral T-cells via CD3 
crosslinking through ADA-TCB complexes. 
B-cell depletion by obinutuzumab (anti-CD20) pretreatment has recently been introduced 
as a way to mitigate these effects. While the ADA risk with RO7172508 is not known at 
this time, language describing an algorithm to evaluate obinutuzumab pretreatment was 
added to the protocol to prepare for an eventuality of ADA formation observed in study 
BP40092.  
Sections: 2.1 Study Rationale, 2.2.2 Background, 2.3 Benefit/Risk Assessment, 4.1.3 
Obinutuzumab Pre-treatment, 4.3.2 Obinutuzumab, 5.2 Exclusion Criteria, 6.0 
Treatments, 6.1.1 Premedications, and Appendix 8.
2.
Evaluation of exploratory endpoints according to modified
RECIST (mRECIST) was removed 
With protocol version 4, the Sponsor specific evaluation of the exploratory endpoints
progression-free survival, PFS, objective response, duration of response (DOR), and 
disease control rate (DCR) according to modified RECIST was removed from the 
exploratory study objectives. These endpoints will continue to be evaluated according to 
industry standards of RECIST 1.1 (secondary endpoints) and immune modified RECIST 
(iRECIST) (exploratory endpoints).


RO7172508—F. Hoffmann-La Roche Ltd
4/Protocol BP40092, Version 4
Sections: 3 Objectives and Endpoints, 8.1.1 Tumor and Response Evaluations, 
9.4.2 Efficacy Analyses, Appendix 6 New Response Evaluation Criteria in Solid Tumors 
[RECIST] – Version 1.1 – Modified Excerpt from Original Publication with Addition of 
Supplementary Explanations (updated), Appendix 7 Modified RECIST v1.1 for Immune-
based Therapeutics (iRECIST) (added). 
3.
Option to administer subcutaneous cohorts Q3W
Rationale: Subcutaneous administration of RO7172508 QW had been planned in the 
previous protocol versions, once the IV dose escalation reached 6 mg to evaluate this 
route of administration. In the current amendment, an additional option was added to 
evaluate RO7172508 SC Q3W starting from a dose of 2 mg. This allows evaluation of 
SC RO7172508 route of administration in the event the MTD/OBD of IV RO7172508 is 
between 2 and 6 mg, which would not allow the planned QW dosing starting at 2 mg 
(minimal injectable dose).
Sections: 4.1 Overall Design and 4.1.2.2 Part II: Multiple-Ascending Dose-Escalation.
4.
Expansion of sCEA thresholds for doses less than 12 mg as additional
inclusion criterion for Part II
Rationale: Preliminary data from the first participants treated in Part I of this study 
suggest that RO7172508 may bind to circulating soluble CEA (sCEA) impacting 
exposure and therefore the pharmacodynamic effects of RO7172508. In Part II of the 
study, selection of participants by sCEA was originally not foreseen (in contrast to Part I). 
To reduce variability and the impact of sCEA on PK and PD, thresholds of sCEA have 
been set to limit baseline sCEA levels in participants receiving up to 12 mg of 
RO7172508. Furthermore, according to protocol version 4, in order to assess the 
relationship between sCEA and RO7172508 clearance relative to safety, at least 
3 participants with low levels of sCEA (≤ 20 ng/mL) will be enrolled in each cohort in Part 
II to assess the exposure-toxicity relationship. Depending on emerging PK and safety 
data, the dose escalation may be evaluated taking into account sCEA levels at baseline 
in a sensitivity analysis (i.e. dose escalating more conservatively in the event toxicity is 
associated with low baseline sCEA levels). 
Sections: 4.2.2 Rationale for Study Population and 5.1 Inclusion Criteria.
5.
Updated pre-medication
Rationale: In order to mitigate RO7172508-related toxicity, the use of pre-medication of 
corticosteroid on Cycle 1 of RO7172508 infusion for IRR/CRS occurrence was updated 
in protocol version 4 to also mitigate gastrointestinal RO7172508-related toxicity. The 
dose and timing of corticosteroid use relative to RO7172508 infusion was also updated. 


RO7172508—F. Hoffmann-La Roche Ltd
5/Protocol BP40092, Version 4
It was added that additional pre-medication regimens may be implemented after 
agreement between Sponsor and Investigators; these are 5-HT3-receptor antagonist 
administration and Budesonide. 10 mg metoclopramide (or equivalent anti-emetic) was 
removed.
Further options regarding the use and timing of pre-medication in subsequent 
RO7172508 infusions were provided, to enable participants to receive oral 
corticosteroids from Cycle 2 onwards, as deemed necessary by the Sponsor and/or 
Investigator.
Sections: 6.1.1 Pre-medication.
6.
Updated safety assessments
Rationale: Safety management guidelines for RO7172508 have been updated and 
aligned with guidelines of in class agent cibisatamab that reflect the evolving evidence 
and recent discussions with the FDA and EU health authorities. 
Sections: 8.2 Safety Assessments, 8.3.8.1 Infusion-Related Reactions/Cytokine-Release 
Syndrome, and 8.3.8.2 Suspected Tumor Inflammation.
7.
Inclusion Criteria 5 – Patients with Colorectal Cancer (CRC)
Inclusion criterion requires central assessment of CEA prior to enrollment, however for 
CRC participants only, the CEA assessment will be performed but the results are not 
required to enroll patients.
This change is based on internal prevalence analysis described in the RO7172508 
Investigator’s Brochure, showing 94% of CRC participants have CEA tumor expression 
meeting the eligibility criteria, therefore in order to simplify the enrollment process this 
assessment will be done at baseline retrospectively. 
8.
Exclusion Criteria 12 – Presence of bilateral lung lesions
Clarification for participants with bilateral lung lesions has been provided. Only 
unequivocal lesions of >1 cm are to be counted for this criterion, unless there is miliary 
metastasis-type diffuse disease, then these participants are ineligible.
Minor Changes
Minor changes to the protocol were made to align with the substantial changes specified 
above and improve consistency and clarity throughout the protocol. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RO7172508—F. Hoffmann-La Roche Ltd
6/Protocol BP40092, Version 4
PROTOCOL AMENDMENT, VERSION 4
SUMMARY OF CHANGES
The Summary of Changes to this protocol has been added in Appendix 9.


RO7172508—F. Hoffmann-La Roche Ltd
7/Protocol BP40092, Version 4
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM.....................................................................2
1.
PROTOCOL SUMMARY.............................................................................17
1.1
Synopsis ................................................................................17
1.2
Schematic of Study Design....................................................25
1.3
Schedule of Activities.............................................................25
2.
INTRODUCTION.........................................................................................55
2.1
Study Rationale......................................................................55
2.2
Background............................................................................56
2.2.1
Background on RO7172508 ..................................................56
2.2.2
Obinutuzumab........................................................................57
2.2.3
Background on Tocilizumab (RO4877533, 
ACTEMRA®, ROACTEMRA®)..............................................57
2.3
Benefit/Risk Assessment .......................................................58
3.
OBJECTIVES AND ENDPOINTS................................................................60
4.
STUDY DESIGN .........................................................................................62
4.1
Overall Design .......................................................................62
4.1.1
Length of the Study................................................................65
4.1.2
Dose-Escalation Decision Criteria..........................................65
4.1.2.1
Part I: Multiple-Ascending Dose-Escalation 
(Single Participant Cohorts)...................................................65
4.1.2.2
Part II: Multiple-Ascending Dose-Escalation 
(Multiple Participant Cohorts).................................................67
4.1.3
Obinutuzumab Pre-treatment.................................................71
4.1.3.1
Dose-Limiting Toxicities.........................................................73
4.1.4
Stopping Rules Criteria..........................................................74
4.1.5
Communication Strategy........................................................75
4.2
Scientific Rationale for Study Design.....................................75
4.2.1
Rationale for Modified Continuous 
Reassessment Method of Escalation with 
Overdose Control...................................................................75
4.2.2
Rationale for Study Population ..............................................76
4.2.3
Rationale for Control Group...................................................78


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8/Protocol BP40092, Version 4
4.2.4
Rationale for Biomarker Assessments...................................78
4.3
Dose Justification...................................................................79
4.3.1
RO7172508 ...........................................................................79
4.3.2
Obinutuzumab........................................................................80
4.4
End of Study Definition ..........................................................81
5.
STUDY POPULATION................................................................................81
5.1
Inclusion Criteria ....................................................................81
5.2
Exclusion Criteria...................................................................84
5.3
Lifestyle Considerations.........................................................85
5.4
Screen Failures......................................................................86
5.5
Recruitment Procedures ........................................................86
6.
TREATMENTS............................................................................................86
6.1
Treatments Administered.......................................................87
6.1.1
Pre-medication.......................................................................89
6.2
Preparation/Handling/Storage/Accountability.........................92
6.3
Measures to Minimize Bias: Randomization and 
Blinding..................................................................................93
6.3.1
Method of Treatment Assignment..........................................93
6.4
Treatment Compliance...........................................................93
6.5
Concomitant Therapy.............................................................93
6.5.1
Permitted Therapy .................................................................93
6.5.1.1
Radiotherapy .........................................................................94
6.5.2
Prohibited Therapy.................................................................94
6.6
Dosage Modification ..............................................................94
6.7
Treatment after the End of the Study.....................................95
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL.................................96
7.1
Discontinuation of Study Treatment.......................................96
7.1.1
Temporary Interruption ..........................................................97
7.2
Participant Discontinuation/Withdrawal from the 
Study......................................................................................97
7.3
Lost to Follow-Up...................................................................98
8.
STUDY ASSESSMENTS AND PROCEDURES..........................................98


RO7172508—F. Hoffmann-La Roche Ltd
9/Protocol BP40092, Version 4
8.1
Efficacy Assessments............................................................99
8.1.1
Tumor and Response Evaluations.........................................99
8.1.1.1
Radiographic Assessments ...................................................99
8.2
Safety Assessments ............................................................100
8.2.1
Physical Examinations.........................................................100
8.2.2
Vital Signs............................................................................100
8.2.3
Electrocardiograms..............................................................101
8.2.4
Clinical Safety Laboratory Assessments..............................102
8.2.5
Medical History and Demographic Data...............................102
8.3
Adverse Events and Serious Adverse Events......................102
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information...........................................................................103
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events....................................................................103
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events....................................................................104
8.3.3.1
Investigator Follow-Up .........................................................104
8.3.3.2
Sponsor Follow-Up ..............................................................104
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events....................................................................104
8.3.4.1
Emergency Medical Contacts ..............................................105
8.3.5
Pregnancy............................................................................105
8.3.6
Non-Serious Adverse Events of Special Interest .................105
8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs...........................106
8.3.8
Management of Specific Adverse Events ............................106
8.3.8.1
Infusion-Related Reactions/Cytokine Release 
Syndrome ............................................................................106
8.3.8.2
Suspected Tumor Inflammation ...........................................108
8.3.8.3
Management of Diarrhea/Colitis...........................................110
8.3.8.4
Management of Immunogenicity..........................................112
8.4
Treatment of Overdose........................................................112
8.5
Pharmacokinetics.................................................................112
8.5.1
Immunogenicity Assessments..............................................113


RO7172508—F. Hoffmann-La Roche Ltd
10/Protocol BP40092, Version 4
8.6
Pharmacodynamics .............................................................114
8.7
Genetics...............................................................................115
8.7.1
Clinical Genotyping..............................................................115
8.7.2
Whole Genome/Exome/Targeted DNA Analysis..................116
8.7.2.1
Transcriptome Analysis........................................................116
8.8
Biomarkers...........................................................................116
8.8.1
Samples for Research Biosample Repository......................118
8.8.1.1
Overview of the Research Biosample Repository................118
8.8.1.2
Sample Collection................................................................118
8.9
Medical Resource Utilization and Health 
Economics ...........................................................................119
8.10
Timing of Study Assessments..............................................119
8.10.1
Screening and Pre-treatment Assessments.........................119
8.10.2
Assessments during Treatment ...........................................120
8.10.3
Assessments at Study Completion/Early 
Termination Visit ..................................................................120
8.10.4
Follow-Up Assessments ......................................................120
8.10.5
Assessments at Unscheduled Visits ....................................120
9.
STATISTICAL CONSIDERATIONS ..........................................................121
9.1
Statistical Hypotheses..........................................................121
9.2
Sample Size Determination .................................................121
9.3
Populations for Analyses .....................................................122
9.4
Statistical Analyses..............................................................122
9.4.1
Demographics and Baseline Characteristics .......................123
9.4.2
Efficacy Analyses.................................................................123
9.4.3
Safety Analyses ...................................................................125
9.4.4
Pharmacokinetic Analyses...................................................126
9.4.5
Immunogenicity Analyses ....................................................127
9.4.6
Pharmacodynamic Analyses................................................127
9.5
Summaries of Conduct of Study ..........................................128
10. REFERENCES..........................................................................................129
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..................................................................................131


RO7172508—F. Hoffmann-La Roche Ltd
11/Protocol BP40092, Version 4
LIST OF TABLES
Table 1
Part I: Single Participant Cohorts IV/Multiple-ascending 
Dose-escalation ..........................................................................26
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple 
Ascending Dose-Escalation ........................................................29
Table 3
Part II: Multiple Participant Cohorts SC QW/Multiple 
Ascending Dose-Escalation ........................................................34
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W..........................39
Table 5
Schedule of Assessments for IRR and CRS related to 
RO7172508.................................................................................44
Table 6
Screening Schedule of Assessments with Obinutuzumab 
Pretreatment.................................................................................46
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC 
Q3W ............................................................................................49
Table 8
Objectives and Endpoints............................................................60
Table 9
Provisional Dose Levels in Absence of DLT................................69
Table 10
sCEA Concentrations Predicted to Result in 80% Recovery 
of RO7172508 at Doses Less Than 12 mg ..................................78
Table 11
RO7172508 Summary of Treatments Administered....................87
Table 12
Obinutuzumab Summary of Treatment Administered ................88
Table 13
Tocilizumab Summary of Treatment Administered......................88
Table 14
Steroid Use on Cycle 1 of RO7172508 Infusion to be 
implemented in the event of frequent IRR/CRS or 
gastrointestinal RO7172508-related toxicity occurrence after 
first administration .......................................................................89
Table 15
Steroid Use on Cycle 1 of RO7172508 or gastrointestinal 
RO7172508-related toxicity to be implemented in the event of 
frequent IRR/CRS persisting despite dose fractionation .............90
Table 16
Premedication Requirements for Obinutuzumab .......................92
Table 17
Recommendations for Management of IRRs and CRS 
considered related to RO7172508a ...........................................107
Table 18
Management of Suspected Tumor Inflammation.......................109
Table 19
Management of Diarrhea/Colitis................................................111
Table 20
Probabilities for Observing Adverse Events..............................121
Table 21
Analysis Populations .................................................................122
Table 22
Efficacy Statistical Analysis Methods ........................................124
Table 23
Safety Statistical Analysis Methods...........................................126
LIST OF FIGURES
Figure 1
Overview of Study Design...........................................................25
Figure 2
Fractionated Dosing Design for Q3W and QW............................64
Figure 3
Part I: Observation and DLT Windows ........................................66
Figure 4
Decision Tree During Dose Escalation .......................................72


 
RO7172508—F. Hoffmann-La Roche Ltd 
12/Protocol BP40092, Version 4 
Figure 5 
Decision Tree at End of Dose Escalation ..................................... 73 
Figure 6 
Recovery of RO7172508 in the Presence of sCEA ..................... 77 
 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ......... 132 
Appendix 2 
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting ........................................................... 140 
Appendix 3 
Procedures for Recording Adverse Events ............................... 148 
Appendix 4 
Clinical Laboratory Tests ........................................................... 154 
Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................ 156 
Appendix 6 
New Response Evaluation Criteria in Solid Tumors [RECIST] – 
Version 1.1 ................................................................................. 160 
Appendix 7 
Modified RECIST v1.1 for Immune-Based Therapeutics 
(iRECIST) ................................................................................. 170 
Appendix 8 
Supporting Statistical Documentation ...................................... 174 
Appendix 9 
Protocol Amendment History ..................................................... 188 


RO7172508—F. Hoffmann-La Roche Ltd
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
bpm
Beats per minute
Cmax
Maximum concentration
Cmin
Minimum concentration
CD3
Cluster of differentiation 3
CD3
CD3 epsilon chain
CEA
Carcinoembryonic antigen
CEACAM5
Carcinoembryonic antigenrelated cell adhesion 
molecule 5
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance
CNS
Central nervous system
CR
CRC
Complete response
Colorectal cancer
CRS
Cytokine release syndrome
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
Cytotoxic T-Lymphocyte Associated Protein 4
DCR
Disease control rate
DLT
Dose-limiting toxicities
DNA
Deoxyribonucleic acid
DOR
Duration of response
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
eCOA
Electronic clinical outcome assessment


RO7172508—F. Hoffmann-La Roche Ltd
14/Protocol BP40092, Version 4
Abbreviation
Definition
EOI
End of infusion
ESF
Eligibility Screening Form
EU
European Union 
FDA
Food and Drug Administration
FFPE
Formaldehyde fixed-paraffin-embedded 
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HLA-DR
Human Leukocyte Antigen – antigen D Related
HRT
Hormonal replacement therapy
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICOS
Inducible co-stimulator
IEC
Independent Ethics Committee
IFN
Interferon
IgE
Immunoglobulin E
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
iRECIST
Immune modified RECIST
irRC
Immune-related response criteria
IRR
Infusion related reaction
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LDH
Lactate dehydrogenase
LOE
Loss of exposure


RO7172508—F. Hoffmann-La Roche Ltd
15/Protocol BP40092, Version 4
Abbreviation
Definition
LPLV
Last participant, last visit
MABEL
Minimal anticipated biological effect level
mCRM-EWOC
Modified continual reassessment method with 
overdose control
MedDRA
Medical Dictionary for Regulatory Activities 
MIP
Macrophage Inflammatory Protein
MoA
Mode-of-action
MMR
Mismatch repair
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NGS
Next generation sequencing
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
OBD
Optimal biological dose
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Pharmacodynamic
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetic
PO
Oral
PR
Partial response
PS
Performance status
PT
Prothrombin time
Q3W
Every 3 weeks
QTc
QT corrected for heart rate
QTcB
QT corrected for heart rate using the Bazett’s 
correction factor
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor


RO7172508—F. Hoffmann-La Roche Ltd
16/Protocol BP40092, Version 4
Abbreviation
Definition
QW
Once a week
RBC
Red blood cell
RBR
Research Biosample Repository
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RR
Rate of response
SAE
Serious adverse event
SC
Subcutaneous
sCD25
Soluble CD25
sCEA
Serum CEA
SD
Stable disease
SI
International System of Units
SoA
Schedule of activities
SLD
Sum of longest diameters
SOC
Standard of care
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
T1/2
Half-life
TCB
T-cell bispecific
TCR
T-cell receptor
TCZ
Tocilizumab
TID
3 times a day
TIL
Tumor infiltrating lymphocytes
TIM3
T-cell immunoglobulin and mucin domain 3
Tmax
Time of maximum concentration
TNF
Tumor necrosis factor
ULN
Upper limit of normal
US
United States
V
Volume of distribution
Vss
Volume of distribution at steady state
WBC
White blood cell
WES
Whole exome sequencing
WGS
Whole genome sequencing
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential


RO7172508—F. Hoffmann-La Roche Ltd
17/Protocol BP40092, Version 4
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A FIRST-IN-HUMAN, OPEN-LABEL, MULTICENTER, DOSE-
ESCALATION PHASE I CLINICAL STUDY OF SINGLE-AGENT 
RO7172508 IN PATIENTS WITH LOCALLY ADVANCED AND/OR 
METASTATIC CEA-POSITIVE SOLID TUMORS
SHORT TITLE
Phase 1 Study of RO7172508 in Patients with CEA-Positive Solid 
Tumors
PROTOCOL NUMBER:
BP40092
VERSION:
4
TEST PRODUCT:
RO7172508 and obinutuzumab
PHASE:
I
RATIONALE
RO7172508 is a T-cell bispecific (TCB) antibody targeting carcinoembryonic antigen (CEA) 
expressed on tumor cells and cluster of differentiation 3 (CD3) epsilon chain (CD3) present on 
T-cells. RO7172508 has shown an increased affinity to CEA, higher potency, and prolonged 
half-life compared with RO6958688 (cibisatamab), a TCB targeting CEA under clinical 
development, which has induced objective radiological responses as a single agent and in 
combination with a programmed death-ligand 1 (PD-L1) checkpoint inhibitor (atezolizumab).
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine the maximum-tolerated 
dose (MTD) and/or the optimal biological 
dose (OBD) for intravenous (IV) and 
subcutaneous (SC) administrations of 
RO7172508 as monotherapy and with 
obinutuzumab pretreatment (if 
applicable)

Nature and frequency of dose limiting 
toxicities (DLTs) and other adverse 
events (AEs), pharmacodynamic (PD) 
and pharmacokinetic (PK) profile

To assess the safety and tolerability 
profile of RO7172508 and with 
obinutuzumab pretreatment (if 
applicable)

Incidence, nature and severity of AEs 
graded according to the National Cancer 
Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) 
v5.0
Secondary

To establish the IV and SC 
pharmacokinetics of RO7172508 given 
as monotherapy and with obinutuzumab 
pretreatment (if applicable)
The PK profiles and parameters derived for 
RO7172508 including where appropriate 
and when data allow, the parameters listed 
below:

Maximum concentration (Cmax)

Time of maximum concentration (Tmax)


RO7172508—F. Hoffmann-La Roche Ltd
18/Protocol BP40092, Version 4
Objectives
Endpoints

Clearance (CL) or apparent clearance 
(CL/F) (dependent on route of 
administration)

Volume of distribution at steady state (Vss)

Area under the curve (AUC)

Half-life (t1/2)

Other PK parameters may be 
determined, as deemed appropriate

To assess the incidence of anti-drug 
antibodies (ADAs) against RO7172508
and with obinutuzumab pretreatment (if 
applicable)

Presence or absence and titer of ADAs 

To characterize PD effects and duration 
of PD response for multiple doses and 
schedules of RO7172508 administration

Changes in frequency, activation status 
and spatial distribution of tumor 
infiltrating lymphocytes (TILs).

To assess preliminary anti-tumor activity 
of RO7172508.

Objective response rate (ORR)

Disease control rate (DCR); defined as 
rate of response [RR] + stable disease 
[SD]

Duration of response (DOR)

Progression-free survival (PFS) 
(on-treatment)
According to Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 
criteria by Investigator’s assessment.
OVERALL DESIGN
Study BP40092 is a first-in-human, open-label, multicenter, dose-escalation, Phase I clinical 
study to determine the maximum-tolerated dose (MTD) and/or the optimal biological dose (OBD) 
as well as the optimal schedule for intravenous (IV) and subcutaneous (SC) administrations of 
RO7172508 as monotherapy in participants with locally advanced and/or metastatic 
carcinoembryonic antigen (CEA)-positive solid tumors who have progressed on standard of 
care (SOC) treatment, are intolerant to SOC, and/or are non-amenable to SOC. 
Study Design
The study will be conducted in two parts.
Part I of the study will consist of an IV single participant cohort/multiple-ascending 
dose-escalation to evaluate the safety of RO7172508 at doses that are expected to be sub-
therapeutic. The starting-dose has been determined by an integrated approach, whereby the in 
vitro data (of both RO7172508 and cibisatamab) and clinical data of cibisatamab have been 
considered. RO7172508 will be administered IV every 3 weeks (Q3W), in up to approximately 5 
participants with high-CEA expression in their tumor (i.e., 20% of tumor cells with 
immunohistochemistry [IHC] 2+ and/or 3+). Intra-participant dose-escalation is allowed up to the 
maximum dose achieved in Part I.
Part II is a multiple participant cohort/multiple-ascending dose-escalation to define the MTD 
and/or OBD of RO7172508 administered as single agent, IV and/or SC, in participants with 
tumors that are expressing high as well as low-CEA (low defined as 20% of tumor cells with 
the sum of any IHC intensity (1+ 2+ and 3+) and not considered CEA-High).


RO7172508—F. Hoffmann-La Roche Ltd
19/Protocol BP40092, Version 4
The study will switch from Part I to Part II when the maximum planned dose for Part I is reached 
or the occurrence of a RO7172508-related Grade 2 adverse event (AE) or dose-limiting 
toxicity (DLT) is observed, whichever comes first. The Sponsor may decide to switch from Part I 
to Part II in the absence of an observed RO7172508-related Grade 2 toxicity or prior to 
maximum planned dose for Part I.
Treatment Groups and Duration
The investigational medicinal products (IMPs) are RO7172508, obinutuzumab and
tocilizumab.
Part I
In Part I, RO7172508 will be administered IV Q3W with a flat dose. The starting-dose of 
RO7172508 will be 65 g and the maximum dose explored will be 1.6 mg. An increment-based 
escalation will be utilized, with a maximum 3-fold increment from one dose-level to the next. 
Each cohort will include one participant in order to minimize the number of participants treated 
below the therapeutically relevant dose. Each participant will be followed up for a 4-week DLT 
window. The DLT window is divided into a 14-day safety observation period, after which the 
next cohort may be opened, and a further observation period of two weeks, to assess any 
potential late toxicity, including up to one week after the second administration on a Q3W 
dosing schedule. 
Part II
The starting-dose for the initiation of Part II IV dose-escalation will be determined by Part I and 
RO7172508 will be initially given Q3W. Dose-escalation will continue based on safety until 
determination of the MTD or the planned maximum dose of 400 mg. If on-target toxicity is 
reported predominantly in the first cycle of treatment, fractionated dosing may be implemented 
for the first cycle to improve tolerability. 
Once the IV schedule has shown RO7172508 preliminary clinical activity, defined by partial 
response (PR) or better, according to RECIST v. 1.1 (Appendix 6), or the MTD has been 
established and is equal to or above 2 mg, the SC multiple-ascending dose-finding cohorts 
could be initiated. The starting-dose and regimen (QW or Q3W) for SC administration will be 
proposed based on the evaluation of the safety and PK data observed following IV 
administration but will not exceed the highest safe dose tested in the IV Q3W dose escalation; 
however, due to practical considerations, a minimum dose of 2 mg is defined for a single SC 
administration. In addition, the QW SC starting-dose will not exceed one third of the IV 
MTD or of the highest safe IV dose tested.
In Part II, a modified continual reassessment method with overdose control (mCRM-EWOC) will 
guide the dose-escalation part to determine the MTD, by using primary safety variables 
(e.g., DLT). 
The MTD is defined as the dose with the highest probability that the DLT rate is within the target 
of 20% to 35%, and a low probability (25%) that the DLT rate is above 35%.
During the dose-escalation, at least 3 evaluable participants will be treated in a staggered 
manner at each dose-level (1 week or more between first and second participant, 1 day or more 
between subsequent participants). After the third evaluable participant in each cohort has 
completed the 3-week DLT period, the logistic regression model will be updated with the 
treatment outcome (i.e., the occurrence of DLT) and a new estimate of the MTD will be derived. 
Further enrollment into the next cohort will only resume after the Sponsor and the Investigators 
have jointly decided on the next dose-escalation step. Dose-escalation decisions and dose-
selection for the next cohort will be subject to clinical judgment (following review of safety and 
available PK and/or PD data [and not based solely on DLT information], as well as being guided 
by the EWOC recommendation). Built-in safety constraints are in place to prevent exposing 
participants to undue risk of toxicity, i.e., for Q3W dosing schedule, maximum allowable 
dose-increment, in absence of DLT, will be 100%; if one DLT occurs then, an increment of 50% 
maximum will be allowed. A new cohort of participants will be dosed at the new estimate of the 
MTD or the highest allowable dose based on pre-specified safety constraints, whichever is 
lower. The design will continue as described, assigning participants to the MTD as estimated 


RO7172508—F. Hoffmann-La Roche Ltd
20/Protocol BP40092, Version 4
from all of the DLT data cumulatively, until one of the pre-defined stopping criteria is satisfied or 
the pre-determined sample size is reached, whichever comes first.
If deemed necessary, at the end of dose escalation, to further characterize the safety, PK, and/or 
PD profile of RO7172508 IV and/or SC, additional participants (maximum of 15 participants) 
may be enrolled at the doses already tested or at doses that have not been explored for the 
determination of the MTD but not higher than MTD. The additional patients could be allocated to one 
or more doses; however, the total number will not exceed 15 participants across all doses.
Administration of Obinutuzumab
Administration of obinutuzumab is based on the incidence of anti-drug antibodies (ADAs) or 
evidence of loss of exposure (LOE) in a significant number of patients treated with 
RO7172508. For specific details of implementation see Section 4.1.3. 
Administration of Tocilizumab
Administration of tocilizumab is based on clinical presentation of cytokine release syndrome 
(CRS) and should follow the guidelines stated in Section 8.3.8.1. 
Length of Study
Study duration for each participant in Part I or Part II will be:
Screening: Days -28 to -1.
Treatment Period: Cycle 1 Day 1 to Month 24 (may be modified if supported by emerging data). 
Safety follow-up: 60 days after last treatment with RO7172508.
Survival follow-up: Every 3 months after the last treatment with RO7172508.
End of Study
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. Because of the exploratory nature of this clinical study, its conduct can be discontinued 
at any time at the discretion of the Sponsor.
PARTICIPANT POPULATION
Participants in this study are patients with locally advanced and/or metastatic CEA-expressing 
solid tumors with cytoplasmic and/or membranous CEA expression in ≥20% of cells at 
intensity of IHC1+ or greater.
Inclusion/Exclusion Criteria
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1.
Signed written informed consent and ability to comply with the study protocol according to 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and local regulations. 
Age
2.
Age 18 years. 
Type of Participants and Disease Characteristics
3.
For Part I (single participant cohorts), participants with locally advanced and/or metastatic 
solid tumor with confirmed cytoplasmic and/or membranous high CEA expression in tumor 
tissue (20% of tumor cells staining with CEA IHC 2+ or 3+ intensity) is required 
(participants without archived tumor tissue available for testing must have a lesion 
amenable to biopsy). Participants must have progressed on a SOC therapy, be intolerant to 
SOC, and/or are non-amenable to SOC.


RO7172508—F. Hoffmann-La Roche Ltd
21/Protocol BP40092, Version 4
4.
For <12 mg dose cohorts, serum CEA (sCEA) levels below a certain threshold is required as 
follows:

For dose cohorts 65-159 g, an sCEA level of 22 ng/mL.

For dose cohorts 160-399 g, an sCEA level of 28 ng/mL.

For dose cohorts 400-799 g, an sCEA level of 44 ng/mL.

For dose cohorts 800-1599 g, an sCEA level of 70 ng/mL.

For the dose cohort of 1.6 - 3.1 mg, an sCEA level of 123 ng/mL.

For the dose cohort of 3.2 - 6.3 mg, an sCEA level of 229 ng/mL.

For the dose cohort of 6.4 -11.9 mg, an sCEA level of 440 ng/mL.
If dose fractionation is implemented, the sCEA threshold for inclusion should correspond to the dose 
range of the first dose administered.
For Part II at least 3 participants in each cohort should have a baseline sCEA level 20 ng/ml.
5.
For Part II, participants with locally advanced and/or metastatic solid tumor expressing 
cytoplasmic and/or membranous on ≥ 20% of tumor cells of high-CEA or low-CEA on 
archival material (or fresh biopsy when archival is not available), who have progressed on a 
SOC therapy, are intolerant to SOC, and/or are non-amenable to SOC. Participants must 
have a lesion amenable to biopsy (except participants with NSCLC, which may be enrolled 
with archival tissue available only). For patients with colorectal cancer (CRC) only, the CEA 
assessment by IHC should be performed but the result is not required to enroll the patient.

High-CEA: 20% of tumor cells with IHC 2+ and/or 3+

Low-CEA: 20% of tumor cells with the sum of any IHC intensity (1+, 2+ and 3+) and 
not considered CEA-High
6.
Radiologically measurable disease according to RECIST v1.1.
7.
Life expectancy (in the opinion of the Investigator) of 12 weeks.
8.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
9.
All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must 
have resolved to Grade 1 or returned to baseline, except alopecia (any grade) and 
Grade 2 peripheral neuropathy.
10. Adequate hematological function: neutrophil count of 1.5 109 cells/L, platelet count 
of 100,000/L, and hemoglobin 8 g/dL (4.9 mmol/L) including lymphocytes within 
normal limits (0.8 109 cells/L).
11. Adequate liver function: total bilirubin 1.5 the upper limit of normal (ULN; excluding 
Gilbert‘s Syndrome), aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) 2.5 ULN (in case of liver metastases, 5 ULN).
12. Adequate renal function: creatinine clearance by Cockcroft Gault formula 60 mL/min for 
participants with, in the Investigator’s judgment, serum creatinine levels that do not 
adequately reflect renal function.
13. Adequate lung function: vital capacity and forced expiratory volume in first second 65% of 
age and body-weight predicted normal. Diffusion capacity 55% of predicted normal.
Sex
14. Male and female participants
The contraception and abstinence requirements are intended to prevent exposure of an embryo 
to the study treatment. The reliability of sexual abstinence for male and/or female enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred 
and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.


RO7172508—F. Hoffmann-La Roche Ltd
22/Protocol BP40092, Version 4
a.
Female Participants
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies:

Women of non-childbearing potential (WONCBP),

Women of childbearing potential (WOCBP), who:
–
Agree to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive methods that result in a failure rate of 1% per year from screening 
until 2 months after the last dose of RO7172508. Examples of contraceptive 
methods with a failure rate of 1% per year include bilateral tubal occlusion, male 
sterilization, and copper intrauterine devices.
–
Have a negative pregnancy test (blood) within one week prior to the first study 
treatment administration (applicable to premenopausal women and women 2 
years after start of menopause (menopause is defined as amenorrhea for 2 
years).
b.
Male Participants
During the treatment period and for at least 2 months after the last dose of study treatment}, 
agreement to:

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures 
such as a condom or a contraceptive method that result in a failure rate of 1% per year, 
with partners who are WOCBP. 

Refrain from donating sperm during the study.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Participants with a history or clinical evidence of central nervous system (CNS) primary 
tumors or metastases including leptomeningeal metastases unless they have been 
previously treated, are asymptomatic, and have had no requirement for steroids or 
enzyme-inducing anticonvulsants in the last 14 days before screening.
2.
Participants with non-irradiated lesions 2 cm at critical sites (e.g., paraspinal, 
paratracheal) where tumor swelling induced by RO7172508 is expected to lead to 
significant complications. 
3.
Participants with another invasive malignancy in the last 2 years (with the exception of 
basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood for 
recurrence).
4.
Evidence of significant, uncontrolled concomitant diseases that could affect compliance 
with the protocol or interpretation of results or contraindicate the use of an investigational 
drug, including diabetes mellitus and history of relevant pulmonary disorders.
Diagnostic Assessments
5.
Uncontrolled hypertension (systolic blood pressure [SBP] 150 mmHg and/or diastolic BP
[DBP] 100 mmHg), unstable angina, congestive heart failure New York Heart Association 
(NYHA) 1, serious cardiac arrhythmia that requires treatment with the exceptions of atrial 
fibrillation and paroxysmal supraventricular tachycardia, and history of myocardial 
infarction within 6 months of enrollment.
6.
Active or uncontrolled infections.
7.
Known hepatitis B or C (active replicating).


RO7172508—F. Hoffmann-La Roche Ltd
23/Protocol BP40092, Version 4
8.
Major surgery or significant traumatic injury 28 days prior to the first RO7172508 
administration (excluding biopsies) or anticipation of the need for major surgery during 
study treatment.
9.
Dementia or altered mental status that would prohibit informed consent.
10. Baseline corrected QT interval of 470 ms. Participants with baseline resting 
bradycardia 45 beats per minute (bpm) or baseline resting tachycardia 100 bpm.
11. Radiotherapy within the last 28 days prior to the first RO7172508 administration with the 
exception of limited-field palliative radiotherapy.
12. Presence of bilateral lung lesions with either 3 lesions per lung or 1 lesion per lung 
with a diameter 3 cm (only unequivocal lesions of >1 cm are to be counted for this 
criterion, unless there is miliary metastatic-type diffuse disease, then these participants 
are ineligible).
Prior/Concomitant Therapy
13. Concurrent therapy with any other investigational drug (defined as treatment for which 
there is currently no regulatory authority-approved indication) 28 days prior to the first 
RO7172508 administration.
14. Last dose with an immunostimulating or immunosuppressive therapy (e.g., interferon
(IFN)-, IFN-, interleukin [IL]-2, etanercept, infliximab, tacrolimus, cyclosporine, or 
mycophenolic acid) less than 28 days prior to the first RO7172508 administration.
15. Last dose of anti-CTLA4, anti-PD-L1 or anti-PD1 less than 180 days prior to the first 
RO7172508 administration.
16. Expected need for regular immunosuppressive therapy (i.e., for organ transplantation, 
chronic rheumatologic disease) within 28 days prior to the first RO7172508 administration.
17. Regular dose of corticosteroids within 28 days prior to Day 1 of this study or anticipated 
need for corticosteroids that exceeds prednisone 10 mg/day or equivalent within 28 days 
prior to the first RO7172508 administration. Inhaled and topical steroids are permitted.
18. Prior treatment with a bispecific T-cell engaging drug targeting CD3e and/or CEA.
Other Exclusions
19. Known hypersensitivity to any of the components of RO7172508.
Specific Exclusion Criteria if Pre-treatment with Obinutuzumab is Implemented
20. Known HIV (HIV testing will be performed at screening if required by local regulations)
21. Positive test results for chronic HBV infection (defined as positive HBsAg serology), HBcAb 
indicating an active viral infection and positive test results for HCV (HCV antibody serology 
testing). 
22. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is 
negative for HCV ribonucleic acid (RNA). 
23. History of progressive multifocal leukoencephalopathy. 
24. Active TB requiring treatment within 3 years prior to baseline. 
25. Latent TB diagnosed during Screening. 
26. Positive test results for human T-lymphotropic virus 1 (HTLV 1) 
27. HTLV testing is required in participants from endemic countries (Japan, countries in the Caribbean 
basin, South America, Central America, sub-Saharan Africa, and Melanesia) 
28. Known hypersensitivity to any of the components of obinutuzumab. 


RO7172508—F. Hoffmann-La Roche Ltd
24/Protocol BP40092, Version 4
NUMBER OF PARTICIPANTS
In Part I, approximately 5 participants will be enrolled. In Part II, up to approximately 
75 participants each dose-escalation, including additional 15 participants (150 participants total in 
both IV and SC) will be enrolled. In case the OBD is evaluated with and without 
obinutuzumab, an additional 15 participants may be enrolled.
CONCOMITANT MEDICATIONS
Permitted Therapy
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant during 
screening until the follow-up visit must be recorded along with reason for use, dates of 
administration (including start and end dates) and dosage information (including dose and 
frequency).
Radiotherapy
The use of palliative radiotherapy is allowed at any time during the study, except for:

Days where study drug is administered.

During the DLT evaluation window.

If radiotherapy is administered during the DLT evaluation window, the participant will 
not be evaluable.
Participants should not receive study treatment during radiation treatment.
Prohibited Therapy
The use of the following therapies is prohibited during the study and for at least 28 days prior to 
initiation of study treatment (unless otherwise specified):

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)

Chronic use of steroids (inhaled and topical steroids are permitted).

Administration of a live, attenuated vaccine within 28 days before Cycle 1 Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study.


RO7172508—F. Hoffmann-La Roche Ltd
25/Protocol BP40092, Version 4
1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in .
Figure 1
Overview of Study Design
1.3
SCHEDULE OF ACTIVITIES
The schedules of the activities (SoAs) are provided in Table 1 , Table 2, Table 3, Table 4
Table 5, Table 6, and Table 7.


RO7172508—F. Hoffmann-La Roche Ltd
26/Protocol BP40092, Version 4
Table 1
Part I: Single Participant Cohorts IV/Multiple-ascending Dose-escalation 
Cycle (21 days)
Screening
Cycle 1
(incl. 14-day observation period)
Cycle 23a
Cycle 4 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upo
Un-
scheduled 
(Safety)
Day
D-28 to 
D-1
Day 1
Day 2
Day 3 Day 8
Day
15
Day 1
Day 8
Day 
15
Day 1
Day 
8
Assessmentsa
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
24hs 
EOI
2 hrs
48hrs 
EOI
4 
hrs
pre-
dose
EOI
+15 
min
s
pre-
dose
EOI
+15 
mins
incl. early 
discont. visit 
(e.g. 
progressive 
disease)
60 Days 
after last 
treatmen
t (5 
Days)
90 Days 
after last 
treatmen
t then 
every 3 
mthso
e.g. In the 
event of an 
IRR ≥G2p
Informed Consentb
x
Eligibility
x
CEA confirmation 
on Archival Tissuej
xj
Demography
x
Medical History
x
Pulmonary 
Function Testst
x
Physical 
Examinationc
x
x
x
x
x
x
x
Anthropometric 
Measurementsd
x
x
x
x
x
x
ECOG 
Performance 
Status
x
x
x
x
x
x
x
Vital Signss
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematologyh
x
x
x
x
x
x
x
x
x
x
x
x
xr
x
x
x
x
Blood Chemistryh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulationh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serologyi
x
Urinalysish
x
x
x
x
x
x
Pregnancy Testf
xf
x
x
x
ECG-12 leade
x
x
x
x
x
xe
x


RO7172508—F. Hoffmann-La Roche Ltd
27/Protocol BP40092, Version 4
Table 1
Part I: Single Participant Cohorts IV/Multiple-ascending Dose-escalation (cont.)
Cycle (21 days)
Screening
Cycle 1
(incl. 14-day observation period)
Cycle 23a
Cycle 4 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival
Follow-
Upo
Un-
scheduled 
(Safety)
Day
D-28 to 
D-1
Day
1
Day
2
Day 
3
Day 
8
Day
15
Day 
1
Day 
8
Day 
15
Day 
1
Day 
8
Assessmentsa
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
24hs 
EOI
2 hrs
48hrs 
EOI
4 
hrs
pre-
dose
EOI
15 
mins
pre-
dose
EOI
+15 
mins
incl. early 
discont. visit 
(e.g. 
progressive 
disease)
60 Days 
after last 
treatmen
t (5 
Days)
90 Days 
after last 
treatmen
t then 
every 3 
mthsno
e.g. In the 
event of an 
IRR ≥G2p
Administration of 
RO7172508g
xl
xg
xg
Adverse Events
x
Previous and 
Concomitant 
Treatments
x
Tumor 
Assessmentk
x
xk
xk
x
sCEA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
RO7172508 PK 
Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA to 
RO7172508
x
x
x
x
x
x
x
x
x
x
PD Blood 
Cytokines
x
x
x
x
x
x
x
x
x
x
xn
xr
xn
x
xp
IgE and Tryptase 
xp
Notes: ADAanti-drug antibody; AEadverse event; CCycle; CEAcarcinoembryonic antigen; Dday; discontdiscontinuation; ECGelectrocardiogram; 
ECOGEastern Cooperative Oncology Group; G2grade 2; HIVhuman immunodeficiency virus; IgEimmunoglobulin E; inclincluding; IRRinfusion related 
reaction; PDpharmacodynamics; PKpharmacokinetic; RECISTResponse Evaluation Criteria in Solid Tumors; sCEAsoluble CEA.
a)
All visits from Cycle 3 onwards should occur within a 3-day time window, unless otherwise indicated and all assessments or samples where indicated should 
be taken prior to the administration of RO7172508.
b)
Informed consent must be obtained before any study-specific procedures and may be obtained > 28 days before the start of study treatment.
c)
Physical examinations to be performed on days of treatment administration, and at the 60-day safety follow‑up.
d)
Weight to be recorded pre-infusion. Height to be measured at screening only.


RO7172508—F. Hoffmann-La Roche Ltd
28/Protocol BP40092, Version 4
Table 1
Part I: Single Participant Cohorts IV/Multiple-ascending Dose-escalation (cont.)
e)
12-lead ECG at screening (within one week before first dose of RO7172508).  After Cycle 5, 12-lead ECG to be done only at every second cycle (i.e., C7, C9 
etc.). Additional unscheduled triplicate ECG assessments should be performed in case of abnormalities and/or if clinical symptoms occur. Recording must be 
done prior to PK sampling.
f)
Serum pregnancy test at screening, within 7 days prior to first dose, and at the safety follow-up visit; a urine pregnancy test will be performed at specified 
subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. Results must be obtained and reviewed prior to 
administration of RO7172508.
g)
All planned assessments are to be performed before administration of RO7172508. All participants in Part I of the study will receive, as a minimum, one dose 
of RO7172508.  If there are no safety concerns, participants may receive further doses Q3W at the same dose level.  Dose escalation for individual 
participants to the next available tolerated dose level can only proceed after a participant has tolerated their current dose for at least two cycles.
h)
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to scheduled dosing. 
Screening results can be within 1 week prior to C1D1. Results must be obtained and reviewed prior to administration of RO7172508.
i)
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results must be 
obtained and reviewed prior to administration of RO7172508.
j)
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material. A fresh tumor biopsy will be collected and assessed for 
eligibility ONLY if no archival tumor sample is available.
k)
Tumor response is assessed by the Investigator per RECIST v1.1 with the use of physical examination and image-based evaluation.  All measurable and 
evaluable lesions should be assessed and documented during the screening period, within 7 days before Cycle 3 Day 1, thereafter every 6 weeks ( 7 days) 
for 12 weeks, and then every 12 weeks ( 7 days) until disease progression or death. (i.e. screening, C3, C5, C7, C11, C15, C19 etc.).
l)
All planned assessments are to be performed before administration of RO7172508. At least 24 hour (overnight) hospital stay required following the 
administration of study drug at Cycle 1 Day 1.
m)
sCEA sample to be taken on Cycle 2 only.
n)
Cytokines from Cycle 5 onwards, samples to be taken every second cycle up to Cycle 15 (e.g. C5, C7 etc.).
o)
Survival follow-up visit to be performed 90 days (7 Days) after the last treatment either in person or a phone call to document any ongoing or resolved AEs, 
and every 3 months ( 2 weeks) thereafter for overall survival.
p)
Sample to be taken only if a ≥ Grade 2 safety event is suspected to be immune‑related (e.g., IRR). Refer to Table 5 for additional assessments if safety event 
is an IRR/CRS (Grade 3) that requires tocilizumab treatment.
q)
sCEA sample at screening to be taken within 14 days of Cycle 1 Day 1.
r)
Samples required for Cycle 4 and Cycle 5 only.
s)
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.
t)
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity (DLCO).


RO7172508—F. Hoffmann-La Roche Ltd
29/Protocol BP40092, Version 4
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple Ascending Dose-Escalation
Cycle (21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-Up
Survival 
Follow-
Upq
Unscheduled 
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
minsI
24 
hrs 
EOI 
2 
hrs
48 
hrs 
EOI
4 
hrs 
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
48 
hrs 
EOI 
1 
day 
pre-
dose
EOIt
+15 
mins
48 
hrs 
EOI 
4 
hrs 
incl. early 
discont. visit 
(e.g. 
progressive 
disease)
60 Days 
after last 
treatment 
(5 Days)
90 Days 
after last 
treatment 
then every 
3 mthsq
e.g. In the 
event of an 
IRR ≥G2o
Informed 
Consentb
x
Eligibility
x
Demography
x
Medical History
x
Pulmonary 
Function Testsw
x
Archival Tissueh
x
Previous and 
Concomitant 
Treatments
x
Adverse Events
x
Physical 
Examination
x
x
x
x
x
x
x
Anthropometric 
Measurementss
x
x
x
x
x
x
x
Vital Signsv
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xt
x
x
x
x
x
ECOG 
Performance 
Status
x
x
x
x
x
x
ECG-12 leadd
x
x
x
x
x
xd
x
Pregnancy Teste
x
x
x
x
Hematologyf
x
x
x
x
x
x
x
x
x
x
x
x
x
xt
x
x
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
30/Protocol BP40092, Version 4
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple Ascending Dose-Escalation (cont.)
Cycle 
(21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-Up
Survival 
Follow-
Upq
Unschedul
ed  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
24 
hrs 
EOI 
2 
hrs
48 
hrs 
EOI
4 
hrs
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
48 
hrs 
EOI 
+/- 1 
day 
pre-
dose
EOIt
+15 
mins
48 
hrs 
EOI 
4 
hrs 
incl. early 
discont. 
visit (e.g. 
progressiv
e disease)
60 Days 
after last 
treatment 
(5 Days)
90 Days 
after last 
treatment 
then every 
3 mthsq
e.g. In the 
event of an 
IRR ≥G2o
Blood Chemistryf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulationf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serologyr
x
Urinalysisf
x
x
x
x
x
x
Fresh Tumor 
Biopsyg
xg
xg
xg
Tumor 
Assessmenti
x
xi
xi
x
Tumor Kineticsl
x
Administration of 
obinutuzumabx
xx
Obinutuzumab PK 
Samplex
xx
x
xu
x
xy
x
ADA to 
obinutuzumab
x
xy
Administration of 
RO7172508j
xj
xj
xj
RO7172508 PK 
Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA to 
RO7172508
x
x
x
x
x
x
x
x
x
x
sCEA
xz
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
31/Protocol BP40092, Version 4
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple Ascending Dose-Escalation (cont.)
Cycle 
(21 days)
Screenin
g
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-Up
Survival 
Follow-Upq Unschedule
d  (Safety)
Day
D-28 to
D-1
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
24 
hrs 
EOI 
2 
hrs
48 
hrs 
EOI
4 
hrs 
pre-
dose
EOI
+15 
mins
2 hrs 
EOI
15 
mins
48 
hrs 
EOI 
1 
day 
pre-
dose
EOIt
+15 
mins
48 
hrs 
EOI 
4 
hrs 
incl. early 
discont. 
visit e.g. 
progressive 
disease
60 Days after 
last treatment 
(5 Days)
90 Days 
after last 
treatment 
then every 
3 mthsq
e.g. In the 
event of an 
IRR ≥G2o
PD Blood Flow 
Cytometry
x
x
x
x
x
xaa
x
PD Blood 
Cytokines
x
x
x
x
x
x
x
x
x
x
x
x
xm
xt
xm
x
xo
TCR Vβk
xk
xk
CtDNA/tumor 
markers
xk
xn
Clinical 
Genotyping
xu
RBR Sample 
(DNA)
xu
RBR Sample 
(RNA)
xu
xn
IgE & Tryptase 
xo
Notes: ADAanti-drug antibody; AEadverse event; CCycle; CEAcarcinoembryonic antigen; ctcirculating tumor; Dday; discontdiscontinuation; 
DNAdeoxyribonucleic acid; ECGelectrocardiogram; ECOGEastern Cooperative Oncology Group; G2grade 2; HIVhuman immunodeficiency virus; 
IgEimmunoglobulin E; inclincluding; IRRinfusion related reaction; PDpharmacodynamics; PKpharmacokinetic; RBRResearch Biosample Repository; 
RECISTResponse Evaluation Criteria in Solid Tumors; RNAribonucleic acid; sCEA soluble CEA; TCR T cell receptor.
a)
All visits from Cycle 3 onwards should occur within a 3-day time window, unless otherwise indicated and all assessments or samples where indicated should 
be taken prior to the administration of RO7172508.
b)
Informed consent must be obtained before any study-specific procedures and may be obtained > 28 days before the start of study treatment.
c)
Visit to be done only every second cycle after Cycle 5. (i.e. C7, C9 etc.).
d)
12-lead ECG at screening (within one week before first dose of RO7172508).  After Cycle 4, 12-lead ECG to be done only at every second cycle (i.e. Cycle 6, 
Cycle 8 etc.). Additional unscheduled ECG assessments in triplicate should be performed in case of abnormalities and if clinical symptoms occur. Recording 
must be done prior to PK sampling.


RO7172508—F. Hoffmann-La Roche Ltd
32/Protocol BP40092, Version 4
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple Ascending Dose-Escalation (cont.)
e)
Serum pregnancy test at screening, within 7 days prior to first dose, and at the safety follow-up visit; a urine pregnancy test will be performed at specified 
subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. Results must be obtained and reviewed prior to 
administration of RO7172508.
f)
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to scheduled dosing. 
Screening results can be within 1 week prior to C1D1. Results must be obtained and reviewed prior to administration of RO7172508.
g)
Tumor biopsy samples will be collected during screening, once during the study treatment period at Cycle 2 Day 8 and optionally at the end of treatment visit 
ONLY if the reason for discontinuation is progressive disease. If a fresh biopsy is performed for screening purposes, this can be used as the baseline sample.
h)
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material, with the exception of CRC participants. If no archival tumor 
sample is available, fresh sample will be collected and be assessed (the same sample would constitute as baseline screening sample if participant is enrolled). 
Archival tissue should be submitted for additional biomarker assessments for all participants (if available).
i)
Tumor response is assessed by the Investigator per RECIST V1.1 with the use of physical examination and image-based evaluation.  All measurable and 
evaluable lesions should be assessed and documented during the screening period, within 7 days before Cycle 3 Day 1, thereafter every 6 weeks (± 7 days) 
for 12 weeks, and then every 12 weeks (± 7 days) until disease progression or death. (i.e. screening, C3, C5, C7, C11, C15, C19 etc.).
j)
All planned assessments are to be performed before administration of RO7172508. At least 24 hours (overnight) hospital stay required following administration 
of study drug at Cycle 1 Day 1.
k)
TCR Vβ and CtDNA/tumor marker samples to be drawn at Cycle 1 Day 1 predose (baseline) and Cycle 5 Day 1 predose.
l)
To allow estimation of tumor growth rate before start of treatment, an exploratory assessment of tumor kinetics will be made by comparing post-treatment 
scans with at least 2 pretreatment scans not older than 12 weeks prior to C1D1, if available. One of the pretreatment scans will be the study baseline scan 
taken during screening and the second will be within the preceding 12 weeks.
m)
Cytokines from Cycle 5 onwards, samples to be taken every second cycle up to Cycle 15 (e.g. C5, C7 etc.).
n)
RBR (RNA) and CtDNA/tumor markers samples to be taken on Cycle 5 only.
o)
Sample to be taken only if Grade 2 the safety event is suspected to be immune‑related (e.g., IRR). Refer to Table 5
for additional assessments if safety 
event is an IRR/CRS (Grade 3) that requires tocilizumab treatment. Any biopsy samples or results done as part of standard of care can be shared with the
Sponsor if applicable.
p)
The Day 3 visit may be adjusted +/- 1 day depending on safety and PD data. The visit optimal timepoint will be communicated to the Investigators for 
consistency and should occur 4 hrs from each complete day of administration (i.e. 24hrs 4hrs; 48 hrs 4hrs; OR 72hrs 4hrs).
q)
Survival follow-up visit to be performed 90 days ( 7 Days) after the last treatment either in person or a phone call to document any ongoing or resolved AEs, 
and every 3 months ( 2 weeks) thereafter for overall survival.


RO7172508—F. Hoffmann-La Roche Ltd
33/Protocol BP40092, Version 4
Table 2
Part II: Multiple Participant Cohorts IV Q3W/Multiple Ascending Dose-Escalation (cont.)
r)
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results must be 
obtained and reviewed prior to administration of RO7172508.
s)
Weight to be recorded pre-infusion. Height to be measured at screening only.
t)
Required for Cycle 5 only.
u)
Samples to be collected only in Cycle 1
v)
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.
w)
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity (DLCO).
x)
Refer to Table 6 in the event obinutuzumab pre-treatment is implemented for specific additional assessments during the screening period.
y)
Obinutuzumab ADA and PK samples to be taken only in Cycle 5 and 7 before administration of RO7172508.
z)
sCEA to be assessed for enrollment in cohorts with RO7172508 doses < 12 mg.
aa)
PD blood flow cytometry to be taken from Cycle 5 onwards only at Cycles 8,12 and 16 at predose


RO7172508—F. Hoffmann-La Roche Ltd
34/Protocol BP40092, Version 4
Table 3
Part II: Multiple Participant Cohorts SC QW/Multiple Ascending Dose-Escalation
Cycle 
(21 days)
Screeningx
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upr
Unscheduled 
(Safety)
Day
D-28 to 
D-1
Day 1
Day 
2
Day 
3
Day 
5t
Day 
8
Day 
10o
Day 
15
Day 
17
Day 
1
Day
5t
Day 
8
Day 
15
Day 
1
Day 
5ct
Day 
8
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
post 
dose 
(2 
hrs)
48 
hrs 
post 
dose 
(4 
hrs)
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
96 hrs 
post 
dose
(1 
day) 
pre-
dose
pre-
dose
pre-
dose
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
pre-
dose
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 days 
after last 
treatment
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2n
Informed 
Consentb
x
Eligibility
x
Demography
x
Medical History
x
Pulmonary 
Function 
Testsw
x
Archival 
Tissueh
x
Previous and 
Concomitant 
Treatments
x
Adverse Events
x
Physical 
Examination
x
x
x
x
x
x
x
Anthropometric 
Measurementsq
x
x
x
x
x
Vital Signsv
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECOG 
Performance 
Status
x
x
x
x
x
x
x
ECG-12 leadd
x
x
x
x
x
xd
x
x
Pregnancy 
Teste
x
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
35/Protocol BP40092, Version 4
Table 3
Part II: Multiple Participant Cohorts SC QW/Multiple Ascending Dose-Escalation (cont.)
Cycle (21 days)
Screeningx
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upr
Unscheduled 
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
5t
Day 
8
Day 
10o
Day 
15
Day 
17
Day 
1
Day
5t
Day 
8
Day 
15
Day 1
Day 
5ct
Day 
8
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
post 
dose 
(2 
hrs)
48 
hrs 
post 
dose 
(4 
hrs)
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
96 
hrs 
post 
dose
(1 
day) 
pre-
dose
pre-
dose
pre-dose
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
pre-
dose
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 days 
after last 
treatment
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2n
Hematologyf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood Chemistryf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulationf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serologyu
x
Urinalysisf
x
x
x
x
x
x
x
Fresh Tumor Biopsyg
x
xg
xg
Tumor Assessmenti
x
xi
xi
x
Tumor KineticsJ
x
Administration of 
obinutuzumabx
xx
Obinutuzumab PK 
Samplexy
xx
x
x
x
xy
x
ADA to obinutuzumabxy
xx
xy
Administration of 
RO7172508s
xs
xs
xs
xs
xs
xs
xs
xs
xs
RO7172508 PK 
Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA to RO7172508
x
x
x
x
x
x
x
x
x
x
sCEA
xz
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PD Blood Flow 
Cytometry
x
x
x
x
x
x
xaa
x
PD Blood Cytokines
x
x
x
x
x
x
x
x
x
x
x
xp
xk
xk
x
xn
TCR Vβl
x
xl
CtDNA/tumor markers
x
xm


RO7172508—F. Hoffmann-La Roche Ltd
36/Protocol BP40092, Version 4
Table 3
Part II: Multiple Participant Cohorts SC QW/Multiple Ascending Dose-Escalation (cont.)
Cycle 
(21 days)
Screeningx
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upr
Unscheduled 
(Safety)
Day
D-28 to
D-1
Day 1
Day 
2
Day 
3
Day 
5t
Day 
8
Day 
10o
Day 
15
Day 
17
Day 
1
Day
5t
Day 
8
Day 
15
Day 
1
Day 
5ct
Day 
8
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
post 
dose 
(2 
hrs)
48 
hrs 
post 
dose 
(4 
hrs)
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
48 
hrs 
post 
dose
(4 
hrs) 
pre-
dose
96 hrs 
post 
dose
(1 
day) 
pre-
dose
pre-
dose
pre-
dose
96 
hrs 
post 
dose 
(5 
hrs)
pre-
dose
pre-
dose
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 days 
after last 
treatment
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2n
Clinical 
Genotyping
x
RBR Sample 
(DNA)
x
RBR Sample 
(RNA)
x
xm
IgE and 
Tryptase 
xn
Notes: ADAanti-drug antibody; AEadverse event; CCycle; CEAcarcinoembryonic antigen; ctcirculating tumor; Dday; discontdiscontinuation; 
DNAdeoxyribonucleic acid; ECGelectrocardiogram; ECOGEastern Cooperative Oncology Group; G2grade 2; HIVhuman immunodeficiency virus; 
IgEimmunoglobulin E; inclincluding; IRRinfusion related reaction; PDpharmacodynamics; PKpharmacokinetic; RBRResearch Biosample Repository; 
RECISTResponse Evaluation Criteria in Solid Tumors; RNAribonucleic acid; sCEAsoluble CEA; TCRT cell receptor.
a)
All visits from Cycle 3 onwards should occur within a 3-day time window, unless otherwise indicated and all assessments or samples where indicated should 
be taken prior to the administration of RO7172508.
b)
Informed consent must be obtained before any study-specific procedures and may be obtained > 28 days before the start of study treatment.
c)
Day 5 visit to be done only every second cycle after Cycle 5. (i.e. C7, C9 etc.).
d)
12-lead ECG at screening (within one week before first dose of RO7172508).  After Cycle 4, 12-lead ECG to be done only at every second cycle (i.e. Cycle 6, 
Cycle 8 etc.). Additional unscheduled ECG assessments in triplicate should be performed in case of abnormalities and if clinical symptoms occur. Recording 
must be done prior to PK sampling.
e)
Serum pregnancy test at screening, within 7 days prior to first dose, and at the safety follow-up visit; a urine pregnancy test will be performed at specified 
subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. Results must be obtained and reviewed prior to 
administration of RO7172508.


RO7172508—F. Hoffmann-La Roche Ltd
37/Protocol BP40092, Version 4
Table 3
Part II: Multiple Participant Cohorts QW SC/Multiple Ascending Dose-Escalation (cont.)
f)
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to scheduled dosing. 
Screening results can be within 1 week prior to C1D1. Results must be obtained and reviewed prior to administration of RO7172508.
g)
Tumor biopsy samples will be collected during screening, once during the study treatment period at Cycle 2 Day 8 and optionally at the end of treatment visit 
ONLY if the reason for discontinuation is progressive disease. If a fresh biopsy is performed for screening purposes, this can be used as the baseline sample.
h)
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material, with the exception of CRC participants. If no archival tumor 
sample is available, fresh sample will be collected and be assessed (the same sample would constitute as baseline screening sample if participant is enrolled). 
Archival tissue should be submitted for additional biomarker assessments for all participants (if available).
i)
Tumor response is assessed by the Investigator per RECIST V1.1 with the use of physical examination and image-based evaluation.  All measurable and 
evaluable lesions should be assessed and documented during the screening period, within 7 days before Cycle 3 Day 1,  thereafter every 6 weeks (± 7 days) 
for 12 weeks, and then every 12 weeks (± 7 days) until disease progression or death. (i.e. screening, C3, C5, C7, C11, C15, C19 etc.).
j)
To allow estimation of tumor growth rate before start of treatment, an exploratory assessment of tumor kinetics will be made by comparing posttreatment 
scans with at least 2 pretreatment scans not older than 12 weeks prior to C1D1, if available. One of the pretreatment scans will be the study baseline scan 
taken during screening and the second will be within the preceding 12 weeks.
k)
Cytokines from Cycle 5 onwards, samples to be taken every second cycle up to Cycle 15 (e.g. C5, C7 etc.).
l)
TCR Vβ samples to be drawn at Cycle 1 Day 1 predose (baseline) and Cycle 5 Day 1 predose.
m)
RBR (RNA) and CtDNA/tumor markers samples to be taken on Cycle 5 only.
n)
Sample to be taken only if a ≥ Grade 2 safety event is suspected to be immune‑related (e.g., IRR). Refer to Table 5 for additional assessments if safety event 
is an IRR/CRS (∃Grade 3) that requires tocilizumab treatment. Any biopsy samples or results done as part of standard of care can be shared with the Sponsor if 
applicable.
o)
Visit may be omitted depending on emerging safety data for SC and/or fractionated dosing regimens after discussion between Investigators and the Sponsor.
p)
Cytokines sample to be taken on Cycle 2 only.
q)
Weight to be recorded pre-infusion. Height to be measured at screening only.
r)
Survival follow-up visit to be performed 90 days ( , 7 Days) after the last treatment either in person or a phone call to document any ongoing or resolved AEs, 
and every 3 months ( , 2 weeks) thereafter for overall survival.
s)
All planned assessments are to be performed before administration of RO7172508.
t)
Day 5 visit optional if it falls on a non-working day and can be performed +/- 1 day.
u)
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results must be 
obtained and reviewed prior to administration of RO7172508.
v)
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.


RO7172508—F. Hoffmann-La Roche Ltd
38/Protocol BP40092, Version 4
Table 3
Part II: Multiple Participant Cohorts QW SC/Multiple Ascending Dose-Escalation (cont.)
w)
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity (DLCO).
x)
Refer to Table 6 in the event obinutuzumab pre-treatment is implemented for specific additional assessments during the screening period.
y)
Obinutuzumab ADA and PK samples to be taken only in Cycle 5 and 7 before administration of RO7172508.
z)
sCEA to be assessed for enrollment in cohorts with RO7172508 doses < 12 mg.
aa)
PD blood flow cytometry to be taken from Cycle 5 onwards only at Cycles 8,12 and 16 at predose


RO7172508—F. Hoffmann-La Roche Ltd
39/Protocol BP40092, Version 4
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W 
Cycle (21 
days)
Screen
-ingw
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treat-
ment
Safety 
Follow
-Up
Survival 
Follow-
Upr
Un-
scheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day
8
Day 
9p
Day 
15
Day 
16p
Day 
1
Da
y 3
Day 
8
Day 
15
Day 1
Day 
3c
Da
y 
15
Assessmentsa
pre-
dose
EOI
+15 
min
s
2 
hrs  
EOI
15 
min
s
24 
hrs  
EOI 
2 
hrs
48 
hrs  
EOI
4 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
2 
hrs 
EOI
15 
min
s
48 
hrs 
EOI
4 
hrs
pre-
dos
e
EOIt
+15 
mins
48 
hrs 
EOI
4 
hrs
incl. 
early 
discont. 
visit 
(e.g. 
progress
ive 
disease)
60 
Days 
after 
last 
treatme
nt (5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2o
Informed 
Consentb
x
Eligibility
x
Demography
x
Medical History
x
Pulmonary 
Function Testsv
x
Archival 
Tissueh
x
Previous and 
Concomitant 
Treatments
x
Adverse Events
x
Physical 
Examination
x
x
x
x
x
x
x
Anthropometric 
Measurementsq
x
x
x
x
x
x
x
Vital Signsu
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xt
x
x
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
40/Protocol BP40092, Version 4
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W (cont.)
Cycle (21 
days)
Screen
-ingw
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treat-
ment
Safety 
Follow
-Up
Survival 
Follow-
Upr
Un-
scheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day
8
Day 
9p
Day 
15
Day 
16p
Day 
1
Day 
3
Da
y 8
Day 
15
Day 1
Day 
3c
Da
y 
15
Assessmentsa
pre-
dose
EOI
+15 
min
s
2 
hrs  
EOI
15 
min
s
24 
hrs  
EOI 
2 
hrs
48 
hrs  
EOI
4 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
2 
hrs 
EOI
15 
min
s
48 
hrs 
EOI 
4 
hrs
pre-
dos
e
EOIt
+15 
mins
48 
hrs 
EOI 
4 
hrs
incl. 
early 
discont. 
visit 
(e.g. 
progress
ive 
disease)
60 
Days 
after 
last 
treatme
nt (5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2o
ECOG 
Performance 
Status
x
x
x
x
x
x
ECG-12 leadd
x
x
x
x
x
xd
x
Pregnancy 
Teste
x
x
x
x
Hematologyf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xt
x
x
x
x
x
Blood 
Chemistryf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulationf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serologys
x
Urinalysisf
x
x
x
x
x
x
Fresh Tumor 
Biopsyg
x
xg
xg
Tumor 
Assessmenti
x
xi
xi
x
Tumor Kineticsl
x
Administration 
of 
obinutuzumabw
xw
Obinutuzumab 
PK Samplewx
xw
x
x
x
xx
x
ADA to 
obinutuzumabwx
xw
xx
Administration 
of RO7172508 j
xj
xj
xj
xj
xj


RO7172508—F. Hoffmann-La Roche Ltd
41/Protocol BP40092, Version 4
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W (cont.)
Cycle (21 
days)
Screen
-ingw
Cycle 1
Cycle 2 - 4a
Cycle 5 onwardsa
End of 
Treat-
ment
Safety 
Follow
-Up
Survival 
Follow-
Upr
Un-
scheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day
8
Day 
9p
Day 
15
Day 
16p
Day 1
Day 
3
Da
y 8
Day 
15
Day 1
Day 
3 c
Da
y 
15
Assessmentsa
pre-
dose
EOI 
+15 
min
s
2 
hrs  
EOI 
15 
min
s
24 
hrs  
EOI 
2 
hrs
48 
hrs  
EOI
4 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
24 
hrs  
EOI 
2 
hrs
pre-
dos
e
EOI
+15 
min
s
2 
hrs 
EOI
15 
min
s
48 
hrs 
EOI
4 
hrs
pre-
dos
e
EOI
t 
+15 
mins
48 
hrs 
EOI 
4 
hrs
incl. 
early 
discont. 
visit 
(e.g. 
progress
ive 
disease)
60 
Days 
after 
last 
treatme
nt (5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsr
e.g. In the 
event of an 
IRR ≥G2o
RO7172508 PK 
Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xt
x
x
x
x
x
ADA to 
RO7172508
x
x
x
x
x
x
x
x
x
x
sCEA
xy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PD Blood Flow 
Cytometry
x
x
x
x
x
x
xz
x
PD Blood 
Cytokines
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xm
xt
xm
x
xo
TCR Vβk
x
xk
CtDNA/tumor 
markers
x
xn
Clinical 
Genotyping
x
RBR Sample 
(DNA)
x
RBR Sample 
(RNA)
x
xn
IgE and 
Tryptase 
xo


RO7172508—F. Hoffmann-La Roche Ltd
42/Protocol BP40092, Version 4
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W (cont.)
Notes: ADAanti-drug antibody; AEadverse event; CCycle; CEAcarcinoembryonic antigen; ctcirculating tumor; Dday; discontdiscontinuation; 
DNAdeoxyribonucleic acid; ECGelectrocardiogram; ECOGEastern Cooperative Oncology Group; G2grade 2; HIVhuman immunodeficiency virus; 
IgEimmunoglobulin E; inclincluding; IRRinfusion related reaction; PDpharmacodynamics; PKpharmacokinetic; RBRResearch Biosample Repository; 
RECISTResponse Evaluation Criteria in Solid Tumors; RNAribonucleic acid; sCEAsoluble CEA; TCRT cell receptor.
a)
All visits from Cycle 3 onwards should occur within a 3-day time window, unless otherwise indicated and all assessments or samples where indicated should 
be taken prior to the administration of RO7172508.
b)
Informed consent must be obtained before any study-specific procedures and may be obtained > 28 days before the start of study treatment.
c)
Day 3 visit to be done only every second cycle after Cycle 5. (i.e. C7, C9 etc.).
d)
12-lead ECG at screening (within one week before first dose of RO7172508).  After Cycle 4, 12-lead ECG to be done only at every second cycle (i.e. Cycle 6, 
Cycle 8 etc.). Additional unscheduled ECG assessments in triplicate should be performed in case of abnormalities and if clinical symptoms occur. Recording 
must be done prior to PK sampling.
e)
Serum pregnancy test at screening, within 7 days prior to first dose, and at the safety follow-up visit; a urine pregnancy test will be performed at specified 
subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. Results must be obtained and reviewed prior to 
administration of RO7172508.
f)
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to scheduled dosing. 
Screening results can be within 1 week prior to C1D1. Results must be obtained and reviewed prior to administration of RO7172508.
g)
Tumor biopsy samples will be collected during screening, once during the study treatment period at Cycle 2 Day 8 and optionally at the end of treatment visit 
ONLY if the reason for discontinuation is progressive disease. If a fresh biopsy is performed for screening purposes, this can be used as the baseline sample.
h)
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material, with the exception of CRC participants. If no archival tumor 
sample is available, fresh sample will be collected and be assessed (the same sample would constitute as baseline screening sample if participant is enrolled).
Archival tissue should be submitted for additional biomarker assessments for all participants (if available).
i)
Tumor response is assessed by the Investigator per RECIST V1.1 with the use of physical examination and image-based evaluation.  All measurable and 
evaluable lesions should be assessed and documented during the screening period, within 7 days before Cycle 3 Day 1, thereafter every 6 weeks (± 7 days) 
for 12 weeks, and then every 12 weeks (± 7 days) until disease progression or death. (i.e. screening, C3, C5, C7, C11, C15, C19 etc.).
j)
All planned assessments are to be performed before administration of RO7172508. At least 24 hours (overnight) hospital stay required following administration 
of study drug at Cycle 1 Day 1.


RO7172508—F. Hoffmann-La Roche Ltd
43/Protocol BP40092, Version 4
Table 4
Part II: Fractionated Dosing IV Cohort for Q3W (cont.)
k)
TCR Vβ samples to be drawn at Cycle 1 Day 1 predose (baseline) and Cycle 5 Day 1 predose.
l)
To allow estimation of tumor growth rate before start of treatment, an exploratory assessment of tumor kinetics will be made by comparing posttreatment 
scans with at least 2 pretreatment scans not older than 12 weeks prior to C1D1, if available. One of the pretreatment scans will be the study baseline scan 
taken during screening and the second will be within the preceding 12 weeks.
m)
Cytokines from Cycle 5 onwards, samples to be taken every second cycle up to Cycle 15 (e.g. C5, C7 etc.).
n)
RBR (RNA) and CtDNA/tumor markers samples to be taken on Cycle 5 only.
o)
Sample to be taken only if a ≥ Grade 2 safety event is suspected to be immune‑related (e.g., ≥ G2 IRR). Refer to Table 5 for additional assessments if safety 
event is an IRR/CRS (∃Grade 3) that requires tocilizumab treatment. Any biopsy samples or results done as part of standard of care can be shared with the Sponsor if 
applicable.
p)
Visit may be omitted depending on emerging safety data for fractionated dosing regimens after discussion between Investigators and the Sponsor.
q)
Weight to be recorded pre-infusion. Height to be measured at screening only.
r)
Survival follow-up visit to be performed 90 days ( , 7 Days) after the last treatment either in person or a phone call to document any ongoing or resolved AEs, 
and every 3 months ( , 2 weeks) thereafter for overall survival.
s)
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results must be 
obtained and reviewed prior to administration of RO7172508.
t)
Required for Cycle 5 only.
u)
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.
v)
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity (DLCO).
w)
Refer to Table 6 in the event obinutuzumab pre-treatment is implemented for specific additional assessments during the screening period.
x)
Obinutuzumab ADA and PK samples to be taken only in Cycle 5 and 7 before administration of RO7172508.
y)
sCEA to be assessed for enrollment in cohorts with RO7172508 doses < 12 mg.
z)
PD blood flow cytometry to be taken from Cycle 5 onwards only at Cycles 8,12 and 16 at predose


RO7172508—F. Hoffmann-La Roche Ltd
44/Protocol BP40092, Version 4
Table 5
Schedule of Assessments for IRR and CRS related to RO7172508
Assessment/Procedure
Pre-TCZ Treatment 
(within 24 hours)g
TCZ 
Administration
Post-TCZ Treatmentc
End of infusion
(15 mins)
2 hours
(15 mins)
24 hours
(2 hrs)
TCZ Administration (8 mg/kg)
X
Vital signsa
X 
Measure at least every 6 hours until resolution to baselinef
Pressor documentationb
X 
Record at least every 6 hours until pressors are discontinuedf
FiO2 or L/min of 100% O2
X
Record at least every 6 hours until patient on room airf
Local Laboratory Assessments
Hematology
X
X
X
X
Blood chemistry 
X
X
X
X
Coagulation 
X
X
X
X
Infection workupd
X
Central Laboratory Assessments
Plasma cytokinese
X
Xh
X
X
X
aPTT activated partial thromboplastin time; CRP C-reactive protein; CRS cytokine release syndrome; eCRF electronic Case Report Form; 
INR international normalized ratio; IL-6 interleukin 6; LDH lactate dehydrogenase; PT prothrombin time; TCZ tocilizumab.
Record abnormalities or worsened clinically significant abnormalities on the Adverse Event eCRF.
a)
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation. 
b)
Document vasopressor type and dose in the concomitant medication eCRF if applicable.
c)
If TCZ dose is repeated, follow Schedule of Assessments following the second TCZ dose.
d)
Includes assessment for bacterial, fungal, and viral infections as clinically indicated.


RO7172508—F. Hoffmann-La Roche Ltd
45/Protocol BP40092, Version 4
Table 5
Schedule of Assessments for IRR and CRS related to RO7172508 (cont.)
e)
Includes the same cytokine analysis as per PD Blood Cytokines.
f)
The maximum and minimum values for any 24-hour period should be recorded in the clinical database if applicable.
g)
Assessments to be performed in addition to an unscheduled (safety) visit. If the unscheduled (safety) or end of infusion local laboratory and cytokine 
assessments have been performed within 24 hours, then duplicated samples for pre-TCZ treatment do not need to be repeated.
h)
To be taken within 2 hours before TCZ treatment 


RO7172508—F. Hoffmann-La Roche Ltd
46/Protocol BP40092, Version 4
Table 6
Screening Schedule of Assessments with Obinutuzumab Pretreatment
Screening Period with Obinutuzumab Pre-treatment
Cycle 1
Day
Day -28 to Day -8
Day -7
Day -6
Day -5 to Day -1
Day 1
Assessments
See relevant SoA 
depending on 
applicable schedule for 
ongoing assessments
Informed Consenta
x
Eligibility
x
Demography
x
Medical History
x
Pulmonary Function Testsb
x
Archival Tissuec
x
Previous and Concomitant Treatments
x
x
x
x
Adverse Events
x
x
x
x
Physical Examination
x
x
x
Anthropometric Measurementsd
x
Vital Signse
x
x
x
x
ECOG Performance Status
x
x
ECG-12 leadf
x
x
Pregnancy Testg
x
x
Hematologyh
x
x
x
Blood Chemistryh
x
x
x
Coagulationh
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
47/Protocol BP40092, Version 4
Table 6
Screening Schedule of Assessments with Obinutuzumab Pretreatment (cont.)
Screening Period with Obinutuzumab Pre-treatment
Cycle 1
Day
Day -28 to Day -8
Day -7
Day -6
Day -5 to Day -1
Day 1
Assessments
See relevant SoA 
depending on 
applicable schedule for 
ongoing assessments
Serologyi
x
Urinalysish
x
Fresh Tumor Biopsyj
xj
Tumor Assessmentk
x
Tumor Kineticsl
x
Administration of obinutuzumabm
x
x
Obinutuzumab PK Sample
xn
xp
ADA to Obinutuzumab
xn
sCEA
xo
PD Blood Flow Cytometry
xn
PD Blood Cytokines
xn
ADA = anti-drug antibody; AE = adverse event; C = Cycle; CEA = carcinoembryonic antigen; ct = circulating tumor; D = day; 
discont = discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
G2 = grade 2; HIV = human immunodeficiency virus; IgE = immunoglobulin E; incl = including; IRR = infusion related reaction; 
PD = pharmacodynamics; PK = pharmacokinetic; RBR = Research Biosample Repository; RECIST = Response Evaluation Criteria in Solid 
Tumors; RNA = ribonucleic acid; sCEA = soluble CEA; TCR = T cell receptor.


RO7172508—F. Hoffmann-La Roche Ltd
48/Protocol BP40092, Version 4
Table 6
Screening Schedule of Assessments with Obinutuzumab Pretreatment (cont.)
a
Informed consent must be obtained before any study-specific procedures and may be obtained > 28 days before the start of study treatment..
b
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity (DLCO).
c
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material, with the exception of CRC participants. If no 
archival tumor sample is available, fresh sample will be collected and be assessed (the same sample would constitute as baseline screening sample if 
participant is enrolled). Archival tissue should be submitted for additional biomarker assessments for all participants (if available).
d
Weight to be recorded pre-infusion. Height to be measured at screening only.
e
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.
f
12-lead ECG at screening (within one week before obinutuzumab pre-treatment and within 5 days of the first dose of RO7172508).  Additional 
unscheduled ECG assessments in triplicate should be performed in case of abnormalities and if clinical symptoms occur. Recording must be done 
prior to PK sampling.
g
Serum pregnancy test at screening, within 7 days prior to first dose of obinutuzumab. Results must be obtained and reviewed prior to administration 
of obinutuzumab. Prior to the first dose of RO7172508 a urine pregnancy test will be performed. If a urine pregnancy test is positive, it must be 
confirmed by a blood pregnancy test.
h
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to scheduled 
dosing. Screening results can be within 1 week prior to C1D1 but after obinutuzumab pre-treatment. Results must be obtained and reviewed prior to 
administration of RO7172508 or obinutuzumab.
i
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results 
must be obtained and reviewed prior to administration of obinutuzumab.
j
Tumor biopsy samples will be collected during screening.  If a fresh biopsy is performed for screening purposes, this can be used as the baseline 
sample. This biopsy should be taken BEFORE obinutuzumab is administered.
k
Tumor response is assessed by the Investigator per RECIST V1.1 with the use of physical examination and image-based evaluation.  All measurable 
and evaluable lesions should be assessed and documented during the screening period before obinutuzumab pre-treatment.
l
To allow estimation of tumor growth rate before start of treatment an exploratory assessment of tumor kinetics will be made by comparing post
treatment scans with at least 2 pre-treatment scans not older than 12 weeks prior to C1D1 if available. One of the pre-treatment scans will be the 
study baseline scan taken during screening and the second will be within the preceding 12 weeks.
m
Obinutuzumab to be administered either on Day-7 (2000 mg) or on Day-7 and Day-6 (1000 mg each day). If obinutuzumab is given only on one day, 
then the schedule for Day-7 should be followed including an end of infusion sample.
n
Samples should be taken BEFORE obinutuzumab is administered. 
o
sCEA to be assessed for enrollment in cohorts with RO7172508 doses < 12 mg.
p Sample to be taken end of infusion only


RO7172508—F. Hoffmann-La Roche Ltd
49/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W
Cycle (21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upq
Unscheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
+/-
2 
hrs 
48 
hrs 
+/-
4 
hrs 
+/-
1 
day
pre-
dose
48 
hrs 
+/-
1 
day 
pre-
dose
48hrs 
+/- 4 
hrs 
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 Days 
after last 
treatment 
(+/- 5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsq
e.g. In the 
event of an 
IRR ≥G2o
Informed 
Consentb
x
Eligibility
x
Demography
x
Medical 
History
x
Pulmonary 
Function 
Testsw
x
Archival 
Tissueh
x
Previous and 
Concomitant 
Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical 
Examination
x
x
x
x
x
x
x
Anthropometric 
Measurementss
x
x
x
x
x
x
x
Vital Signsv
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


RO7172508—F. Hoffmann-La Roche Ltd
50/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W (cont.)
Cycle (21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upq
Unscheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
+/-
2 
hrs 
48 
hrs 
+/-
4 
hrs 
+/-
1 
day
pre-
dose
48 
hrs 
+/-
1 
day 
pre-
dose
48hrs 
+/- 4 
hrs 
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 Days 
after last 
treatment 
(+/- 5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsq
e.g. In the 
event of an 
IRR ≥G2o
ECOG 
Performance 
Status
x
x
x
x
x
x
ECG-12 leadd
x
x
x
xd
x
Pregnancy 
Teste
x
x
x
x
Hematologyf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Blood 
Chemistryf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulationf
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serologyr
x
Urinalysisf
x
x
x
x
x
x
Fresh Tumor 
Biopsyg
xg
xg
xg
Tumor 
Assessmenti
x
xi
xi
x
Tumor 
Kineticsl
x
Administration 
of 
obinutuzumabx
xx


RO7172508—F. Hoffmann-La Roche Ltd
51/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W (cont.)
Cycle (21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upq
Unscheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
+/-
2 
hrs 
48 
hrs 
+/-
4 
hrs 
+/-
1 
day
pre-
dose
48 
hrs 
+/-
1 
day 
pre-
dose
48hrs 
+/- 4 
hrs 
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 Days 
after last 
treatment 
(+/- 5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsq
e.g. In the 
event of an 
IRR ≥G2o
Obinutuzumab 
PK Samplex
xx
x
xu
x
xy
x
ADA to 
obinutuzumabx
xx
xy
Administration 
of RO7172508j
xj
xj
xj
RO7172508 PK 
Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADA to 
RO7172508
x
x
x
x
x
x
x
x
x
x
x
sCEA
x
x z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PD Blood Flow 
Cytometry
x
x
x
x
x
xaa
x
PD Blood 
Cytokines
x
x
x
x
x
x
x
x
xm
xm
x
xo
TCR Vβk
xk
xk
CtDNA/tumor 
markers
xk
x
xn
Clinical 
Genotyping
xu
RBR Sample 
(DNA)
xu


RO7172508—F. Hoffmann-La Roche Ltd
52/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W (cont.)
Cycle (21 days)
Screeningx
Cycle 1 - 2
Cycle 3 - 4a
Cycle 5 onwardsa
End of 
Treatment
Safety 
Follow-
Up
Survival 
Follow-
Upq
Unscheduled  
(Safety)
Day
D-28 to 
D-1
Day 
1
Day 
2
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3p
Day 
8
Day 
15
Day 
1
Day 
3c, p
Day 
15
Assessmentsa
pre-
dose
24 
hrs 
+/-
2 
hrs 
48 
hrs 
+/-
4 
hrs 
+/-
1 
day
pre-
dose
48 
hrs 
+/-
1 
day 
pre-
dose
48hrs 
+/- 4 
hrs 
incl. early 
discont. 
visit (e.g. 
progressive 
disease)
60 Days 
after last 
treatment 
(+/- 5 
Days)
90 Days 
after last 
treatment 
then 
every 3 
mthsq
e.g. In the 
event of an 
IRR ≥G2o
RBR Sample 
(RNA)
xu
xn
IgE & Tryptase 
xo
ADA anti-drug antibody; AE adverse event; C Cycle; CEA carcinoembryonic antigen; ct circulating tumor; D day; 
discont discontinuation; DNA deoxyribonucleic acid; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; 
G2 grade 2; HIV human immunodeficiency virus; IgE immunoglobulin E; incl including; IRR infusion related reaction; 
PD pharmacodynamics; PK pharmacokinetic; RBR Research Biosample Repository; RECIST Response Evaluation Criteria in Solid 
Tumors; RNA ribonucleic acid; sCEA soluble CEA; TCR T cell receptor.
a
All visits from Cycle 3 onwards should occur within a 3-day time window, unless otherwise indicated and all assessments or samples where 
indicated should be taken prior to the administration of RO7172508.
b
Informed consent must be obtained before any study-specific procedures and can be obtained > 28 days from the start of screening. 
c
Visit to be done only every second cycle after Cycle 5. (i.e. C7, C9 etc.).
d
12-lead ECG at screening (within one week before first dose of RO7172508).  After Cycle 4, 12-lead ECG to be done only at every second cycle 
(i.e. Cycle 6, Cycle 8 etc.). Additional unscheduled ECG assessments in triplicate should be performed in case of abnormalities and if clinical 
symptoms occur. Recording must be done prior to PK sampling.
e
Serum pregnancy test at screening, within 7 days prior to first dose, and at the safety follow-up visit; a urine pregnancy test will be performed 
at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a blood pregnancy test. Results must be obtained and 
reviewed prior to administration of RO7172508.
f
Hematology, blood chemistry, coagulation, and urinalysis can be performed within 24 hours (up to 72 hours if during weekend) prior to 
scheduled dosing. Screening results can be within 1 week prior to C1D1. Results must be obtained and reviewed prior to administration of 
RO7172508.


RO7172508—F. Hoffmann-La Roche Ltd
53/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W (cont.)
g
Tumor biopsy samples will be collected during screening, once during the study treatment period at Cycle 2 Day 8 and optionally at the end of 
treatment visit ONLY if the reason for discontinuation is progressive disease. If a fresh biopsy is performed for screening purposes, this can be 
used as the baseline sample.
h
As part of the eligibility procedure, CEA expression will be confirmed on archival tumor material, with the exception of CRC participants. If no 
archival tumor sample is available, fresh sample will be collected and be assessed (the same sample would constitute as baseline screening sample 
if participant is enrolled). Archival tissue should be submitted for additional biomarker assessments for all participants (if available).
i
Tumor response is assessed by the Investigator per RECIST V1.1 with the use of physical examination and image-based evaluation.  All 
measurable and evaluable lesions should be assessed and documented during the screening period, within 7 days before Cycle 3 Day 1, thereafter 
every 6 weeks (± 7 days) for 12 weeks, and then every 12 weeks (± 7 days) until disease progression or death. (i.e. screening, C3, C5, C7, C11, 
C15, C19 etc.).
j
All planned assessments are to be performed before administration of RO7172508. At least 24 hours (overnight) hospital stay required following 
administration of study drug at Cycle 1 Day 1.
k
TCR Vβ and CtDNA/tumor marker samples to be drawn at Cycle 1 Day 1 predose (baseline) and Cycle 5 Day 1 predose.
l
To allow estimation of tumor growth rate before start of treatment, an exploratory assessment of tumor kinetics will be made by comparing 
post-treatment scans with at least 2 pretreatment scans not older than 12 weeks prior to C1D1, if available. One of the pretreatment scans will 
be the study baseline scan taken during screening and the second will be within the preceding 12 weeks.
m
Cytokines from Cycle 5 onwards, samples to be taken every second cycle up to Cycle 15 (e.g. C5, C7 etc.).
n
RBR (RNA) and CtDNA/tumor markers samples to be taken on Cycle 5 only.
o
Sample to be taken only if Grade 2 the safety event is suspected to be immune-related (e.g., IRR). Refer to Table 5 for additional assessments 
if safety event is an IRR/CRS (³ Grade 3) that requires tocilizumab treatment. Any biopsy samples or results done as part of standard of care can 
be shared with the Sponsor if applicable.
p
The Day 3 visit may be adjusted +/- 1 day depending on safety and PD data. The visit optimal timepoint will be communicated to the 
Investigators for consistency and should occur 4 hrs from each complete day of administration (i.e. 24hrs 4hrs; 48 hrs 4hrs; OR 
72hrs 4hrs).
q
Survival follow-up visit to be performed 90 days ( 7 Days) after the last treatment either in person or a phone call to document any ongoing 
or resolved AEs, and every 3 months ( 2 weeks) thereafter for overall survival.
r
Serology (as per local regulations) includes HIV, hepatitis B surface antigen, total hepatitis B core antibody, hepatitis C virus antibody.  Results 
must be obtained and reviewed prior to administration of RO7172508.
s
Weight to be recorded pre-infusion. Height to be measured at screening only.
t
Required for Cycle 5 only.
u
Samples to be collected only in Cycle 1
v
Vital signs include systolic and diastolic blood pressure; pulse rate; temperature; respiratory rate and oxygen saturation.
w
Pulmonary function tests should include spirometry; forced expiratory volume (FEV1), forced vital capacity (FVC) and Diffusion capacity 
(DLCO).


RO7172508—F. Hoffmann-La Roche Ltd
54/Protocol BP40092, Version 4
Table 7
Schedule of Assessments Part II: Multiple Participant Cohorts SC Q3W (cont.)
x
Refer to Table 6 in the event obinutuzumab pre-treatment is implemented for specific additional assessments during the screening period.
y
Obinutuzumab ADA and PK samples to be taken only in Cycle , 5 and 7 before administration of RO7172508.
z
sCEA to be assessed for enrollment in cohorts with RO7172508 doses < 12 mg.
aa
PD blood flow cytometry to be taken from Cycle 5 onwards only at Cycles 8,12 and 16 at predose


RO7172508—F. Hoffmann-La Roche Ltd
55/Protocol BP40092, Version 4
2.
INTRODUCTION
2.1
STUDY RATIONALE
RO7172508 is a novel T-cell bispecific (TCB) antibody that targets carcinoembryonic 
antigen (CEA) expressed on tumor cells and cluster of differentiation 3 (CD3) epsilon 
chain (CD3e) present on T-cells.
Despite great progress in recent years, management of patients with many types of 
advanced solid tumors remains highly challenging. There has been renewed interest 
over the last few years in engaging the immune system to fight cancer. One approach 
currently in development is to activate T-cells against the tumor by using TCBs. The 
Sponsor has developed a novel TCB (RO7172508) that targets human CEA on tumor 
cells and CD3 on T-cells, which results in selective T-cell-mediated killing of cancerous 
CEA-expressing cells. CEArelated cell adhesion molecule 5 (CEACAM5) or CD66e, is 
a protein with molecular weight of 180200 kDa that belongs to the CEACAM 
superfamily. High expression of CEA is found in various tumor types (Thompson et al 
1991), including colorectal cancer, pancreatic cancer, gastric cancer, non-small cell lung
cancer (NSCLC), head and neck cancer, and breast cancer among others, whereas low 
expression of CEA was found in smallcell lung cancer and glioblastoma (RO7172508 
Investigator’s Brochure). RO7172508 will be used in indications where significant 
subsets of patients have tumors expressing CEA. 
The clinical proof-of-concept was demonstrated with cibisatamab
(RO6958688¸CEA-TCB), a TCB antibody targeting CEA currently in clinical development, 
which induced objective radiological responses both as a single agent and in 
combination with a programmed death-ligand 1 (PD-L1) checkpoint inhibitor 
atezolizumab with an acceptable safety profile (Study BP29541 [NCT02324257], 
Study WP29945 [NCT02650713]). RO7172508 differentiates from cibisatamab by having 
a different binding CEA domain with increased affinity to CEA exhibiting tumor cell lysis 
in cells with lower CEA expression level and a prolonged half-life. RO7172508 is 
therefore expected to show enhanced anti-tumor activity, resulting in an increased 
response rate in high-CEA-expressing tumors when compared to cibisatamab, and 
enabling treatment of low-CEA-expressing tumors which are not targeted by cibisatamab. 
The aim of the current study is to define the safety profile of RO7172508 when used as a 
single agent, generate pharmacokinetic (PK), pharmacodynamics (PD), and efficacy 
data that will allow selection of an optimal route of administration and schedule for 
further development.


RO7172508—F. Hoffmann-La Roche Ltd
56/Protocol BP40092, Version 4
The development of anti-drug antibodies (ADAs) can result in a partial or complete loss 
of exposure and is thought to be mainly mediated by the stimulation of B-cells, which 
leads to generation of antibody-producing plasma cells. The use of obinutuzumab as a 
pre-treatment (if needed) to inhibit or attenuate ADA responses by depletion of B-cells 
has been implemented in this study and is supported by nonclinical and clinical studies 
further described in Section 2.2.2. For the benefit/risk assessment of obinutuzumab pre-
treatment, please refer to Section 2.3.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Background on RO7172508
RO7172508 is a tumor-targeted, T-cell engaging, bispecific antibody that induces 
T-cell-mediated killing of tumors expressing CEA. RO7172508 contains a humanized
CEA binder that binds to the A3-B3 domain of CEA with high monovalent affinity 
(Kd 90 pM). This is the major differentiating characteristic of this antibody relative to 
cibisatamab, which contains a humanized and stabilized CEA binder that binds to the B3 
domain of CEA with an affinity of Kd 16 nM. Binding of RO7172508 to tumor cells and 
T-lymphocytes resulted in secretion of cytotoxic granules and ultimately, tumor cell lysis 
(killing). Upon TCB-mediated activation, T-cells undergo proliferation and expand at sites 
of tumor cell killing and, by release of pro-inflammatory cytokines, attract more immune 
cells into the tumor which leads to increased effector-to-target cell ratio within tumors. 
There is no suitable pharmacologically relevant animal model to assess the toxicity of 
RO7172508; therefore, in vivo toxicity studies have not been performed. Instead, an 
integrated approach incorporating in vitro data (of both RO7172508 and cibisatamab) 
and clinical activity data of cibisatamab was used to define the starting-dose for the 
entry-into-human study. Results from in vitro studies on human cells using the most
sensitive test systems and assay conditions yielded a starting-dose for RO7172508 of 
65 g for this study (see Section 4.3).
A detailed description of the additional in vitro studies, the chemistry, pharmacology, and 
safety of RO7172508 is provided in the Investigator’s Brochure.


RO7172508—F. Hoffmann-La Roche Ltd
57/Protocol BP40092, Version 4
2.2.2
Obinutuzumab
RO7172508 may induce the production of ADAs that could result in the complete or 
partial loss of exposure. Obinutuzumab, a humanized and glycoengineered Type II anti-
CD20 monoclonal antibody that recognizes the CD20 antigen present on normal and 
malignant B-cells. Obinutuzumab is approved for the use in untreated and 
relapsed/refractory follicular lymphoma as well as untreated chronic lymphocytic 
leukemia. The use of obinutuzumab has demonstrated effective B-cell depletion 
following administration in cynomolgus monkeys (Mössner et al 2010) and patients 
with B-cell malignancies (Salles et al 2012; Cartron et al 2014 ). The use of 
obinutuzumab as a pre-treatment to inhibit or attenuate ADA responses in participants 
with solid tumors is supported by nonclinical and clinical studies. Pre-clinically, 
obinutuzumab pre-treatment resulted in strong suppression of de novo antibody 
responses while protective humoral memory responses remained intact both in human 
CD20 transgenic mice and cynomolgus monkeys. In Studies BP28920 (RO6895882; 
Phase I), BP29435 (RO6895882 + atezolizumab; Phase Ib) and BP29541 (cibisatamab; 
Phase I), obinutuzumab pre-treatment effectiveness was confirmed as pre-treated 
patients did not lose exposure of the investigational compounds. For the benefit/risk 
assessment of obinutuzumab pre-treatment, please refer to Section 2.3.
For more details on obinutuzumab, please refer to the obinutuzumab IB.
2.2.3
Background on Tocilizumab (RO4877533, ACTEMRA®, 
ROACTEMRA®)
Tocilizumab blocks IL-6 from binding to its receptor, both in membrane-bound and 
soluble states (Singh et al 2011). With a primary indication for juvenile idiopathic 
arthritis (JIA), tocilizumab is approved by the Food and Drug Administration (FDA) for 
children as young as 2 years. It is also approved for adults with rheumatoid arthritis and 
for Castleman disease in Japan. Tocilizumab has been extensively studied in adults, 
with 8 randomized controlled trials treating more than 2000 patients (Singh et al 2011) 
and in children in phase 1 to phase 3 trials for JIA (Woo et al 2005, Yokota et al 2005, 
De Benedetti et al 2012).
In patients with severe CRS associated with T cell–engaging therapies, IL-6 levels peak 
during maximal T cell proliferation. A growing body of evidence suggests that IL-6 
blockade by tocilizumab result in rapid, dramatic reversal of life-threatening CRS in 
patients treated with T cell engaging therapies (Grupp et al 2013, Teachey et al 
2013). Whereas tocilizumab is typically dosed every 2 to 4 weeks, extended treatment is 
not necessary in the management of CRS, which is self-limited and in most cases 
reported to require a single administration in order to control the clinical signs of CRS 
after treatment with T cell engaging agents. Tocilizumab was approved for the treatment 
of CAR-T cell induced CRS in the US only since August 2017 (Actemra USPI). 
Since CRS is a potential risk for RO7172508, tocilizumab will be administered if required, 
for the management of severe CRS (Table 17).


RO7172508—F. Hoffmann-La Roche Ltd
58/Protocol BP40092, Version 4
2.3
BENEFIT/RISK ASSESSMENT
The bispecific nature of RO7172508 brings immune cells into the proximity of tumor cells 
to exert their effector function, which has been a challenge for other classes of 
immunomodulatory compounds that often rely on pre-existing infiltration of immune cells 
for clinical activity. In pre-clinical models, RO7172508 has consistently demonstrated 
superior efficacy relative to cibisatamab suggesting the potential to expand the 
indications that could benefit from immunotherapies compared to cibisatamab, which has 
already shown objective clinical responses in high-CEA-expressing tumors. 
The nature of adverse events (AEs) for RO7172508 is expected to be similar to 
cibisatamab, a T-cell, bispecific antibody targeting CEA which is currently in clinical 
development (Study BP29541). The potential AEs are: infusion-related reactions; 
cytokine-release syndrome, isolated pyrexia, diarrhea, events associated with tumor 
inflammation/tumor flare affecting organs related to the tumor site such as tumor pain, 
edema, impaired function of the affected organ, such as dyspnea, hypoxia, and 
increased levels of liver function enzymes, colitis, enteritis; immunoglobulin E (IgE)-
mediated hypersensitivity reactions (theoretical risk for all biologics); risk of 
immunogenicity and potential safety impact (theoretical risk for all biologics); skin 
exfoliation; hematotoxicities; central nervous system disorders. In addition, given pre-
clinical data regarding the staining of pneumocytes, signs of lung inflammation (dyspnea, 
hypoxia, pneumonitis) cannot be excluded even in participants without lung lesions. 
Administration of monoclonal antibodies may cause a spectrum of symptoms, such as 
fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, sweating, 
flushing, skin rash, tachycardia, tachypnoea, headache, tumor pain, nausea, and/or 
vomiting. Typically these symptoms are reported as infusion-related reactions (IRRs) 
when they occur during or shortly after the first or second infusion, or within 24 hours 
after study drug administration. 
Symptoms of IRRs and CRS, during or after infusion of RO7172508, may be 
indistinguishable from each other and might be life-threatening. CRS is a disorder 
characterized by nausea, headache, tachycardia, hypotension, rash, dyspnea, and renal, 
coagulation, hepatic and neurologic disorders; CRS is caused by the release of 
cytokines from cells (Lee et al 2014). Severe CRS may be associated with other 
clinical sequelae such as disseminated intravascular coagulation and capillary leak 
syndrome. Standard of care for severe or life threatening CRS resulting from immune-
based therapy has not been established, especially in solid tumors.
In case of IRR/CRS, the recommended management is detailed in Table 17.


RO7172508—F. Hoffmann-La Roche Ltd
59/Protocol BP40092, Version 4
The activity of RO7172508 at the tumor site leads to the destruction of the tumor cells 
and tumor inflammation/flare. Given this mechanism of action, AEs associated with 
tumor inflammation are expected. These AEs are expected to occur shortly following 
RO7172508 administration and can affect organ systems with the location of the tumor 
lesions. These events might be life-threatening especially in case of critical location of 
the tumor (respiratory tract) or extensive tumor size.
Because of a higher affinity to CEA of RO7172508 compared to cibisatamab, the 
severity of adverse reactions may be higher; however, the difference in the potency has
been taken into account in the evaluation of the starting-dose proposed in this study. 
Stringent risk mitigation measures, including required appropriate organ function at 
baseline (cardiac, pulmonary, liver, hematologic function), close monitoring of 
participants, especially around the first infusion (including 24-hour hospitalization after
the first infusion), staggered enrollment, dose-escalation rules and detailed instructions 
regarding management of specific AEs are designed to minimize risks. Overall, these 
potential risks are considered manageable and acceptable in the context of anticipated 
benefit.
Risk mitigation has been considered in the study design and management of potential 
AEs is described in Section 8.3.8 of the protocol and the RO7172508 Investigator’s 
Brochure.
There is a potential risk for RO7172508 to induce the production of ADAs. ADA 
formation against RO7172508 can potentially reduce its efficacy by blocking CEA or 
CD3e targeting and/or potentially result in symptomatic hypersensitivity reactions, in 
particular immune complex reactions. Therefore, Part II of the BP40092 study allows 
obinutuzumab pretreatment to attenuate the formation of ADAs if a predefined number 
of patients experience a loss of exposure to RO7172508 (see Section 4.1.3). 
If obinutuzumab pretreatment is introduced as a way to mitigate ADA formation and 
subsequent loss of exposure, the safety profile of RO7172508 given after obinutuzumab 
will be carefully monitored. Only if the safety profile of RO7172508 after 
obinutuzumab pretreatment is shown to be acceptable and comparable to RO7172508 
alone (i.e., without obinutuzumab pretreatment if applicable) will the Sponsor consider 
investigating obinutuzumab pretreatment in further development.
On the basis of all available information, the Sponsor concluded that there is an
acceptable preliminary benefit-risk balance for the clinical investigation of RO7172508 in 
participants with locally advanced and/or metastatic CEApositive solid tumors who
have progressed on standard of care (SOC) treatment, are intolerant to SOC, and/or are 
non-amenable to SOC.


RO7172508—F. Hoffmann-La Roche Ltd
60/Protocol BP40092, Version 4
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 8.
Table 8
Objectives and Endpoints
Objectives
Endpoints
Primary

To determine the maximum-tolerated dose 
(MTD) and/or the optimal biological dose 
(OBD) for intravenous (IV) and 
subcutaneous (SC) administrations of 
RO7172508 as monotherapy and with 
obinutuzumab pre-treatment (if applicable)

Nature and frequency of dose-
limiting toxicities (DLTs) and other 
AEs, PD and PK profile

To assess the safety and tolerability 
profile of RO7172508 and with 
obinutuzumab pre-treatment (if applicable)

Incidence, nature and severity of 
AEs graded according to the 
National Cancer Institute (NCI) 
Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0
Secondary

To establish the IV and SC 
pharmacokinetics of RO7172508 given as 
monotherapy and with obinutuzumab pre-
treatment (if applicable)
The PK profiles and parameters 
derived for RO7172508 including 
where appropriate and when data 
allow, the parameters listed below:

Maximum concentration (Cmax)

Time of maximum concentration 
(Tmax)

Clearance (CL) or apparent 
clearance (CL/F) (dependent on 
route of administration)

Volume of distribution at steady state
(Vss)

Area under the curve (AUC)

Half-life (t1/2)

Other PK parameters may be 
determined, as deemed appropriate.

To assess the incidence of anti-drug 
antibodies (ADAs) against RO7172508
with obinutuzumab pre-treatment (if 
applicable)

Presence or absence and titer of 
ADAs 

To characterize PD effects and duration of 
PD response for multiple doses and 
schedules of RO7172508 administration

Changes in frequency, activation 
status and spatial distribution of 
tumor infiltrating lymphocytes (TILs).


RO7172508—F. Hoffmann-La Roche Ltd
61/Protocol BP40092, Version 4
Table 8
Objectives and Endpoints (cont.)
Objectives
Endpoints
Secondary (cont.)

To assess preliminary anti-tumor activity 
of RO7172508.

Objective response rate (ORR)

Disease control rate (DCR); defined 
as rate of response (RR) + stable 
disease (SD)

Duration of response (DOR)

Progression-free survival (PFS) 
(on-treatment)
According to Response Evaluation 
Criteria in Solid Tumors (RECIST) 
Version 1.1 criteria by Investigator’s
assessment
Tertiary/Exploratory

To further characterize PD effects and 
duration of PD response for multiple 
doses and schedules of RO7172508 
administration

To assess dose and exposure response 
relationship of RO7172508 and PD 
biomarkers and clinical endpoints

Duration of immune activation 
(changes in peripheral blood 
immune cells and TILs, cytokines) 
after repeated administrations of 
RO7172508.

Absolute numbers and changes 
from baseline of immune cells 
(including but not limited to 
activated CD8+ T-cells) in 
peripheral blood and tumor 
biopsies.

Absolute levels and changes from 
baseline for cytokines (including but 
not limited to soluble CD25 
[sCD25]) in peripheral blood.

Gene expression profile changes on 
tumor biopsies following treatment.

Changes in CEA tumor expression.

Absolute levels and changes from 
baseline of soluble tumor markers 
(including but not limited to CEA, 
etc.) in peripheral blood.


RO7172508—F. Hoffmann-La Roche Ltd
62/Protocol BP40092, Version 4
Table 8
Objectives and Endpoints (cont.)
Objectives
Endpoints
Tertiary/Exploratory (cont.)

To investigate potential 
prognostic/predictive biomarkers

Absolute number, frequency and 
activation status of immune cells 
(including but not limited to CD8+ 
T-cells) in peripheral blood and/or 
tumor biopsies at baseline.

Absolute expression levels of 
cytokines (including but not limited 
to sCD25) in peripheral blood at 
baseline.

Absolute levels of soluble tumor 
markers (including but not limited to 
serum CEA [sCEA]) at baseline.

Gene expression profile on tumor 
biopsies at baseline.

Mismatch repair 
(MMR)/microsatellite instability 
(MSI) status and tumor mutations 
on archival tissue and whole 
genome.

To further assess preliminary anti-tumor 
activity of RO7172508.

PFS, objective response, DOR, and 
DCR according to immune modified
RECIST (iRECIST).

Overall survival (OS).

To estimate depth and duration of 
response on target lesion size due to 
RO7172508 and the effect on the risk of 
appearance of new lesions during 
treatment by tumor kinetic modeling

Sum of lesion diameter from 
computed tomography (CT) scans 

To assess ADA specificity

Development of ADAs directed 
against either the CEA or CD3 
binding moiety.

To make a preliminary assessment of the 
efficacy of tocilizumab 
(Actemra®/RoActemra®) in ameliorating 
the symptoms of severe CRS following 
RO7172508 treatment, if data allows.

Changes in the nature and severity 
of CRS following administration of 
tocilizumab for severe CRS.

To assess the incidence of anti-drug antibodies 
(ADAs) against obinutuzumab (if applicable)

Presence or absence and titer of ADAs 

Serum concentration of obinutuzumab
4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.


RO7172508—F. Hoffmann-La Roche Ltd
63/Protocol BP40092, Version 4
Study BP40092 is a first-in-human, open-label, multicenter, dose-escalation, Phase I 
clinical study to determine the maximum-tolerated dose (MTD) and/or the optimal 
biological dose (OBD) as well as the optimal schedule for intravenous (IV) and 
subcutaneous (SC) administrations of RO7172508 as monotherapy, with or without 
obinutuzumab pre-treatment, in participants with locally advanced and/or metastatic 
CEA-positive solid tumors who have progressed on SOC treatment, are intolerant to 
SOC, and/or are non-amenable to SOC. The study will be conducted in two parts.
PART I
Part I of the study is an IV single participant cohort/multiple-ascending dose-escalation 
study to evaluate the safety of RO7172508 at doses that are expected to be below a 
level that induces relevant biological effects. The starting-dose has been determined by 
an integrated approach, whereby the in vitro data (of both RO7172508 and cibisatamab) 
and clinical activity of cibisatamab have been considered (see Section 4.3). RO7172508 
will be administered IV every 3 weeks (Q3W), in up to approximately 5 participants with 
confirmed cytoplasmic and/or membranous high-CEA expression in their tumor (i.e., 
20% of tumor cells with CEA immunohistochemistry [IHC] 2+/3+). Intra-participant 
dose-escalation is allowed up to the maximum dose achieved in Part I (see 
Section 4.1.2).
PART II
Part II is a multiple participant cohort/multiple-ascending dose-escalation study to define 
the MTD and/or OBD of RO7172508 administered as single agent, IV or SC, in 
participants who have tumors with cytoplasmic and/or membranous CEA expression in 
20% of cells at intensities greater than at least IHC 1+ on archival material (or fresh 
biopsy when archival is not available). The starting-dose for the initiation of the IV 
dose-escalation will be determined by Part I and RO7172508 will be initially given Q3W. 
Dose-escalation will be undertaken based on safety until determination of the MTD or 
the highest safe dose if MTD is not reached.
Once the IV schedule has shown RO7172508 preliminary clinical activity, defined by 
partial response (PR) or better, according to RECIST v. 1.1 (Appendix 6), or the MTD 
has been established and is equal to or above 2 mg, the SC multiple-ascending dose-
finding cohorts could be initiated. The starting-dose and regimen (QW or Q3W) for SC 
administration will be proposed based on the evaluation of the safety and PK data 
observed following IV administration but will not exceed the highest safe dose tested in 
the IV Q3W dose escalation; however, due to practical considerations, a minimum dose 
of 2 mg is defined for a single SC administration. In addition, the QW SC starting-dose 
will not exceed one third of the IV MTD or of the highest safe IV dose tested.
Dose escalation in the SC treatment group will proceed until the SC MTD/OBD has been 
determined (see Section 4.1.2). If the SC treatment group is started Q3W at a dose <6 


RO7172508—F. Hoffmann-La Roche Ltd
64/Protocol BP40092, Version 4
mg, the QW schedule can be evaluated once the dose is ≥6 mg. Data from this treatment 
group will establish if the SC route of administration, which will have a lower Cmax than IV 
after first administration, can show comparable efficacy and/or comparable or improved 
safety profile of a TCB either QW and/or Q3W.
During the course of this study, the need for obinutuzumab pretreatment will be 
assessed based on loss of RO7172508 exposure and/or ADA-related safety events. 
Details, including decision criteria, are provided in Section 4.1.3 and Appendix 9. If 
on-target toxicity is reported predominantly in the first cycle of treatment, fractionated
dosing may be implemented for the first cycle to improve tolerability. RO7172508 
treatment would start with 10% of the planned dose on Cycle 1 Day 1, 30% of the 
planned dose on Cycle 1 Day 8 and 60% of the planned target dose on Cycle 1 Day 15, 
followed by the full dose treatment from Cycle 2 Day 1 onwards as described in Figure 2. 
By using a step-up fractionated dosing approach, it is predicted that the lower peak 
exposures (Cmax) will result in lower cytokine levels to that when the full dose is given on 
Day 1. The fractionated dosing regimen may be adjusted depending on emerging data 
and in discussion with the Investigators. A similar approach to increase the dose 
administered during the first three weeks as applied with dose-fractionation in the Q3W 
treatment group, may also be employed in the once weekly (QW) treatment group. If a 
patient in the fractionated dose cohort experiences any adverse event that results in a 
delay of the next administration of RO7172508 beyond one week, the dose at which the 
treatment should be restarted will require agreement between the investigator and the 
Sponsor.
Figure 2
Fractionated Dosing Design for Q3W and QW
At least 3 evaluable participants will be treated in each cohort during the IV or SC 
dose-escalation regimen.


RO7172508—F. Hoffmann-La Roche Ltd
65/Protocol BP40092, Version 4
If deemed necessary, at the end of dose escalation, to further characterize the safety, 
preliminary anti-tumor activity, PK, and/or PD profile of RO7172508 (IV and/or SC) with 
or without obinutuzumab pre-treatment, additional participants (up to approximately 
15 participants) may be enrolled at the doses already tested; or at doses that have not 
been explored for the determination of the MTD, but not higher than MTD; or the highest 
safe dose tested if MTD has not be determined. The additional patients could be
allocated to one or more doses; however, the total number will not exceed
15 participants across all doses. If new cohorts are opened at a dose equal to or lower 
than already explored, the cohorts will follow the same recruitment rules and safety 
windows as per dose escalation rules. Patients enrolled at dose levels that have already 
been assessed, will also be staggered as per dose escalation rules (i.e. at least one day 
between consecutive patients). If DLT events are observed, the estimated MTD and the 
probability of overdosing at the current recruiting cohort will be re-assessed with all 
available data. If the updated estimated MTD indicate that the current recruiting 
cohort is not safe, recruitment will be stopped.
4.1.1
Length of the Study
Participants will be treated for up to 24 months (the treatment period may be modified if 
supported by emerging data) or until disease progression, loss of clinical benefit, 
unacceptable toxicities, or withdrawal from treatment for other reasons or death.
Specifically, the duration of the study for each participant will be:

Screening: Days -28 to -1.

Treatment Period: Cycle 1 Day 1 to Month 24 (may be modified if supported by 
emerging data). 

Safety follow-up: 60 days after last treatment with RO7172508.

Survival follow-up: Every 3 months after the last treatment with RO7172508.
4.1.2
Dose-Escalation Decision Criteria
4.1.2.1
Part I: Multiple-Ascending Dose-Escalation (Single Participant 
Cohorts) 
In Part I, RO7172508 will be administered IV Q3W with a flat dose. The starting-dose of 
RO7172508 will be 65 g (see Section 4.3 for starting dose justification) and the 
maximum dose explored will be 1.6 mg. An increment-based escalation will be utilized. 
The first 2-step increments (up to 400 g) are 2.5 as the first doses are considered low 
and sub-therapeutic. From 400 g dose, a maximum of 3-fold increments will apply (see 
Section 4.3).
Thus, the 65 g starting-dose is followed by doses of 160 g, 400 g, 800 g and 
1600 g. Incremental dose-increases may be altered based on emerging PK, PD and 
safety data but will not exceed 3-fold. 


RO7172508—F. Hoffmann-La Roche Ltd
66/Protocol BP40092, Version 4
Each cohort will include one participant in order to minimize the number of participants 
treated below the predicted therapeutically relevant dose. Each participant will be 
followed up for a 4-week dose limiting toxicity (DLT) window (Figure 3). The DLT window 
is divided into a 14-day safety observation period, after which the next cohort could be 
opened, and a further observation period of two weeks, to assess any potential late 
toxicity including up to one week after the second administration (i.e., total of 4 weeks). 
Enrollment into the subsequent cohort will occur after the Sponsor and the Investigators 
have jointly decided on the next dose-escalation step. A telephone conference will be 
held with Investigators before a new dose-level is opened, where all available safety, PK 
and PD data will be evaluated. The next cohort will open if no RO7172508-related AE of 
Grade 2 (or DLT) is reported in a participant during the 14-day safety observation 
period. If a related Grade 2 AE or DLT occurs after the 14-day safety window and 
within the 4 weeks DLT window in a lower dose cohort, then participants at a higher 
dose may have their dose reduced for subsequent cycles and the switch from Part I to 
Part II of the study is triggered.
Figure 3
Part I: Observation and DLT Windows
Intra-participant dose-escalation is allowed in Part I. A participant (e.g., 
Cohort 1/Participant 1) can progressively escalate to a dose-level tolerated by 
subsequent cohorts if:

Participant has completed his/her current cohort’s 4-week DLT window and 
experienced no RO7172508-related Grade 2 AEs.
AND

Participant in the next highest level cohort (i.e., Cohort 2/Participant 2) has safely 
passed his/her 14-day safety observation window.
The maximum dose-level allowed for participants in Part I will be the highest dose-level 
administered in Part I. Participants may continue to receive RO7172508 for up to 
24 months, until disease progression, or loss of benefit (see Section 7). 
Participants who undergo dose-escalation will not need to complete another 4-week DLT 
assessment period. All other rules for subsequent escalations still apply as noted above.


RO7172508—F. Hoffmann-La Roche Ltd
67/Protocol BP40092, Version 4
The Sponsor will switch from Part I to Part II when either a dose of 1.6 mg IV (flat dose) 
is reached or the occurrence of a RO7172508-related Grade 2 AE (or DLT) is 
observed, whichever comes first. The Sponsor may decide to switch from Part I to Part II 
in the absence of an observed RO7172508-related Grade 2 toxicity or prior to the 
dose-level reaching 1.6 mg.
4.1.2.2
Part II: Multiple-Ascending Dose-Escalation (Multiple 
Participant Cohorts)
A modified continual reassessment method with overdose control (mCRM-EWOC) will 
guide the dose-escalation to determine the MTD, by using primary safety variables (e.g., 
DLT). This model-based design assigns participants to dose-levels and defines the MTD 
based on the estimation of the target toxicity level by a model depicting the dose-toxicity 
relationship. The dose-toxicity relationship is described by a two-parameter logistic 
regression model, which is continuously updated as additional participant information 
becomes available. 
The prior distribution for the parameters of the DLT dose-response curve will be a 
mixture of informative and minimally informative components. The minimally informative 
component makes the design robust against unforeseen deviations from the informative 
component and will be constructed based on the assumed not toxic and toxic doses. For 
the dose toxicity relationship of the minimally informative component, it is conservatively 
assumed that it would be very unlikely that 10% or higher DLT rates are associated with 
the first dose of the monotherapy dose-escalation and that it would be very unlikely that 
a 25% or lower DLT rate is associated with a dose of 400 mg (additional details provided 
in Appendix 8). The informative component will be the posterior distribution of the CEA 
TCB (cibisatamab) monotherapy toxicity data without obinutuzumab pre-treatment, as of 
cutoff date 20 July 2017, approximated with a bivariate normal distribution. The two 
components will be mixed in a 10/90% ratio (informative prior component 10%; minimally 
informative component 90%). Further details are provided in Appendix 8.


RO7172508—F. Hoffmann-La Roche Ltd
68/Protocol BP40092, Version 4
The MTD is defined as the dose with the highest probability that the DLT rate is within 
the target of 20% to 35%, and a relatively low probability (25%) that the DLT rate is 
above 35%.

Dose-escalation to IV MTD
The Part II dose-escalation will start with a dose of 1.6 mg (flat dose) IV Q3W 
(Section 4.3 Dose Justification) if this dose has been reached in Part I and considered 
safe. In the eventuality that Part I has been stopped because of the occurrence of a 
RO7172508-related Grade 2 AE (or DLT) then, the starting-dose of Part II will not 
exceed the dose-level at which the AE that delineated the end of Part I occurred. 
Furthermore, the grade and type of AE will also be considered, when choosing the 
dose-level for Part II. In the eventuality that the Sponsor decides to initiate Part II in the 
absence of an observed RO7172508-related Grade 2 toxicity and prior to the 
dose-level reaching 1.6 mg, then the starting-dose of Part II will not exceed the highest 
dose tested in Part I. If the starting-dose of Part II is the same as the last dose in Part I, 
the participant treated at the last dose in Part I could be considered as the first 
participant of the cohort for Part II. If the initial dose is not tolerated, then participants for 
the subsequent cohort may be enrolled at a lower RO7172508 dose than the initially 
selected Part II starting-dose. The maximum dose of RO7172508 will be 400 mg (flat 
dose IV). The initial dosing regimen in Part II may also be adapted depending on 
emerging data in Part I.
In Part II dose-escalation, a minimum of 3 participants per cohort will be enrolled who have 
a baseline sCEA level 20 ng/ml. Participants within a cohort will be treated in a sequential 
manner with one week between the first and second participant, and at least one day 
between subsequent participants. However, if the first participant experiences a DLT 
within the first 7 days, then the time between the treatment of subsequent participants 
within the same cohort may be increased. The DLT evaluation window in Part II is 
defined as a period of 3 weeks after the first administration of RO7172508 in an IV Q3W 
schedule. Based on emerging data, the interval between dosing of each participant 
within a cohort or the DLT window may be adjusted if deemed appropriate by the 
Investigators and/or the Sponsor.
For each cohort, all participants will be followed through a 3-week DLT window 
(i.e., 21 days after the first dose of RO7172508). If fractionated dosing is implemented in 
Cycle 1 to improve tolerability, the DLT window will be extended to include the cycle 
where the planned target dose is administered in full i.e., Cycle 1 Day 1 until the end of 
Cycle 2. The DLT window will therefore be 6 weeks (42 days), or 8 weeks (56 days) if 
treatment has been delayed for no more than 14 days.


RO7172508—F. Hoffmann-La Roche Ltd
69/Protocol BP40092, Version 4
A new cohort can be opened when at least 3 evaluable participants of the previous 
cohort have completed the DLT window. At least 3 evaluable participants must have a 
baseline sCEA level of 20 ng/ml. If participants experience a DLT before completion of the 
last day of their DLT window, they will be considered as having completed their DLT 
window. Prior to opening a new cohort, the logistic regression model will be updated with 
the treatment outcome (i.e., the occurrence of DLT) and a new estimate of the MTD will 
be derived. 
Enrollment into the next cohort will only resume after the Sponsor and the Investigators 
have jointly decided on the next dose-escalation step. Subject to clinical judgment, a 
new cohort of participants will be dosed at the new estimate of the MTD or the highest 
allowable dose based on pre-specified safety constraints as described below, whichever 
is lower and as guided by the mCRM-EWOC model. The design will continue as 
described, assigning participants to the MTD as estimated from all of the DLT data 
cumulatively, until one of the pre-defined stopping criteria is satisfied (see Section 4.1.4) 
or the pre-determined sample size of 60 DLT-evaluable participants is reached, 
whichever comes first. Depending on emerging PK and safety data, the dose escalation may be 
evaluated taking into account sCEA levels at baseline in a sensitivity analysis (i.e. dose escalating 
more conservatively in the event toxicity is associated with low baseline sCEA levels).
Built-in safety constraints are in place to prevent exposing participants to undue risk of 
toxicity, i.e., for Q3W dosing schedule, maximum allowable dose-increment, in absence 
of DLT, will be a maximum of 100%; if one DLT occurs then, an increment of 50% 
maximum will be allowed. The maximum dose that could be assessed in Part II will be 
400 mg IV (see Section 4.3). 
Provisional dose-levels in absence of DLT are listed in Table 9.
Table 9
Provisional Dose Levels in Absence of DLT
Dose Level
Dose
(mg)
Dose-Increment
if no DLT (%)
Next Dose
if no DLT (mg)
1
1.6
100
3.2
2
3.2
97
6.3
3
6.3
90
12
4
12
67
20
5
20
100
40
6
40
100
80
7
80
88
150
8
150
100
300
9
300
33
400
10
400
N/A
N/A


RO7172508—F. Hoffmann-La Roche Ltd
70/Protocol BP40092, Version 4
Dose-frequency may be adjusted depending on the emerging PK data for RO7172508 
and given an appropriate previously observed safety and tolerability profile. Different 
dosing schedules (e.g., non-fractionated and/or fractionated dosing) may be tested in 
parallel. If a decision is made to adjust the dosing schedule during the course of 
dose-escalation, the mCRM-EWOC algorithm will be updated with the available 
participant data and adapted to account for any difference in exposure of the new 
schedule. The initial starting-dose will not exceed a dose already tested and considered 
safe. Safety and DLT window may also be adapted. If fractionated dosing is 
implemented, the DLT window will be extended until the end of the cycle in which the 
planned full dose is administered.

Dose-escalation to SC MTD
Once an MTD or OBD has been defined, or relevant clinical activity is seen (e.g., PR or 
better according to RECIST) for IV route of administration and schedule, SC 
administration will be tested. The starting dose and regimen for SC will be proposed 
based on the evaluation of the safety and efficacy data observed following IV 
administration; however, due to practical considerations, a minimum dose of 2 mg is 
defined for a single SC administration (Section 4.3). 
In the QW cohorts, RO7172508 will be administered three times per cycle (i.e. QW), 
with a maximum starting-dose of one third of the RO7172508 IV MTD dose or, in case 
MTD has not been reached, of the highest safe dose ≥6 mg tested in the IV 
dose-escalation part. For a Q3W regimen the starting dose will not exceed the highest 
safe dose tested in the IV Q3W dose escalation. 
The maximum allowed dose will be 160 mg QW or 400 mg Q3W (flat dose). Different 
dosing schedules (e.g., non-fractionated and/or fractionated dosing) may be tested.
For the SC administration, the mCRM-EWOC model will be updated to account for the 
available IV administration participant data and the difference in exposure with added 
uncertainty, given that the different routes of administration could lead to different safety 
profile. Each cohort will enroll a minimum of 3 participants. Enrollment and 
dose-escalation rules (i.e., stopping rules and maximum allowed increments) in Part II 
SC will be the same as the ones applied in Part II IV. DLT window will be the same as in 
Part II IV but may be updated based on emerging data. The dose-escalation will 
continue as described until one of the pre-defined stopping criteria is satisfied (see 
Section 4.1.4) or the pre-determined sample size of 60 DLT-evaluable participants is 
reached, whichever comes first.
No intra-participant dose-escalation will be allowed in Part II.
The OBD (IV and SC) will be selected based on the overall clinical safety and activity, as 
well as available PK and PD data for RO7172508. Data will be listed and summarized by
dose group as described in the analysis section (see Section 9.4). 


RO7172508—F. Hoffmann-La Roche Ltd
71/Protocol BP40092, Version 4
Once a schedule, route of administration and OBD has been selected, and in case 
efficacy is observed during dose-escalation, disease-specific expansions may be 
opened to confirm these efficacy signals. The protocol will be amended in this case to 
describe treatment of these cohorts. If one route of administration is not unequivocally 
superior, and a decision cannot be taken during or at the end of dose escalation, both routes of 
administration may be compared in disease specific expansions. Criteria for selection of a route of 
administration will then be added via the protocol amendment preceding the expansions, 
including endpoints.
4.1.3
Obinutuzumab Pre-treatment
During the course of the study, the need for obinutuzumab pre-treatment will be 
assessed based on loss of RO7172508 exposure and/or ADA-related safety events. 
Previous experience with the combination of immunotherapy and obinutuzumab has 
shown the capacity of obinutuzumab to abrogate ADA formation, thereby maintaining 
exposure to the investigational compound as determined by PK analysis (see 
Section 2.2.2  and the RO7172508 investigator’s brochure for further references).
During the course of the dose escalation, the decision to implement obinutuzumab will 
be based on a Bayesian posterior probability approach (see Appendix 8 for further 
details). At the time of the evaluation, if there is high confidence (80% confidence level) 
that the underlying true rate of participants with relevant loss of exposure is above 
50% then obinutuzumab pre-treatment will be introduced for all subsequent 
participants in the study (see Section 6.1 and Appendix 8). If the criteria are not met, 
the dose escalation will proceed without obinutuzumab pre-treatment until the next 
assessment or the end of the dose escalation, whichever is reached first (see Appendix 8).
If obinutuzumab will be implemented during the course of the dose escalation, then the 
dose escalation will be run under the same condition as defined for Part II without 
obinutuzumab. The starting dose will be a dose that has been safely tolerated in Part II 
without obinutuzumab. Escalation, stopping rules and maximum number of 
participants applied to Part II will also apply to Part II with obinutuzumab pre-
treatment.  
The first assessment on the implementation of obinutuzumab will be conducted once PK 
data following 3 cycles of treatment are available from at least 14 participants across 
both Part I and II (see Appendix 8). Loss of exposure is defined as at least a 70% 
reduction in Cmax at Cycle 3 from Cycle 1 in a participant. This threshold may be 
adapted based on emerging PK data. Ongoing assessments of safety and PK data will be 
performed for each cohort and at the end of dose escalation, to continuously evaluate the 
criteria for implementation of obinutuzumab pre-treatment. In addition, the incidence 
and titer of ADAs will be assessed on an ongoing basis throughout the study.






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
Grade 3 non-hematological toxicity with the following exceptions:
–
Alopecia (any grade)
–
Grade 3 nausea or vomiting that resolves to Grade 1 with or without 
supportive therapy within one week.
–
Grade 3 hypophosphatemia and transient Grade 3 hyperbilirubinemia resolved 
within one week.
–
Grade 3 fatigue that resolves to Grade 2 within one week.
–
Fever 40C (i.e., Grade 3) that occurs within 48 hours of RO7172508 infusion 
and improves to 40C (Grade 2) within 48 hours and fully resolves within 
one week.
–
Grade 3 arthralgia that can be adequately managed with supportive care or that 
improves/resolves to Grade 2 within one week.
–
Grade 3 diarrhea, colitis, enteritis that resolves to Grade 1 within one week
with no fever or dehydration.
–
Laboratory values of Grade 3 that are judged not clinically significant by the 
Investigator.
–
Grade 3 tumor pain that starts within 24 hours of infusion and 
improves/resolves to Grade 2 within one week.
–
Grade 3 hypoxia that starts within 24 hours of infusion and improves/resolves to 
Grade 2 within one week.
–
In participants with lung lesions, Grade 3 transient dyspnea secondary to 
localized lung edema that starts within 24 hours of infusion and resolves to 
Grade 1 or baseline within one week, and transient bronchospasm that resolves 
within 24 hours.
–
In participants with liver lesions, Grade 3 transient increase of bilirubin, 
transaminases (aspartate aminotransferase [AST]/alanine aminotransferase 
[ALT]) and/or gamma-glutamyl transferase (GGT) that starts within 24 hours of 
infusion and recovers to Grade 1 or baseline within one week.
Failure to recover from any RO7172508-related toxicity that results in a dose-delay of 
more than 14 days (any regimen) is defined as a DLT.
4.1.4
Stopping Rules Criteria
The dose-escalation will be halted if, for each route of administration or schedule, either:

The MTD has been reached as determined by the model (Appendix 8) and at least 
6 participants have been already dosed at the current estimate of the MTD (20%).

The maximum of 60 DLT-evaluable participants is reached.
Due to the exploratory nature of this clinical study, any part of its conduct can be 
discontinued at any time at the discretion of the Sponsor. This will not constitute a 


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premature termination of the study. The Sponsor will notify the Investigators and Health 
Authorities if the study is discontinued or the development program is terminated.
4.1.5
Communication Strategy
The Investigators and the Sponsor will communicate regularly and on an ad-hoc basis to 
discuss the occurrence of any safety events including DLTs. At the end of each 
treatment cohort, the Sponsor will convene a joint teleconference with the participating 
Investigators. Dose-escalation decisions and selection of the dose for the next cohort of 
participants will be guided by the pre-defined escalation steps for Part I and 
mCRM-EWOC recommendation for Part II in addition to the review of all relevant 
available data including DLT information. Study Investigators and the Sponsor should 
reach a consensus on the next dose-level and may include de-escalation and/or 
expansion of recruitment into particular cohorts.
In addition to these communications, the Sponsor and Investigators will be in regular 
contact throughout the study by email/telephone per normal interactions during the 
conduct of a clinical study and, when required the Sponsor will arrange teleconferences 
and meetings to discuss the study status. 
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
The biomarker/PD assessments in this study are guided by the mode-of-action (MoA) 
and will focus on measuring CEA-expression (soluble in blood, and tumor by IHC) and 
immune cell activation in both tumor and blood (soluble and cellular assessments).
4.2.1
Rationale for Modified Continuous Reassessment Method of 
Escalation with Overdose Control
The Part II dose-escalation of this trial will use a Bayesian model-based approach, 
i.e., the mCRM-EWOC design (Neuenschwander et al 2008). The use of Bayesian
model-based Phase I designs has been advocated by Rogatko (Rogatko et al 2007) and 
is one of the key elements of the Food and Drug Administration (FDA)’s Critical Path 
Initiative. Clinical judgment can always override the Bayesian adaptive design 
recommendations in the dose-selection process.
The primary objective of a dose-escalation trial, including the present trial, is to 
determine a MTD or recommended dose for Phase II. DLTs are the driver of 
dose-allocation and act as an important factor to define the MTD; however, DLTs are not 
equal to severe DLTs. DLTs traditionally are defined by the occurrence of severe 
toxicities during a relatively shorter period of time of systemic cancer therapy, which is 
called the DLT observation window.
The DLT observation window is usually the first treatment cycle of systemic cancer 
therapy in order for treated participants to have complete information on toxicities (DLTs) 


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prior to the next dose assignment in conventional dose-escalation designs. Toxicity 
induced by cibisatamab occurred predominantly within the first few days after the initial 
administration of the drug. Therefore, in line with this, a 3-week DLT window will be 
implemented in Part II of this study (or 6-week DLT window if a fractionated dosing 
schedule is implemented). 
The mCRM-EWOC design has many favorable characteristics; first, it adaptively fits a
DLT dose-response curve by incorporating toxicity data from eligible participants among 
different cohorts, and non-clinical or clinical information from compounds with similar 
MoA contributes by building an informative prior distribution of the statistical model. 
Second, it locates the MTD efficiently without pre-specifying dose-levels in each cohort. 
Dose-selections are made based on the DLT dose-response curve measured by a two-
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.
Such model-based designs have been successfully applied in many Phase I 
dose-escalation studies (Schöffski et al 2004; Le Tourneau et al 2009; Neuenschwander 
et al 2008).
In addition, hypothetical dose-escalation runs using the design and simulations 
demonstrate the validity of the operating parameters of the design as implemented for 
this study (Appendix 8).
4.2.2
Rationale for Study Population
The study will be conducted in adult male and female participants with locally advanced 
and/or metastatic CEA-positive solid tumors who have progressed on SOC treatment, 
are intolerant to SOC, and/or are non-amenable to SOC. 
Clinical and non-clinical studies have suggested that a wide array of tumors may 
respond to CEA-targeted TCBs. Therefore, this study will recruit participants with all 
types of advanced and/or metastatic solid tumors with cytoplasmic and/or membranous 
CEA expression in20% of cells at intensities greater than at least IHC 1+ on archival 
material (or fresh biopsy when archival is not available) which are not amenable to SOC 
treatment. In the single participant cohort part of the study (Part I), participants require a 
high CEA expression (20% of cells at intensity 2+/3+) to ensure interpretability of safety 
parameters including potential tumor inflammation. 
RO7172508 has the potential to bind to circulating sCEA, therefore, the exposure may 
be impacted following administration of low doses of RO7172508. A maximum baseline 
sCEA level has been indicated for doses < 12 mg to minimize the impact of RO7172508 
binding to sCEA. Preliminary PK data from the current study suggest sCEA may also impact 
the clearance of RO7172508. In order to further explore this relationship, at least 3 patients in 
each cohort in Part II should have a baseline sCEA level of ≤20 ng/mL.


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The maximum concentration of sCEA in a participant was calculated in order to observe 
at least 80% recovery of free RO7172508 at the predicted Cmax. Assuming instantaneous 
equilibrium and a monovalent binding of RO7172508 to sCEA, one could express 
free-concentration of RO7172508 in plasma at time of administration as follows:
(Ltot Rtot Kd)2 4 Ltot Kd
where Ltot is the total concentration of RO7172508, Rtot is the total concentration of sCEA, 
and Kd is the dissociation constant of the complex RO7172508-sCEA.
All calculations are performed assuming following parameter values:

Kd 390 pM,

MWRO7172508 195000 Da,

MWsCEA 180000-200000 Da,

Vc 40 mL.Kg-1

BWhuman 70 Kg
where MW stands for molecular weight, Vc stands for central volume of distribution and
BW stands for body weight.
The recovery of RO7172508 at Cmax was calculated using the above parameters for 
predicted doses < 12 mg (Figure 6).
Figure 6
Recovery of RO7172508 in the Presence of sCEA
Ltot - Rtot - Kd - 0.5
RO7172508free 
2
10
-2
10
-1
10
0
10
1
0
20
40
60
80
100
Conc sCEA (pmol/mL)
Recovery (%)
65ug
160ug
400ug
800ug
1600ug
Cut off 80% Recovery


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According to those simulations, sCEA concentration expected to produce 80% recovery 
for RO7172508 at Cmax for the different clinical doses are presented in Table 10:
Table 10 sCEA Concentrations Predicted to Result in 80% Recovery of 
RO7172508 at Doses Less Than 12 mg
Dose (g)
65
160
400
800
1600
sCEA concentration (ng/mL)
22-24
28-31
44-49
70-78
123-137
Dose (mg)
3.2
6.4
12
sCEA concentration (ng/mL)
229-254
440-489
809-899
4.2.3
Rationale for Control Group
Not applicable.
4.2.4
Rationale for Biomarker Assessments
RO7172508 was designed to target tumors that express CEA and to concomitantly 
engage immune cells leading to their activation and proliferation, which culminates in 
tumor lysis. Non-clinical studies have confirmed the expected MoA of RO7172508 by 
mediating tumor killing, induction of T-cell activation markers (CD25 and CD69), cytokine 
release (interferon (IFN), tumor necrosis factor (TNF), granzyme B, interleukin (IL)-2, 
IL-6, and IL-10), and proliferation of T-cells. Furthermore, the MoA of RO7172508 occurs 
only if simultaneous binding (cross-linking) of T-cells to CEA-expressing tumor cells 
takes place. RO7172508 treatment may result in changes in peripheral blood immune 
cells and soluble circulating markers such as cytokines or tumor markers that are related 
to the MoA of RO7172508. Hence, plasma samples will be collected and analyzed for 
exploration of soluble factor changes (including but not limited to sCD25, IL-6, IFN, 
TNF, etc) and tumor markers (including but not limited to sCEA, etc) that may be 
associated with treatment benefits or toxicities. Blood samples will also be collected and 
analyzed with respect to alterations in the number and activation/differentiation of 
immune cells (including but not limited to CD8+/HLA-DR/Ki67+, etc) as a consequence 
to treatment with RO7172508. 
Tumor biopsy samples will only be collected from participants enrolled in Part II of the 
study. Mandatory tumor biopsies will be performed on two occasions: once during 
screening (pre-treatment) and once during treatment with RO7172508 on Cycle 2 Day 8),
except for NSCLC patients where there is no accessible lesion. An optional biopsy may 
be taken at disease progression or long-lasting stable disease if the participant consents 
to this sample being taken. If preliminary data suggest that modification of the 
on-treatment tumor biopsy time-point would be more appropriate, alternative on-
treatment tumor biopsy time-points may be considered in the future cohorts. The goals 
of these analyses will be (i) to establish a dose−response relationship and (ii) to 
understand the MoA of RO7172508 at the tumor site.


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It is expected that upon treatment, the number and activation/differentiation status of 
intra-tumoral immune cells as well as their location will change. Such changes will be 
determined by flow cytometric and/or IHC methods and will be analyzed. Changes such 
as the density of different immune cell lineages (including but not limited to CD4T-cells, 
CD8T-cells, B-cells, natural killer (NK) cells, and macrophages) and their 
activation/differentiation status (including but not limited to CD25, Ki67, PD1, TIM3, etc) 
as well as TCR Vrepertoire changes will be examined. The expression of tumor 
markers (including but not limited to PD-L1) will also be examined.
Administration of therapeutic antibodies can be associated with IRRs and cytokine 
release syndrome (CRS). Therefore, cytokines, including but not limited to IL-6, IFN,
TNF, and inflammation markers, will be assessed in serum or plasma samples during 
treatment and in the event of an IRR/CRS. Because these measurements also represent 
safety measures, they will be examined in participants enrolled in both Part I and Part II.
The specimens will be used for research purposes to identify biomarkers that are useful 
to predict and monitor response to RO7172508 treatment and safety, assess PD effects 
of RO7172508 treatment, and investigate the mechanism of resistance to therapy.
4.3
DOSE JUSTIFICATION
4.3.1
RO7172508
The entry-into-human starting flat dose of 65 g was derived from incorporating an 
integrated approach, which was informed by in vitro activity in high-CEA expressing 
tumor cells as well as clinical safety experience with cibisatamab (see RO7172508 
Investigator’s Brochure). Compared to a classical minimum anticipated biological effect 
level (MABEL) approach, the approach used here reduces the number of participants 
exposed to sub-therapeutic doses of RO7172508 while ensuring that the starting-dose is 
in a safe range. 
Taking into account 20-fold potency increase, a 400 g dose of RO7172508 would be 
equivalent to 8 mg dose of cibisatamab (dose with no relevant cytokine increase 
documented and no Grade 3-related AEs reported).
Based on the available data, the Sponsor has defined the following intermediate doses 
in Part I:

Second cohort: 160 g

Third cohort: 400 g

Fourth cohort: 800 g

Fifth and last cohort: 1.6 mg
Incremental dose-increases may be altered based on emerging PK, PD and safety data 
but will not exceed 3-fold. If there is no safety concern reported in Part I during the safety 


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observation period (stopping rule: any RO7172508-related event of Grade 2 toxicity
reported within the DLT window), Part II of the study will start with a dose of 1.6 mg. 
Dose-escalation for Part II will follow the mCRM-EWOC design (see Section 4.1.2).
A maximum dose of 400 mg Q3W of RO7172508 has been defined. The Cmax observed 
at Cycle 1 of 400 mg (MTD) cibisatamab was 113 g/mL. Assuming a potency factor of 
20, an equivalent RO7172508 Cmax of 5.6 g/mL is estimated to be achieved by 25 mg. 
The clinical potency may differ from the in vitro levels; therefore, a maximum dose of 400 
mg has been defined to allow this to be tested. The dose-escalation will only take place 
once a full evaluation of safety data has taken place and the dose-increment levels may 
be reduced to ensure the participant’s safety. Dose-fractionation may also be 
implemented in Cycle 1 where a dose not exceeding 400 mg will be administered over 
one cycle e.g., 40 mg on Day 1, 120 mg on Day 8 and 240 mg on Day 15. The maximum 
SC dose administered QW will be 160 mg QW which is 480 mg over a three-week 
period/cycle. By applying a conservative bioavailability of ~80% this would equate to 
400 mg Q3W IV.
Further details are provided in the RO7172508 Investigator’s Brochure.
4.3.2
Obinutuzumab
If required, during the course of this study, based on the incidence of ADA-induced loss 
of exposure or safety events, obinutuzumab will be administered as detailed in the SoA 
(Section 1.3). Obinutuzumab will be administered as pre-treatment for RO7172508 
either as 2000 mg of obinutuzumab IV on one day (Day -7) or as 1000 mg of 
obinutuzumab IV on 2 consecutive days (Day -7 and Day -6) as specified in the SoA as 
per the site’s choice. Details regarding the infusion process are provided in Section 6.1. 
ADA titers and PK of both RO7172508 and obinutuzumab will be monitored as 
described in Section 4.1.3. 
The interval between obinutuzumab and the start of treatment has been determined 
based on Study BP39365, which is exploring the clinical activity of RO6874281 (FAP-
IL2v) in combination with atezolizumab. Five patients were pretreated with 
obinutuzumab 7 days prior to the combination treatment. It could be confirmed that 
complete B cell depletion was observed at the start of the combination treatment seven 
days after obinutuzumab was administered. There was no evidence of ADA formation 
in these participants when assessing ADA titers for RO6874281 (FAP-IL2v) and 
atezolizumab (RO5541267) up to 32 weeks of treatment. One patient showed positive 
ADA titers after 32 weeks of RO6874281/atezolizumab combination, which correlated 
with the reconstitution of B cells. Another patient remains on study after 52 weeks with 
no evidence of ADA titers and B cells remain depleted. Without obinutuzumab 
pretreatment in Study BP39365, the incidence of ADAs is approximately 80%. The 
kinetics of B-cell depletion and repletion have also been studied in Study BO20999 and 
following the administration of obinutuzumab a rapid depletion of B-cells was observed 
by Study Day 8 in CLL patients (first measurement after administration).


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Further details are provided in the obinutuzumab Investigator’s Brochure.
4.4
END OF STUDY DEFINITION
The end of the study is defined as the date of the last visit of the last participant in the 
study globally. 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 4.2.2.
Participants in this study are patients who have locally advanced and/or metastatic 
tumors with cytoplasmic and/or membranous CEA expression in20% of cells at 
intensities greater than at least IHC 1+.
In Part I, approximately 5 participants will be enrolled. In Part II, up to approximately 
75 participants during each dose-escalation, including additional 15 participants (150 
participants total in both IV and SC) will be enrolled (Section 9.2). In case the OBD is 
evaluated with and without obinutuzumab, an additional 15 participants may be 
enrolled.
Further participants may be treated in disease-specific expansions, once optimal 
schedule, route of administration and OBD have been determined.
Prospective approval of protocol deviations from recruitment and enrollment criteria, 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:
Informed Consent
1. Signed written informed consent and ability to comply with the study protocol 
according to International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and local regulations.
Age
2. Age 18 years.
Type of Participants and Disease Characteristics
3. For Part I (single participant cohorts), participants with locally advanced and/or 
metastatic solid tumor with confirmed cytoplasmic and/or membranous high CEA 
expression in tumor tissue (20% of tumor cells staining with CEA IHC 2+ or 3+ 


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intensity) is required (participants without archived tumor tissue available for testing 
must have a lesion amenable to biopsy). Participants must have progressed on a 
SOC therapy, be intolerant to SOC, and/or are non-amenable to SOC.
4. For < 12 mg dose cohorts, serum CEA (sCEA) levels below a certain threshold is 
required as follows:

For dose cohorts 65-159 g, an sCEA level of 22 ng/mL.

For dose cohorts 160-399 g, an sCEA level of 28 ng/mL.

For dose cohorts 400-799 g, an sCEA level of 44 ng/mL.

For dose cohorts 800-1599 g, an sCEA level of 70 ng/mL.

For the dose cohort of 1.6 - 3.1 mg, an sCEA level of 123 ng/mL.

For the dose cohort of 3.2 - 6.3 mg, an sCEA level of 229 ng/mL.

For the dose cohort of 6.4 -11.9 mg, an sCEA level of 440 ng/mL.
If dose fractionation is implemented, the sCEA threshold for inclusion should correspond to the 
dose range of the first dose administered. 
For Part II, at least 3 participants in each cohort should have a baseline sCEA level ≤20 ng/mL.
5.
For Part II, participants with locally advanced and/or metastatic solid tumor 
expressing cytoplasmic and/or membranous high-CEA or low-CEA on archival 
material (or fresh biopsy when archival is not available), who have progressed on a 
SOC therapy, are intolerant to SOC, and/or are non-amenable to SOC. Participants 
must have a lesion amenable to biopsy (except participants with NSCLC, which may 
be enrolled with archival tissue available only). For participants with colorectal cancer 
(CRC) only, the CEA assessment by IHC should be performed but the result is not required 
to enroll the participant.

High-CEA: 20% of tumor cells with IHC 2+ and/or 3+

Low-CEA: 20% of tumor cells with the sum of any IHC intensity (1+, 2+ and 3+)
and not considered CEA-High
6. Radiologically measurable disease according to RECIST v1.1.
7. Life expectancy (in the opinion of the Investigator) of 12 weeks.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
9. All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure 
must have resolved to Grade 1 or returned to baseline except alopecia (any grade) 
and Grade 2 peripheral neuropathy.
10. Adequate hematological function: neutrophil count of 1.5 109 cells/L, platelet 
count of 100,000/µL, and hemoglobin 8 g/dL (4.9 mmol/L) including lymphocytes 
within normal limits (0.8 109 cells/L).
11. Adequate liver function: total bilirubin 1.5 the upper limit of normal (ULN; 
excluding Gilbert‘s Syndrome), aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) 2.5 ULN (in case of liver metastases, 5 ULN).


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12. Adequate renal function: creatinine clearance by Cockcroft Gault 
formula 60 mL/min for participants with, in the Investigator’s judgment, serum 
creatinine levels that do not adequately reflect renal function.
13. Adequate lung function: vital capacity and forced expiratory volume in first second 
65% of age and body-weight predicted normal. Diffusion capacity 55% of 
predicted normal.
Sex
14. Male and female participants
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for male and/or 
female enrollment eligibility needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are 
not acceptable methods of contraception.
a) Female Participants
A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies:

Women of non-childbearing potential (WONCBP), as defined in Appendix 5.

Women of childbearing potential (WOCBP), who:
–
Agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of 1% per year from 
screening until 2 months after the last dose of RO7172508. Examples of 
contraceptive methods with a failure rate of 1% per year include bilateral 
tubal occlusion, male sterilization, and copper intrauterine devices (see 
Appendix 5).
–
Have a negative pregnancy test (blood) within one week prior to the first 
study treatment administration (applicable to premenopausal women and 
women 2 years after start of menopause (menopause is defined as 
amenorrhea for 2 years).
b) Male Participants
During the treatment period and for at least 2 months after the last dose of study 
treatment, agreement to:

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom or a contraceptive method that result in a failure rate 
of 1% per year, with partners who are WOCBP (as defined in Section 1 of 
Appendix 5).

Refrain from donating sperm during the study.


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5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participants with a history or clinical evidence of central nervous system (CNS)
primary tumors or metastases including leptomeningeal metastases unless they 
have been previously treated, are asymptomatic, and have had no requirement for 
steroids or enzyme-inducing anticonvulsants in the last 14 days before screening.
2. Participants with non-irradiated lesions 2 cm at critical sites (e.g., paraspinal, 
paratracheal) where tumor swelling induced by RO7172508 is expected to lead to 
significant complications. 
3. Participants with another invasive malignancy in the last 2 years (with the exception 
of basal cell carcinoma and tumors deemed by the Investigator to be of low 
likelihood for recurrence).
4. Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results or contraindicate the use of 
an investigational drug, including diabetes mellitus and history of relevant pulmonary 
disorders.
Diagnostic Assessments
5. Uncontrolled hypertension (systolic blood pressure [SBP] 150 mmHg and/or 
diastolic BP [DBP] 100 mmHg), unstable angina, congestive heart failure (New 
York Heart Association (NYHA) 1, serious cardiac arrhythmia that requires 
treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular 
tachycardia, and history of myocardial infarction within 6 months of enrollment.
6. Active or uncontrolled infections.
7. Known hepatitis B or C (active replicating).
8. Major surgery or significant traumatic injury 28 days prior to the first RO7172508 
administration (excluding biopsies) or anticipation of the need for major surgery 
during study treatment.
9. Dementia or altered mental status that would prohibit informed consent.
10. Baseline corrected QT interval of 470 ms. Participants with baseline resting 
bradycardia 45 beats per minute (bpm) or baseline resting tachycardia 100 bpm.
11. Radiotherapy within the last 28 days prior to the first RO7172508 administration with 
the exception of limited-field palliative radiotherapy.
12. Presence of bilateral lung lesions with either 3 lesions per lung or 1 lesion per 
lung with a diameter 3 cm (only unequivocal lesions of > 1cm are to be counted for this 
criterion, unless there is miliary metastatic-type diffuse disease, then these participants are 
ineligible).


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Prior/Concomitant Therapy
13. Concurrent therapy with any other investigational drug (defined as treatment for 
which there is currently no regulatory authority-approved indication) 28 days prior 
to the first RO7172508 administration.
14. Last dose with an immunostimulating or immunosuppressive therapy (e.g., IFN-, 
IFN-, IL-2, etanercept, infliximab, tacrolimus, cyclosporine, or mycophenolic 
acid) 28 days prior to the first RO7172508 administration.
15. Last dose of anti-CTLA4, anti-PD-L1, or anti-PD1 180 days prior to the first 
RO7172508 administration.
16. Expected need for regular immunosuppressive therapy (i.e., for organ 
transplantation, chronic rheumatologic disease) within 28 days prior to the first 
RO7172508 administration.
17. Regular dose of corticosteroids within 28 days prior to Day 1 of this study or 
anticipated need for corticosteroids that exceeds prednisone 10 mg/day or 
equivalent within 28 days prior to the first RO7172508 administration. Inhaled and 
topical steroids are permitted.
18. Prior treatment with a bispecific T-cell engaging drug targeting CD3e and/or CEA.
Other Exclusions
19. Known hypersensitivity to any of the components of RO7172508.
Specific Exclusion Criteria if Pre-treatment with Obinutuzumab is 
Implemented
20. Known HIV (HIV testing will be performed at screening if required by local regulations)
21. Positive test results for chronic HBV infection (defined as positive HBsAg serology), HBcAb 
indicating an active viral infection and positive test results for HCV (HCV antibody serology 
testing). 
22. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) 
is negative for HCV ribonucleic acid (RNA). 
23. History of progressive multifocal leukoencephalopathy. 
24. Active TB requiring treatment within 3 years prior to baseline. 
25. Latent TB diagnosed during Screening. 
26. Positive test results for human T-lymphotropic virus 1 (HTLV 1) 
27. HTLV testing is required in participants from endemic countries (Japan, countries in the 
Caribbean basin, South America, Central America, sub-Saharan Africa, and Melanesia) 
28. Known hypersensitivity to any of the components of obinutuzumab. 
5.3
LIFESTYLE CONSIDERATIONS
There are no study-specific restrictions to meals and dietary requirements.


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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.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure.
Individuals who do not meet the criteria for participation in this study (screen failure) may
be re-screened once providing they have not received the study drug and after 
discussion and agreement with the Sponsor. Re-screened participants should be 
assigned the same participant number as for the initial screening. Some essential 
procedures, such as biopsies, may be used from the initial screening period in 
agreement with the Sponsor. In the event that a fresh biopsy is taken during the 
screening period and the participant is not enrolled into the study, the 
formaldehyde-fixed paraffin-embedded (FFPE) biopsy block can be returned to the site 
upon site request.
5.5
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment by the Investigator and referring 
physicians using pre-screening enrollment logs, clinical databases and Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) approved 
newspaper/radio/social-media advertisements prior to consenting to take place on this 
study.
6.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.


RO7172508—F. Hoffmann-La Roche Ltd
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The investigational medicinal products (IMP) required for completion of this study 
(RO7172508, obinutuzumab and tocilizumab) will be provided by the Sponsor. 
Administration of study treatment will be at the study centers under supervision of 
qualified site staff.
6.1
TREATMENTS ADMINISTERED
Table 11 summarizes the treatments administered.
Table 11 RO7172508 Summary of Treatments Administered
Study Treatment 
Name:
Part I
RO7172508
Part II
RO7172508
Dosage Formulation:
Solution for infusion and 
injection
Solution for infusion and 
injection
Unit Dose 
Strength(s)/Dosage 
Level(s):
20 mg/mL
20 mg/mL
Dose:
65 g up to a maximum of 
1.6 mg
1.6 mg up to a maximum of 
400 mg IV
2 mg up to a maximum of 
160 mg SC
Route of 
Administration:
IV
IV and SC
Dosing Instructions:
see Pharmacy Manual
see Pharmacy Manual
Packaging and 
Labeling:
Study treatment will be provided 
in a carton box (one labeled vial 
per box). Each carton box will 
be labeled as required per 
country requirement.
Study treatment will be provided 
in a carton box (one labeled vial 
per box). Each carton box will be 
labeled as required per country 
requirement.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the RO7172508 Investigator’s Brochure and Pharmacy Manual for more
details.
Administration of Obinutuzumab
The obinutuzumab Drug Product will be supplied by the Sponsor as a 50 mL single 
dose glass vial containing 1000-mg liquid concentrate in 40 mL (25 mg/mL) for 
infusion. In addition to the drug substance, the liquid is also composed of 
histidine/histidine-HCl, trehalose and poloxamer 188 (see Table 12).


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Obinutuzumab will be administered either as a single dose of 2000 mg 7 days (D-7) 
before the first dose of RO7172508 (C1D1) or two doses of 1000 mg over days 6 and 
7 days (D-6 and D-7) before the first dose of RO7172508 (C1D1).  
For information on the formulation and handling of obinutuzumab, refer to the 
pharmacy manual and Obinutuzumab Investigator’s Brochure.
Table 12 Obinutuzumab Summary of Treatment Administered
Study Treatment Name
Obinutuzumab
Dosage Formulation
Concentrate for solution for IV 
infusion
Unit Dose Strength(s)/Dosage Level(s)
25 mg/mL
Dose
2000 mg or split doses of 2x 1000 mg
Route of Administration
IV
Dosing Instructions
see Pharmacy Manual
Packaging and Labeling
Study treatment will be provided in 
a carton (one labeled vial per box). 
Each carton will be labeled as 
required per country requirement.
Administration of Tocilizumab
Administration of tocilizumab is based on clinical presentation of CRS and should follow 
the guidelines stated in Section 8.3.8.1. 
Please see the tocilizumab Investigator’s Brochure and Pharmacy Manual for more 
details.
Table 13 Tocilizumab Summary of Treatment Administered
Study Treatment Name:
Tocilizumab
Dosage Formulation:
Concentrate for solution for IV 
infusion
Unit Dose Strength(s)/Dosage Level(s):
200 mg/10 mL
Dose:
8 mg/kg IV
Route of Administration:
IV
Dosing Instructions:
see Pharmacy Manual
Packaging and Labeling:
Study treatment will be provided in a 
carton box (one labeled vial per box). 
Each carton box will be labeled as 
required per country requirement.


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6.1.1
Pre-medication 
All pre-medications should be captured as concomitant medications in the participant’s 
electronic Case Report Form (eCRF). If during dose-escalation Grade 2 IRRs/CRS or 
tumor inflammatory events occur in the majority of participants, the utility of prophylactic 
pre-medication with systemic corticosteroids in preventing such events may be tested 
using the regimen as outlined in Table 14 (flat dosing) and Table 15 (for fractionated 
dosing). If successful, this regimen will then be used in future cohorts. 
In the event that the change in the route of administration from IV to SC does not 
mitigate the tumor inflammatory events or IRRs, then the same steroid regimen may be 
implemented as described in Table 14 and Table 15. These regimens are based on the 
expected duration of inflammatory events and they may be reduced or modified based 
on emerging data. Also, they may be extended from Cycle 1 to subsequent cycles, in 
case tumor inflammation and/or IRR occur at later cycles. Pre-medication may also 
include 1000 ml saline, 50 mg indomethacin (or equivalent non-steroidal anti-
inflammatory [NSAID]), and 50 mg diphenhydramine (or equivalent H1 antagonist).
Table 14 Steroid Use on Cycle 1 of RO7172508 Infusion to be implemented 
in the event of frequent IRR/CRS or gastrointestinal 
RO7172508-related toxicity occurrence after first administration
Timing
Dose
C1D1: 4 to 6 hours before RO7172508 infusion
1 mg/kg methylprednisolone IV*
1 g paracetamol PO TID
2 mg loperamide PO
C1D1: approximately 2 hours after RO7172508 infusion
1 mg/kg methylprednisolone IV*
C1D2: approximately 24 hours post-RO7172508 EOI
1 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
2 mg loperamide PO**
C1D3: approximately 48 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
C1D4: approximately 72 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
C: Cycle; D: Day; EOI: end of infusion; IV: intravenous; PO: oral; TID: 3 times a day.
* rounded up to next multiple of 10 mg (or equivalent doses of mid acting steroids) 
** subsequent treatment with loperamide only to be given as clinically indicated 


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Table 15 Steroid Use on Cycle 1 of RO7172508 or gastrointestinal
RO7172508-related toxicity to be implemented in the event of frequent 
IRR/CRS persisting despite dose fractionation
Timing
Dose
C1D1: 4 to 6 hours before RO7172508 infusion
1 mg/kg methylprednisolone IV*
1 g paracetamol PO TID
2 mg loperamide PO
C1D1: approximately 2 hours post-RO7172508 EOI
1 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D2: approximately 24 hours post-RO7172508 EOI
1 mg/kg prednisone IV/PO
C1D8: 60 minutes before RO7172508 infusion
1 mg/kg methylprednisolone IV*
1 g paracetamol PO TID
2 mg loperamide PO**
C1D8: approximately 2 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D9: approximately 24 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO
C1D15: 60 minutes before RO7172508 infusion
1 mg/kg methylprednisolone IV*
1 g paracetamol PO TID
2 mg loperamide PO **
C1D15: approximately 2 hours post-RO7172508 EOI
1 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D16: approximately 24 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO
C: Cycle; D: Day; EOI: end of infusion; IV: intravenous; PO: oral; TID: 3 times a day.
* rounded up to next multiple of 10 mg (or equivalent doses of mid acting steroids) 
** subsequent treatment with loperamide only to be given as clinically indicated 
In addition to the above mentioned premedication regimens, additional premedication may be 
implemented after agreement between Sponsor and Investigators for prophylaxis of RO7172508-
related toxicity at cycle 1 and/or at subsequent cycles:

From 30 to 60 minutes before administration of RO7172508, 5-HT3-receptor antagonist 
administration (preferably a long acting antagonist such as palonosetron 500 µg); 

Budesonide 9mg daily to start 3 days before first RO7172508 and to be continued up to 7 
days after first RO7172508 administration.


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Subsequent RO7172508 Infusions
Participants who experienced a Grade 2 IRR or other RO7172508-related toxicity within 24 
hours of RO7172508 administration on a previous infusion, should be pre-medicated for 
subsequent infusions. The regimen indicated in Table 14 will be recommended for subsequent 
cycles, however in lieu of IV methylprednisolone administration, an equal oral dose of 
methylprednisolone (or equivalent) can be used. Similarly, the additional premedication regimens 
may be moved to subsequent cycles to prevent recurrence of the toxicity that occurred in Cycle 1. 
Premedication regimens for subsequent cycles may be reduced or omitted in case of ≤ Grade 1 
events in the previous cycle.
For participants who experience an IRR-like reaction with a single and isolated symptom, 
such as fever that occurs within 24 hours after the study treatment infusion was 
completed, the use of pre-medication such as paracetamol, anti-histamine, and 
corticosteroids is not foreseen prior to subsequent RO7172508 administrations. The 
event will be reported as a single AE (e.g., fever). Pre-medication with corticosteroids of 
those participants at subsequent infusions needs approval from the Sponsor and the 
treatment and management at the time of an event is at the discretion of the Investigator.
Pre-medication may be changed based on emerging data and the regimens described above 
should be considered as the maximum suggested regimens. After collecting information on the 
effectiveness of the above mentioned premedication regimens scheduling and dose intensities may 
be reduced but not increased.
Premedication Prior to Obinutuzumab Administration
The use of corticosteroids, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) 
and/or antihistamines is required to minimize expected IRR reactions associated with 
the administration of obinutuzumab. Pre-medication must be administered prior to
obinutuzumab administration. A list of the mandatory pre-medications is provided in
Table 16.
Hypotension may occur as a result of an IRR adverse event. Therefore, it is 
recommended that antihypertensive drugs not be given on the morning of, and 
throughout the infusion of obinutuzumab, even if clinically indicated. Patients with a 
history of cardiac disease should be monitored closely.


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Table 16
Premedication Requirements for Obinutuzumab
Pre-Medication
Timing of Administration
Prednisolone 100 mg administered by IV 
infusion (or equivalent)
At least 60 minutes prior to the 
obinutuzumab infusion
Analgesic/anti-pyretic (e.g., paracetamol/oral 
acetaminophen 500 1000 mg) administered 
orally or by IV infusion
At least 30 minutes prior to the 
obinutuzumab infusion
Antihistamine (e.g., oral diphenhydramine 
50 100 mg) administered orally or by IV 
infusion (or an alternative anti-histamine at 
an adequate dose)
At least 60 minutes prior to the 
obinutuzumab infusion
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Sponsor’s clinical trial supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.
The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
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 Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the defined dose-level.
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments 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 site staff.
The Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).


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IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) 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.
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
This is an open-label, non-randomized study. 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. For Part I and 
Part II of the study, the assigned dose will be documented in the Confirmation of 
Enrollment and a participant number will be assigned. A participant Enrollment and 
Identification Code List must also be maintained by the Investigator.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the defined dose-level and the instructions given in the 
Pharmacy Manual. This individual will write the date dispensed and participant number 
on the study treatment box 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
6.5.1
Permitted Therapy
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant 
during screening until the follow-up visit must be recorded 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 concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF. All therapy and/or medication administered to manage 
adverse events should be recorded on the AE eCRF.


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6.5.1.1
Radiotherapy
The use of palliative radiotherapy is allowed at any time during the study, except for:

On days when RO7172508 is administered.

During DLT evaluation period.
–
If radiotherapy is administered during the DLT evaluation period, the participant 
will not be evaluable.
Participants should not receive study treatment during radiation treatment.
6.5.2
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF. As a general rule, no concomitant medication will be 
permitted, with the exception of medications to treat AEs, unless the rationale for 
exception is discussed and clearly documented between the Investigator and the 
Sponsor.
The use of the following therapies is prohibited for at least 28 days prior to initiation of 
study treatment and during the study, unless otherwise specified below:

Investigational or unlicensed/unapproved agents

Immunotherapy/radio-immunotherapy

Chemotherapy/targeted therapy

Radiotherapy (with the exception of limitedfield palliative radiotherapy; see 
Section 6.5.1.1).

Biologic agents (e.g., bevacizumab, erlotinib).

Chronic use of steroids (inhaled and topical steroids are permitted).

Administration of a live, attenuated vaccine within 28 days before Cycle 1 Day 1 or 
anticipation that such a live attenuated vaccine will be required during the study.
6.6
DOSAGE MODIFICATION
In the event a dose-reduction is necessary, any subsequent study treatment will be 
administered after agreement with the Sponsor.
Should a participant experience a DLT in the first or in subsequent cycles or experience 
a toxicity of the same nature at the same or higher grade following re-exposure to 
RO7172508, the Investigator, after discussion with the Sponsor, will have the option to 
reduce the dose of RO7172508, if deemed clinically beneficial.
A delay of RO7172508 administration for up to two cycles independent of the schedule, 
will be acceptable to allow for resolution of toxicity to NCI CTCAE Grade 2 for 
hematological toxicities or Grade 1 for non-hematological toxicities (with the exception 
of a toxicity considered as non-RO7172508-related). 


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If the toxicity does not resolve to NCI CTCAE Grade 2 for hematological toxicities or 
1 for non-hematological toxicities and the participant is unable to resume treatment 
with RO7172508 after this time (omission of two doses), no additional doses will be 
administered and the participant will be withdrawn from study treatment, unless the 
participant exhibits a clinical benefit and this is agreed by the Investigator and the 
Medical Monitor. It should be noted that infusions/cycles not occurring at the anticipated 
schedule, are considered as delayed, not missed.
Further dose-reductions may be implemented once safety and toxicity data from the 
dose-escalation have been evaluated.
If a participant experiences obinutuzumab-related toxicity on Day -7 that requires the 
subsequent administration of obinutuzumab on Day -6 to be delayed, administration of 
obinutuzumab up to Day -5 is acceptable. Any obinutuzumab-related toxicity should 
resolve to NCI CTCAE Grade ≤ 2 for hematological toxicities or ≤ 1 for non-
hematological toxicities before RO7172508 administration. The first RO7172508 
administration can be delayed for of up to 1 week and if toxicity persists, the start of 
RO7172508 treatment will need to be agreed with the Medical Monitor.  
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor will offer post-trial access to the study treatment (RO7172508) free of 
charge to eligible participants in accordance with the Sponsor’s Global Policy on 
Continued Access to Investigational Medicinal Product.
A participant will be eligible to receive study treatment after the end of the study if all of 
the following conditions are met:

The participant has a life-threatening or severe medical condition and requires 
continued study treatment for his/her well-being.

There are no appropriate alternative treatments available to the participant.

The participant and his/her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.
A participant will not be eligible to receive study treatment after the end of the study if 
any of the following conditions are met:

The study treatment is commercially marketed in the participant's country and is 
reasonably accessible to the participant (e.g., is covered by the participant's 
insurance or would not otherwise create a financial hardship for the participant).

The Sponsor has discontinued development of the study treatment or data suggest 
that the study treatment is not effective for cancer.

The Sponsor has reasonable safety concerns regarding the study treatment as 
treatment for cancer.


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
Provision of study treatment is not permitted under the laws and regulations of the 
participant's country.
7.
DISCONTINUATION OF 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 
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. 
7.1
DISCONTINUATION OF STUDY TREATMENT
See the SoA (Section 1.3 for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.
Participant must discontinue study treatment if they experience any of the following:

Pregnancy

Grade 3 IRR/CRS for RO7172508

IgE-mediated hypersensitivity reactions, including anaphylaxis.

Any toxicity which is not manageable with dose-delays (as allowed per protocol), 
dose-decrease and/or appropriate treatment.

Symptomatic disease progression when there is a consensus that the participant will 
not benefit from study treatment.

If a patient develops alanine aminotransferase or aspartate aminotransferase 
increase 10x ULN associated with the 3rd infusion of RO7172508 or later.
Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for an End-of-Treatment visit (see Section 8.10.3) and may undergo follow‑up 
assessments (see Section 8.10.4). The primary reason for premature study treatment 
discontinuation should be documented on the appropriate eCRF. Participants who 
discontinue study treatment prematurely may be replaced for the following reasons to 
ensure adequate numbers of evaluable participants:

Participant who withdraws from the study prior to the treatment start may be 
replaced.

Participants who fail to complete their DLT assessment period because of 
non-drugrelated reasons.

In the case of a major protocol violation when participants are excluded from 
Cycle 1 of treatment (these participants will be excluded from the MTD/DLT analysis 


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but might continue the treatment if deemed beneficial and according to clinical 
judgment).

Cohorts may be expanded to acquire additional paired tumor biopsies.
Participants will be treated for 24 months (the treatment period may be modified if 
supported by emerging data) or until disease progression, loss of clinical benefit, 
unacceptable toxicities, or withdrawal from treatment for other reasons or death.
As with other immunotherapies, treatment beyond RECIST (Appendix 6) progression 
could be considered. The criteria below will be needed to continue treatment beyond 
initial apparent progressive disease per RECIST v1.1 (e.g., radiological progression 
secondary to tumor inflammation):

Absence of clinical deterioration and Investigatorassessed potential clinical benefit 
for the participant and

The participant is tolerating study treatment.
7.1.1
Temporary Interruption
If an IRR/CRS develops, the infusion of RO7172508 should be slowed down or 
interrupted. The participant should be monitored until complete resolution of the 
symptoms and treated as clinically indicated. Treatment or concomitant medication may 
include acetaminophen/paracetamol, antihistamine, IV saline, oxygen, bronchodilators, 
corticosteroids, and vasopressors, depending on the symptoms (see Section 8.3.8.1. 
Study treatment should be re-started as soon as medically justified in the opinion of the 
Investigator.
The infusion may be resumed at 50% (Grade 1 IRR/CRS) or 25% (Grade 2 
IRR/CRS) of the previous rate. The infusion can be re-escalated to the initial rate if study 
treatment is considered well-tolerated after one hour of infusion.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
In addition, the Investigator has the right to withdraw a 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.


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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 remain as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of specimens 
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 only as 
described in Section 7.1.
See the SoA (Section 1.3) 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.
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 he/she 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.

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 be 
lost to follow-up.
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.


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Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-frame defined in the SoA.
Based on continuous analysis of the data in this study, any sample type or biomarker 
evaluation not considered to be critical for safety may be stopped at any time if the data 
from the samples collected does not produce useful information.
8.1
EFFICACY ASSESSMENTS
8.1.1
Tumor and Response Evaluations
Tumor assessments will be performed at the time-points defined in the SoA (Section 1.3). 
Tumor response will be evaluated according to RECIST v1.1 (Appendix 6) using 
unidimensional measurement such as CT scan or magnetic resonance imaging (MRI). 
Assessment of CT/MRI scans as tumor assessments will be performed at the sites 
during the whole study.
The data collected for RECIST v1.1 (Appendix 6)will be used by the Sponsor to calculate 
programmatically time-point responses for iRECIST (Appendix 7), 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).
Tumor assessment will be performed according to the SoA until disease progression or 
death. All tumor assessments after baseline may be done within one week of the 
scheduled visit. 
Confirmation of PRs and complete responses (CRs) will be done at the next scheduled 
visit after at least 28 days from the initial response.
The criteria are needed for continuing treatment beyond RECIST v1.1-defined 
progression as defined in Section 7.1.
Submission of the latest pre-study or historical CT scans is required for assessment of 
tumor kinetic modelling within 12 weeks of participant entering the study if available. 
8.1.1.1
Radiographic Assessments
Diagnostic CT scans should be acquired according to the guidelines in Appendix 6. At
the Investigator’s discretion, CT scans may be repeated at any time if progressive 
disease is suspected.


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MRI or positron emission tomography (PET)/CT (without contrast) scans may be used 
instead of CT scans in participants for whom CT scans are contraindicated, provided 
they permit consistent and precise measurement of target lesions during the study 
treatment period.
The same radiographic assessment modality and acquisition protocol should be used for 
all response evaluations, in order to ensure consistency across different time-points. A 
full radiographic assessment must be performed any time disease progression or if a 
relapse is suspected.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3). In 
order to better understand related adverse events, if any unscheduled assessments are 
performed during the study as part of standard of care, such as biopsies at the time of 
inflammation, these samples and/or results can be shared with the Sponsor for further 
analysis. 
8.2.1
Physical Examinations
A physical examination will be performed by trained medical personnel at the study 
center at the visits indicated in the SoA (see Section 1.3). Physical examination will 
include body weight (at screening, during treatment, at the final or early termination visit, 
and at the safety follow-up visit) and height (at screening).
The physical examination should cover head and neck including lymph nodes, and the 
cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
neurological systems, and others, as applicable.
Further examination of other body systems may be performed in case of evocative 
symptoms at the Investigator’s discretion.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the AE eCRF.
8.2.2
Vital Signs
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed as 
outlined in the SoA (see Section 1.3).
Blood pressure and pulse measurements will be assessed in supine position with a 
completely automated device. Manual techniques will be used only if an automated 


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device is not available. When possible, the same arm should be used for all blood 
pressure measurements.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones).
Vital signs will be taken before blood collection for laboratory tests but after 
electrocardiogram (ECG) collection when scheduled at the same time-point. At the 
discretion of the Investigator, measurements can be repeated if the values are abnormal 
or borderline.
Not every vital sign abnormality qualifies as an AE. Criteria for vital sign results that 
should be reported as an AE are listed in Appendix 3, Section 5.
8.2.3
Electrocardiograms
A single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR interval, 
QRS complex, QT interval, and QT corrected for heart rate (QTc) interval.
In case of abnormalities or clinical symptoms, unscheduled ECG assessments should be 
performed in triplicate. At each time-point at which triplicate ECGs are required, three 
individual ECG tracings should be obtained as closely as possible in succession. To 
minimize variability, it is important that participants be in a resting position for at 
least10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to meals and 
any scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.
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 heart rate, QRS complex, and PR and QT intervals, will 
be recorded on the eCRF. QTc using Bazett’s correction factor (QTcB), QTc using 
Fridericia’s correction factor (QTcF) and RR interval will be calculated by the Sponsor.
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.


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8.2.4
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the separate 
Laboratory Manual and 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 eCRF if it 
fulfills the criteria defined in Appendix 2. 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.

In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to 
the normal range and/or an adequate explanation of the abnormality is found.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
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 is considered uncertain, 
screening laboratory tests may be repeated before randomization to confirm eligibility.
8.2.5
Medical History and Demographic Data
Medical history includes clinically significant diseases, demographic data (including age, 
sex, and self-reported race/ethnicity), surgeries, cancer history (including prior cancer 
therapies and procedures), reproductive status, smoking history and all medications 
(e.g., prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional 
supplements).
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or serious AE (SAE) can be found in Appendix 2. The non-
serious adverse events of special interest (NSAESI) and disease-related events and/or 
disease-related outcomes not qualifying as AEs or SAEs are discussed in Sections 8.3.6
and 8.3.7.


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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 AE 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 AE 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 90 days after the last dose of study treatment. 
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for AEs after the end of the AE reporting period.
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 
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 time-points.


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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 to be related to 
study treatment or trial-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the AE
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 AE 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 case details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case.
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.
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, IRBs/IECs, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) 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 Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.


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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. Medical monitors’ contact details will be available on a 
separate list generated by the study management team.
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 2 months after the last 
dose of study treatment.
Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 2 months after 
the last dose of study treatment.
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, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest
NSAESIs are required to be reported by the Investigator to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event (Appendix 2 for reporting instructions). 
NSAESIs of special interest 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, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.
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.


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8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
No disease-related events are expected for this study.
8.3.8
Management of Specific Adverse Events
Guidelines for the management of participants who experience specific AEs to the IMPs 
other than RO7172508 (obinutuzumab and tocilizumab) are provided in the 
obinutuzumab and tocilizumab Investigator's Brochure and local prescribing 
information. Guidelines for the management of participants who experience AEs 
associated with RO7172508 are provided in Table 17, Table 18, and Table 19. For cases in 
which management guidelines are not covered in this protocol or in the 
obinutuzumab/tocilizumab Investigator's Brochure and local prescribing information, 
toxicities should be treated as deemed appropriate by the Investigator according to best 
medical judgment and local medical guidelines. Please see the RO7172508 
Investigator’s Brochure for further details of the safety profile.
8.3.8.1
Infusion-Related Reactions/Cytokine Release Syndrome
Administration of RO7172508 may cause a spectrum of infusion-related adverse events 
that typically occur during, shortly after, or within 24 hours after the infusion and 
could be associated with an IRR or CRS. 
IRRs are typically seen with the first two cycles and without symptoms of hypoxia 
and/or hypotension. In contrast, CRS is more likely to occur with the symptoms of 
hypoxia and/or hypotension at any cycle and with any symptom following from the 
third cycle onward. IRR events are therefore defined as taking place in association with 
the first two infusions and without symptoms of hypotension and/or hypoxia.
Given the overlap in signs and symptoms, IRRs may be indistinguishable from CRS, 
defined as a disorder characterized by nausea, headache, tachycardia, hypotension, rash, 
shortness of breath, and renal, coagulation, hepatic, and neurologic disorders (Lee et al. 
2014). Severe CRS may be associated with other clinical sequelae, such as disseminated 
intravascular coagulation and capillary leak syndrome.
Given that IRRs may be indistinguishable from CRS based on symptomatology, single-
treatment management guidelines are being recommended for both IRRs and CRS, 
during or up to 24 hours after infusion of RO7172508. The approach to have single-
treatment management guidelines for IRR and CRS will continue to be reviewed as 
additional safety data accumulate.
Table 17 provides guidelines for management of infusion-related reactions/ cytokine 
release syndrome.


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Table 17 Recommendations for Management of IRRs and CRS considered 
related to RO7172508a
Symptoms
Guidance
Grade 1
Fever, 
constitutional 
symptoms
–
If RO7172508 infusion is ongoing, slow infusion to ≤50% or interrupt infusion
–
Symptomatic treatment and supportive care
–
Monitor fluid balance and administer IV fluids as clinically indicated
–
At next cycle administer pre-medications that may include antihistamine, 
antipyretics/NSAIDS, antiemetic, and corticosteroids (See Table 14 and 
Table 15)
Grade 2
Hypotension:
responds to
fluids 
OR
Hypoxia*: 
requires 
<40% FiO2
(or ≤5 L/min 
of 100% O2) 
to maintain 
adequate 
hemoglobin 
oxygen 
saturation
–
Follow all Grade 1 recommendations
–
Hold further RO7172508 treatment until symptoms completely resolved
–
At the restart of the infusion, slow down the rate of infusion to 25% of 
original rate
–
If event occurred during infusion, and symptoms recur with the same or 
greater severity following interruption of RO7172508 infusion, the infusion 
must be stopped immediately.  Consider to manage as a Grade 3 event. No 
further RO7172508 will be administered for the cycle
–
Monitor cardiac and other organ functions closely
–
Hemodynamic support as indicated and oxygen for hypoxia
–
Admit to ICU as appropriate
–
Consider administering a single dose of tocilizumab IV 8 mg/kg
–
If no improvement within 24 hours:
a)
Notify Medical Monitor
b)
Administer IV corticosteroids (e.g., methylprednisolone [2 mg/kg/day] 
or dexamethasone 10 mg if neurologic symptoms are present)
–
Additional monitoring and evaluation:
–
Consider 24 hour hospitalization
–
Work up for organ functions (e.g. liver, cardiac) based on clinical 
assessment of the Investigator
–
May receive RO7172508 in next cycle if symptoms resolve to Grade 
≤1 with the approval of the Medical Monitor including considerations for 
dose reduction and/or reduction of infusion rate at the next 
administration. 
–
At next cycle administer pre-medications that may include 
antihistamine, antipyretics/NSAIDS, antiemetic, and corticosteroids 


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Table 17 Recommendations for Management of IRRs and CRS considered 
related to RO7172508 a (cont.)
Grade 3
Hypotension: 
requires 
vasopressor 
support   
OR
Hypoxia*: 
requires >40
%
FiO2 or >5 
L/min O2 to 
maintain 
adequate 
hemoglobin 
oxygen 
saturation
–
If RO7172508 infusion is ongoing, stop infusion immediately
–
No further RO7172508 will be administered for the cycle
–
Cardiopulmonary and organ function monitoring in ICU
–
Closely monitor and maintain fluid balance; and other supportive care as 
clinically indicated
–
Vasopressor support for hypotension with high and repeated doses if 
required
–
Notify Medical Monitor
–
Initiate IV corticosteroids (e.g., methylprednisolone [2 mg/kg/day] or 
dexamethasone 10 mg if neurologic symptoms are present)
–
Administer tocilizumab 8 mg/kg  IV 
–
If no clinical improvement within 24 h: repeat dose of tocilizumab 
8 mg/kg
–
Additional monitoring and evaluation:
–
Hospitalize patient for 24 hours
–
Work up for organ functions (e.g. liver, cardiac) based on clinical 
assessment of the Investigator
–
Permanently discontinue RO7172508 and follow the Schedule of 
Assessments (Table 5)
Grade 4
Hypoxia:
Mechanical
ventilation 
required
–
Follow all Grade 3 guidelines
–
Permanently discontinue RO7172508
a Grading of events is based on CTCAE V5.0 
* Isolated hypoxia (without hemodynamic instability) requiring oxygen support in a patient with tumor 
(primary or metastatic) in the lung should be managed as per tumor inflammation guidelines (Table 18) and 
not per CRS guidelines (Table 17).
8.3.8.2
Suspected Tumor Inflammation
Adverse events associated with tumor inflammation have been reported with T-cell 
engaging therapies and are consistent with the mechanism of action of such therapies 
that lead to influx of T-cells into tumor sites. Tumor inflammation is driven by influx 
of T cells and it is dependent on the mechanism of action of RO7172508. Along with 
the volume increase dependent on the influx of T cells, there may be an additional 
volumetric component possibly dependent by local inflammation. Events involving 
tumor inflammation, including tumor flare, have been reported in studies with in-class 
agent cibisatamab. These events tend to occur with a short time to onset following 
administration and may present with varying degrees of severity. 


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In addition, depending on tumor size and anatomic location, events associated with 
tumor inflammation may potentially result in mass effects on vital structures, 
including airways, major blood vessels, and/or major organs. Depending on the nature 
of the tumor inflammation, further medical and/or surgical management may be 
necessary (e.g. anti-inflammatory agents, airway management, decompression, cardiac 
function monitoring in terms of ejection fraction). Participants with tumors involving 
critical anatomic locations should be closely monitored for tumor inflammation and 
prospective consideration for preventive or interventional measures may need to be 
considered or planned prior to dosing. The treating physician/study investigator should 
contact the Medical Monitor to discuss risk assessment and mitigation strategies prior 
to initiating RO7172508 treatment in case participants present disease closed to vital 
structures. 
For further safety information, refer to the RO7172508 Investigator Brochure.
Table 18 provides guidelines for management of suspected tumor inflammation.
If corticosteroids are administered, taper before stopping treatment. In case of 
concurrent respiratory and other organ toxicities, follow the management 
recommendations for respiratory toxicities.
Table 18 Management of Suspected Tumor Inflammation
Event
Initial Management 
Recommendation
Action to be Taken with 
RO7172508
Respiratory toxicities
Supportive measures, e.g., oxygen support and intubation, as indicated.
Grade 1
Monitor participant closely.
Continue treatment.
Grade 2
Monitor participant closely.
If no resolution to Grade 1 within 
48 hours, administer 1 mg/kg/day of 
IV methylprednisolone or equivalent 
followed by tapering with oral 
steroids until Grade 1.
Hold until resolution to 
Grade 1.
Grade 3
Administer 2 mg/kg/day of IV 
methylprednisolone or equivalent 
followed by tapering with oral 
steroids until resolution to Grade 1 or 
baseline.
Ensure participant access to an 
intensive care unit is available
Hold until resolution to 
Grade 1.
Grade4
Consider permanent 
discontinuation after 
discussion with Medical 
Monitor.


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Table 18 Management of Suspected Tumor Inflammation (cont.)
Toxicities in other organs systems
Grade 1 or 2
Monitor participant closely
Continue if Grade 1 event (for 
Grade 2 events, hold until 
resolution to Grade 1).
Grade 3
Administer 1 mg/kg/day of IV 
methylprednisolone or equivalent 
followed by tapering with oral 
steroids until Grade 1 or baseline
(consider escalating next day to 2 
mg/kg/day if no improvement, or 
escalate to 2 mg/kg directly if event 
occurs during prophylactic treatment 
with steroids).
Ensure participant access to an 
intensive care unit is available.
Hold until resolution to 
Grade 1. For grade ≥3 
toxicity and duration ≥5 days 
permanent discontinuation 
(including liver enzyme 
elevations). Exceptions may be 
warranted after discussion of 
benefit/risk profile of a specific 
patient with Medical Monitor
Grade 4
Administer 2 mg/kg/day of IV 
methylprednisolone or equivalent 
until Grade 1 or better.
Ensure participant access to an 
intensive care unit is available.
8.3.8.3
Management of Diarrhea/Colitis
Table 19 provides guidelines for management of suspected diarrhea.
Patients should be closely monitored (including monitoring of renal function) and should 
be hydrated if clinically indicated to prevent renal insufficiency due to fluid depletion. 
For Grade 2 diarrhea associated with the 3rd administration of RO7172508 or later, 
patient referral to a GI Specialist is recommended (including a colonoscopy and/or 
biopsy based on specialist input).


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Table 19 Management of Diarrhea/Colitis
Event 
Management Recommendations
Grade 1

Continue treatment with RO7172508.

Initiate anti-diarrheal treatment (e.g., loperamide) as 
soon as possible.

Monitor the participant closely.

Ensure appropriate fluid intake.

If symptoms persist despite optimal anti-diarrheal 
treatment for more than 5 days, perform 
gastrointestinal (GI) work up*.
Grade 2

Withhold treatment with RO7172508.

Initiate anti-diarrheal treatment (e.g., loperamide) as 
soon as possible

Monitor the participant closely, perform GI work up*.

Ensure appropriate fluid intake

If symptoms do not improve to Grade 1 despite 
optimal anti-diarrheal treatment within 2 days, consider 
treatment with IV or oral corticosteroids (1mg/kg/day 
oral prednisolone or equivalent).

If diarrhea does not improve after 48 hours of 
corticosteroid treatment of 1mg/kg/day, increase dose 
to 2mg/kg/day.

If symptoms do not resolve despite corticosteroid 
treatment, consider referring the participant to GI 
specialist 

RO7172508 can be re-started if symptoms resolve to 
Grade 1.
Grade 3
a.
Withhold treatment with RO7172508.
b.
Refer the participant to GI specialist for diagnostic 
procedures (stool culture, endoscopy) and appropriate 
treatment.

Initiate corticosteroid treatment IV (2mg/kg/day IV 
methylprednisolone or equivalent).

Ensure appropriate fluid intake.

RO7172508 can be re-started if symptoms resolve to 
Grade 1.

If no improvement after 24 hours, consider treatment 
as per Grade 4 guidelines
Grade 4

Permanently discontinue treatment with RO7172508.

Refer the participant to GI specialist for diagnostic 
procedures (stool culture, endoscopy) and appropriate 
treatment.

Manage all symptoms by aggressive symptomatic 
treatment.

Initiate corticosteroid treatment IV.

If the there is no improvement for more than 48 hours, 
immunosuppressive treatment might be considered 
(such as infliximab).
* GI work up for further evaluation (e.g. endoscopy) and includes stool culture


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8.3.8.4
Management of Immunogenicity
Administration of therapeutic antibodies may cause the formation of ADAs and 
immunogenicity is a potential risk for RO7172508. Severe AEs (including two fatal 
events) associated with ADA formation were observed during clinical development of in 
class agent cibisatamab. 
All participants will be monitored at regular intervals for the development of ADAs 
against RO7172508 (see Section 8.5.1 for details). In case of emergence of AEs (in 
particular hypersensitivity reactions and CRS) possibly related to the development of 
ADAs against RO7172508, management will follow guidelines as summarized in
Table 17. In all cases of AEs suspected to be associated with the development of ADAs, 
treatment discontinuation should be immediately considered even if the event is low 
grade after discussion with Medical Monitor. 
As an additional mitigation strategy, obinutuzumab pre-treatment will be initiated if 
there is evidence of ADA mediated hypersensitivity reactions or other safety signals 
that are likely related to ADAs (see Section 4.1.3 for details). In such instance, 
obinutuzumab will be implemented for all subsequent participants and the enrollment 
of participants without obinutuzumab will be stopped.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental or intentional use of the drug in an amount 
higher than the dose being studied. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Appendix 2 for 
further details).
Decisions regarding dose-interruptions or modifications will be made by the Investigator 
or treating physician in consultation with the Medical Monitor based on the clinical 
evaluation of the participant.
In the event of an overdose, the Investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
resolved.
3.
Obtain a blood sample for PK analysis from the date of the last dose of study 
treatment, if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF.
8.5
PHARMACOKINETICS
Serum samples will be collected for RO7172508 PK analyses for both IV and SC 
administrations.


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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. RO7172508
concentrations will be analyzed by using a validated assay. The PK samples will be 
taken as outlined in the SoA (see 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 
RO7172508 can be adequately characterized (but without increasing overall blood 
collection volume for PK). Additional PK samples will be taken at the time of treatment 
discontinuation, if the participant experiences an infusion-related AE (such as an IRR, 
CRS), or if the participant experiences an AE leading to dose-reduction or delay of 
RO7172508 administration (see Section 6.6 Dosage Modifications).
Remaining volumes of PK samples may also be used for assay development or 
validation, for RO7172508-related exploratory analyses, or to help develop further blood 
tests, after they are used for the mentioned intended uses.
Serum samples will be collected for obinutuzumab PK analyses in those participants 
who receive obinutuzumab as pre-treatment.
sCEA will be measured as outlined in the SoA tables to investigate the impact on 
quantification of RO7172508 levels by the PK assay.
The PK samples will be destroyed within 2 years after the date of final Clinical Study 
Report (CSR), unless the participant agrees to participate in the RBR. Details on 
sampling procedures, sample storage, and shipment are given in the Study Flow Chart 
and Laboratory Manual.
8.5.1
Immunogenicity Assessments
As RO7172508 is a human antibody, there is a risk that ADAs against RO7172508 could 
develop, potentially reducing its efficacy and/or potentially resulting in symptomatic 
hypersensitivity reaction, in particular immune-complex reactions.
Antibodies to RO7172508 will be evaluated in blood samples collected from all 
participants according to the SoA (Section 1.3). Additional ADA samples should also be 
collected at the time of treatment discontinuation or at the safety follow-up visit. In each 
case, for each collected ADA sample, a corresponding PK sample will be collected at the 
same time-point for the determination of the RO7172508 concentration. Participants 
experiencing a Grade 3 toxicity potentially related to ADAs will not be further treated 
with RO7172508 (see Section 7.1).
Validated screening, confirmatory, and titer assays will be employed to detect ADAs 
against RO7172508. The date and time of each sample will be recorded in the eCRF.


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Remaining volumes of ADA samples may also be used for assay development or 
validation, for compound-related exploratory analyses, or to help develop further blood 
tests, after they are used for the mentioned intended uses.
Antibodies to obinutuzumab will be evaluated in all participants who receive 
obinutuzumab as pre-treatment according to the SoA.
The PK/ADA samples will be destroyed within 2 years after the date of final CSR, unless 
the participant agrees to participate in the RBR.
Details on sampling procedures, sample storage, and shipment are given in the Study 
Flow Chart and Laboratory Manual.
8.6
PHARMACODYNAMICS
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 (CD4+ T-cells, CD8+ T-cells, 
NK cells, monocytes, T-regulatory cells, and B-cells), activation (including but not 
limited to HLA-DR, etc.), differentiation (including but not limited to Ki67, etc.) and 
TCR Vrepertoire changes.

Serum and/or plasma samples: PD biomarkers such as cytokines and 
inflammation markers (including but not limited to TNF, IFN, IL-6, Macrophage 
Inflammatory Protein [MIP], etc.) will be analyzed. Because these measurements are 
also safety measure assessments during any IRRs, they will be examined in 
participants enrolled in both Part I and Part II of the study. Disease-monitoring 
markers that include but are not limited to sCEA will also be assessed.

Archival tissue and fresh tumor biopsy: Study enrollment will be based on CEA 
status assessed on archival tissue (with the exception of participants with CRC). If 
archival is not available, fresh biopsy collected at baseline will be used. Mandatory 
tumor biopsy samples obtained in Part II for all participants (including participants 
with CRC) at baseline and on-treatment (Cycle 2 Day 8; see SoA, Section 1.3) will 
be assessed for changes in immune cell numbers and activation characteristics as 
well as changes in tumor markers such as PD-L1. These analyses will be performed 
by flow cytometry, molecular and/or immunohistochemistry methods with respect to 
changes in the characteristics of lineage (CD4+ T-cells, CD8+ T-cells, NK cells, 
monocytes, T-regulatory cells, and B-cells), activation (including but not limited to 
CD25, CD69, etc.), differentiation (including but not limited to Ki67, PD1, TIM3, 
ICOS, etc.), and TCR Vrepertoire.
Whole blood, serum/plasma, and tissue samples will be collected at time-points 
specified in the SoA (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.


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Residual blood, serum/plasma and tissue samples may also be used for additional
(assay) validation experiments after the specified analyses were performed.
Details on sampling procedures, sample storage, and shipment are given in 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 8.8.1).
8.7
GENETICS
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 8.8.1). 
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 patients in the future. The specimens will also be made 
available for future biomarker research towards further understanding RO7172508, 
treatment of related diseases and AEs.
See RBR (Section 8.8.1) for related pharmacogenomics or genetic analysis.
8.7.1
Clinical Genotyping
A mandatory clinical genotyping whole blood sample will be taken for deoxyribonucleic 
(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 RO7172508, 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 impact on 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.
Details on sampling procedures, sample storage, and shipment are given in 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 Appendix 1, Section 1.4.


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8.7.2
Whole Genome/Exome/Targeted DNA Analysis
Archival tumor tissue, fresh tumor tissue sample and blood will be collected at the visits 
specified in the SoA and may be used for DNA and/or ribonucleic acid (RNA) extraction 
for exploratory research on genomic biomarkers (including, but not limited to, cancer-
related genes and biomarkers associated with common molecular pathways, or immune-
related markers [e.g., T-cell receptor sequence/TCR V], microsatellite instability [MSI]
and tumor mutation burden), and for DNA and/or RNA extraction to enable genomic 
analysis for exploratory research on genetic biomarkers.
8.7.2.1
Transcriptome Analysis
Blood and tissue samples may be used for potential 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
BIOMARKERS
The specimens will be used for research purposes to identify biomarkers useful to 
predict and monitor response to RO7172508 treatment, identify biomarkers useful to 
predict and monitor RO7172508 safety, assess PD effects of RO7172508 treatment, and 
investigate potential mechanism of therapy resistance. Additional markers may be 
measured in case a strong scientific rationale for these analyses develops.
Whole blood, serum/plasma, and tissue samples will be collected at time-points 
specified in the SoA (Section 1.3). See Section 8.6 for additional details.
Tumor
Mandatory tumor biopsy samples (each time-point consisting of at least two tissue 
specimens [preferably three]) will be collected from all participants who participate in 
Part II of the study on two occasions (once at baseline and once during the study 
treatment period [C2D8]). 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. Three core 
biopsies will be obtained from all participants. 
Cytological, fine needle aspiration or biopsy of bone lesions is not acceptable.


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The baseline and on-treatment biopsies should preferably be taken from 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 timepoints may be considered upon joint agreement between 
Investigators and the Sponsor.
Archival tumor tissue is to be obtained from all participants, if available, in order to 
perform CEA assessment for participant eligibility except for participants with CRC 
(refer to the Laboratory Manual). Both archival and fresh tumor biopsy specimens will be 
analyzed with respect to changes as described (Section 8.6) including but not limited to 
immune and tumor cell characteristics, TCR Vrepertoire etc.
Whole Blood
In Part II of the study during dose-escalation, whole blood samples will be collected for 
flow cytometry for determination of immune cell markers (including but not limited to 
immune cell subsets, activation and proliferation markers). A whole blood sample will be 
taken for TCR Vsequencing (the CDR3-TCR beta chain repertoire). The DNA will be 
used to determine in peripheral T-cells the repertoires of TCR VCDR3 and analyze 
TCR diversity.
Serum and/or plasma
Blood for serum/plasma isolation will be collected in Part I and Part II for investigation of 
markers and cytokines including but not limited to sCD25, IL-6, IFN, TNFand others, 
and soluble tumor markers including but not limited to sCEA, etc. In the event of an IRR, 
an additional sample will be collected.
Clinical Genotyping Samples
From every participant in Part II, a baseline mandatory whole blood sample will be taken 
for DNA/RNA extraction. The DNA will be used to determine if alleles at genes 
associated with immune responses such as chemotaxis, HLA, immunosuppression, etc, 
affect the PK/PD/efficacy/safety of RO7172508. Data arising from this study will be 
subject to the same confidentiality as the rest of the study.
Other Safety Biomarkers
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.


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The blood and tumors samples will be destroyed within 2 years after the date of final 
closure of the clinical database. Archival tumor blocks will be returned. 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
Samples for Research Biosample Repository
8.8.1.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives there of 
(e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of these 
specimens 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.
8.8.1.2
Sample Collection
DNA and RNA RBR samples will be collected from participants who give specific 
consent to participate in this optional RBR. Collected specimens will be used to achieve 
the following objectives:

To study the association of biomarkers with efficacy, AEs, or progressive disease.

To increase knowledge and understanding of disease biology.

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.
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 or 
diseases:

Leftover plasma samples

Leftover serum samples

Leftover blood samples

Leftover tumor samples

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 whole genome sequencing (WGS), whole exome sequencing (WES), next
generation sequencing (NGS), or other genomic analysis methods.


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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 will 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 WGS/WES and other 
genomic analyses 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. The participant will not be identified 
by name or any other personally identifying information. WGS/WES data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies to increase researcher's understanding of disease pathobiology and guide 
the development of new therapeutic approaches. Given the complexity and exploratory 
nature of these analyses, WGS/WES data and analyses will not be shared with 
Investigators or study participants unless required by law.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate Laboratory Manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The RBR storage period will be in accordance with the IRB/IEC‑approved 
ICF and applicable laws (e.g., Health Authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1).
8.9
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
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. ICFs for enrolled 
participants and for participants who are not subsequently enrolled will be maintained at 
the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 


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screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) 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.
Screening and pre-treatment assessments will be performed within 28 days prior to 
Cycle1 Day 1 unless otherwise specified. Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within 28 days prior to 
Cycle1 Day 1 may be used (and do not need to be repeated for screening).
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study.
All assessments must be performed as per the SoA (see 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 SoA.
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study or discontinue from the study early (e.g., due to 
progressive disease) will be asked to return to the clinic 28 days after the last dose of 
study treatment for a follow‑up visit. The visit at which a response assessment shows 
progressive disease may be used as the study completion/early termination visit. Refer 
to Section 1.3 for the schedule of activities.
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3.
8.10.5
Assessments at Unscheduled Visits 
Please see the SoA (Section 1.3) for activities that are required to be performed in case 
of an unscheduled visit.


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9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES 
Not applicable
9.2
SAMPLE SIZE DETERMINATION
Part I will enroll up to approximately 5 participants. The sample size is determined by the 
dose-increment steps implemented in this part.
In Part II, it is anticipated that a maximum of approximately 60 participants will be 
enrolled in each dose-escalation phase (IV and SC) (up to approximately 75 participants 
if one or several cohorts are expanded). In case the OBD dose cohort is expanded both 
with and without obinutuzumab, an additional 15 participants may be enrolled. 
The probability of observing at least one event out of 15 participants for a true 
underline rate of 10% is 79% while out of 5 patients is 41%. Probabilities of the 
occurrence of 1 or more events for different ranges of true underline rates and different 
participant numbers are summarized in Table 20.
The exact sample size for the dose-escalation part cannot be pre-determined and 
depends on the number of cohorts needed to reach the MTD (or highest safe dose if 
MTD is not reached).
Table 20 Probabilities for Observing Adverse Events 
Total N of 
Participants
True AE 
Probability
Probability 
that AE ≥ 1
Probability 
that AE ≥ 2
Probability 
that AE ≥ 3
15
0.1
0.79
0.45
0.18
0.2
0.96
0.83
0.60
0.3
1.00
0.96
0.87
0.4
1.00
0.99
0.97
0.5
1.00
1.00
1.00
10
0.1
0.65
0.26
0.07
0.2
0.89
0.62
0.32
0.3
0.97
0.85
0.62
0.4
0.99
0.95
0.83
0.5
1.00
0.99
0.95
5
0.1
0.41
0.08
0.01
0.2
0.67
0.26
0.06
0.3
0.83
0.47
0.16
0.4
0.92
0.66
0.32
0.5
0.97
0.81
0.50


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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 21.
Table 21 Analysis Populations
Population
Description
Efficacy
All participants who received at least one dose of 
RO7172508.
Safety
All participants enrolled in the study who received at 
least one dose of study treatment (RO7172508 and/or 
obinutuzumab if applicable) will be included in the 
safety population. Unless otherwise specified, the safety 
population will be the default analysis set used for all 
analyses.
DLT evaluable
DLT–evaluable participants are those who have 
completed the DLT window without a DLT, or 
participants who reported with a DLT. This population 
will be used in the determination of the MTD.
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
Participants who had at least one pre-dose and one 
post-dose ADA assessment will be included and 
analyzed according to the treatment they actually 
received. The relationship between ADA status and 
safety, efficacy, PK, and biomarker endpoints will be 
analyzed and reported descriptively via subgroup 
analyses.
9.4
STATISTICAL ANALYSES
The data will be analyzed by the Sponsor and/or designated Contract Research 
Organization (CRO). 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, 
pharmacokinetic and biomarker measurements. Data will be summarized by cohort and 
regimen within each part and CEA level where applicable, including the additional 
participants that may be enrolled in expanded cohorts (see Section 4.1.2.2). Participants who 
receive only obinutuzumab but no dose of RO7172508 will be summarized separately.


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The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment (RO7172508 or obinutuzumab (if applicable) as 
appropriate).  
The following endpoints may be used to select a route of administration for further development: 
PD parameters including T-cell activation in blood and in the tumor; pharmacokinetic 
parameters such as AUC, Cmax and half-life; tolerability and safety; as well as incidence of ADAs 
and their effect on exposure. Clinical efficacy will be considered, but is not expected to be a key 
criterion, as efficacy will likely be affected by parameters which cannot be controlled for in such 
small cohorts. Data will be listed and summarized by dose group as described in this analysis 
section. Analyses are exploratory in nature and no formal hypothesis testing will be performed.  
If one route of administration is not unequivocally superior, and a decision cannot be taken 
during or at the end of dose escalation, both routes of administration will be compared in disease 
specific expansion. Criteria for selection of a route of administration will then be added via the 
amendment preceding the expansions, including endpoints. 
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 
analysis will be based on the safety analysis population. Data will be summarized by 
cohort and regimen within each part. 
9.4.2
Efficacy Analyses
The primary and secondary efficacy analyses will include all participants in the efficacy 
population with participants grouped according to cohort (and schedule if applicable) 
within each study part. Primary, secondary, and exploratory endpoints are described in 
Section 3.
The efficacy endpoints of ORR, DCR and PFS according to RECIST v1.1 will be 
evaluated using the methods described in Table 22: 

Objective response is defined as a CR or PR, as determined by the Investigator’s
assessment using RECIST v1.1 and confirmed by repeat assessments 4 weeks 
after initial documentation. 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.

ORR and DCR are both determined as the rate of participants with an observed 
tumor response of CR or PR (ORR) or CR, PR or SD (DCR). ORR and DCR will be 
derived for RECIST v1.1.

Among participants with an objective response (responders), DOR will be defined as 
the time from first occurrence of a documented objective response until the time of 
documented disease progression or death within 30 days from last study treatment 
from any cause during treatment, whichever occurs first. Censoring methods will be 


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the same as the one applied for PFS (on-study drug treatment). This will be 
calculated for participants who have a best overall response of CR or PR as defined 
per RECIST v1.1 and per iRECIST.

PFS (on-treatment) will be defined as the time from study treatment initiation 
(Cycle 1 Day 1) to the first occurrence of documented disease progression or death 
from any cause during treatment (death within 30 days from last study treatment), 
whichever occurs first. For participants who do not have documented progressive 
disease or death during the study, PFS will be censored at the day of the last tumor 
assessment. If no post study drug treatment tumor assessment is available, PFS will 
be censored at the day of the first study drug administration 1 day.

OS is defined as the time from the first dose of study treatment to the time of death 
from any cause on study. 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).
Table 22 Efficacy Statistical Analysis Methods
Endpoint
Statistical Analysis Methods

ORR

DCR

DOR

PFS (on-treatment)

According to RECIST 
v1.1 criteria and iRECIST

OS 
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 participants will be classified as non-responders. 
Reasons for 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.
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. Response data will 
be listed. This will be carried out for RECIST v1.1
(secondary efficacy endpoints) and iRECIST (exploratory 
efficacy endpoints).
An exploratory assessment of tumor kinetic modelling may be performed by comparing 
on-treatment and post-treatment scans with at least two pre-treatment scans not older 
than 12 weeks prior to Cycle 1 Day 1, if available. For this exploratory assessment, all 
measurable lesions should be reported. The two pre-treatment scans consist of a 
pre-study scan and the study baseline scan and will allow estimation of depth and 
duration of response on target lesion size due to RO7172508 and the effect of 


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RO7172508 on the risk of the appearance of new lesions during the treatment period. 
Data will be explored by using linear and/or exponential models, as appropriate, in 
non-linear mixed effect modeling software, and this exploratory assessment of tumor 
kinetic modelling will be performed if the data collected allow it.
This will be presented separately from the main clinical study report (CSR).
9.4.3
Safety Analyses
Unless otherwise specified, the safety population will be the default analysis set used for 
all analyses. Those participants who receive only obinutuzumab, but withdraw from the 
study before receiving RO7172508, will be summarized separately.
DLT evaluable participants will be used in the determination of the MTD.


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The safety endpoints and appropriate analyses are summarized in Table 23.
Table 23 Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Incidence, nature,
and severity of 
AEs
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor. For classification purposes, preferred terms will be 
assigned by the Sponsor to the original terms entered on the eCRF. AEs will 
be graded according to guidelines provided in Section 3.1 of Appendix 2.
AEs will be summarized by mapped term and appropriate thesaurus level. 
Toxicity grade, seriousness and relationship to study treatment will be 
presented, as well as listings of deaths, AEs leading to death and premature 
withdrawal from study treatment. Glossary of AEs, medication and 
procedures will be provided. AE occurring between obinutuzumab pre-
treatment (if applicable) and the first administration of RO7172508 will be 
summarized separately. 
Nature and 
frequency of DLTs
DLT events will be presented by individual listings. The MTD will be 
estimated by the mCRM-EWOC using DLT evaluable participants. The MTD 
estimate will be presented along with 90% Credible Intervals. 
Clinical laboratory 
tests
All clinical laboratory data will be stored on 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.
Shifts in NCI CTCAE v5.0 grades from baseline to the worst grade observed 
during treatment and summary tables of change from baseline over time 
based on SI units will be presented for selected laboratory parameters. 
Individual participant listings (abnormal values or out of range) will be 
produced. See Appendix 4 for details on standard reference ranges and data 
transformation and the definition of laboratory abnormalities. Additional 
figures/tables/listings will be produced as deemed appropriate.
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
Abnormal 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 participants’ eCRF by the Investigator for 
concomitant medications will be standardized by the Sponsor by assigning 
preferred terms.
Concomitant medications will be presented in summary tables and listings.
Exposure to study 
medication
Exposure to study medication will be summarized by total duration of study 
medication, number of cycles started and cumulative dose using descriptive 
statistics. Dose interruptions and their reasons will be presented by schedule 
and dose level.
9.4.4
Pharmacokinetic Analyses
PK parameters will be read directly from the serum concentration-time profiles or 
calculated by using standard non-compartmental methods. Estimates for PK parameters, 


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including Cmax, AUC, t1/2, minimum drug concentration (Cmin), clearance (CL) and volume 
of distribution at steady state (Vss) will be tabulated and summarized.
Analyses will be carried out on the PK analysis population. All PK parameters will be 
presented by listings and descriptive summary statistics (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum) separately by group or cohorts.
Individual and mean serum RO7172508 concentration versus time data will be tabulated 
and plotted by dose-level. Graphical displays of PK data may also be provided.
Monitoring and characterization of ADA responses and their potential impact on PK will 
also be investigated.
In addition, data may be analyzed using population PK modeling; results will be reported 
separately.
Individual and mean serum obinutuzumab concentration versus time data will be 
tabulated.
9.4.5
Immunogenicity Analyses
Antibodies to RO7172508 will be evaluated in blood samples collected from all 
participants using appropriate assays. 
Listings and/or summaries will be prepared for results from screening, confirmatory, 
and/or titer assays employed to detect ADAs against to RO7172508.
Monitoring and characterization of ADA responses and their potential impact on PK, PD, 
safety, and efficacy of RO7172508 will also be investigated.
Antibodies to obinutuzumab will be evaluated in blood samples using appropriate 
assays from all participants who receive obinutuzumab as pre-treatment.
Additional analyses may be conducted as appropriate.
9.4.6
Pharmacodynamic Analyses 
All PD parameters will be presented by listings and descriptive summary statistics 
separately by group or cohorts.
The PD analysis will be based on the availability of evaluable blood or tumor samples.
All PD parameters will be listed by participant and tabulated by dose-level/regimen and 
time-point. Descriptive statistics will be used in summarizing peripheral blood and tumor 
PD markers.


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Absolute and percentage change from baseline will be calculated for the PD markers. 
Graphical techniques will be employed to better understand the relationship of the PD 
markers with dose and time. Correlations between PD markers, PK of RO7172508, and 
clinical response will be assessed through data tabulations and graphical techniques. 
The potential prognostic value of the PD markers may also be investigated.
Correlations between the CEA expression level and pharmacodynamics and efficacy
outcomes will be explored using graphical and modelling techniques.
9.5
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed.


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10.
REFERENCES
Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in 
relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 
GAUGUIN study. Blood. 2014;124:2196−2202.
De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, et al. Randomized trial of 
tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 
2012;367(25):2385-95.
Flynn JM, Byrd JC, Kipps TJ, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg 
in patients with chronic lymphocytic leukemia (CLL): results of the phase II 
GAGE (GAO4768g) trial. 2014. ASCO 
[https://meetinglibrary.asco.org/recod/92456/abstract]
Gomez-Mantila JD, Troconiz IF, Parra-Guillen Z, Garrido MJ. Review on modeling anti-
antibody responses to monoclonal antibodies. J Pharmacokinet Pharmacodyn. 
2014;41(5):523-536.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, et al. Chimeric antigen receptor-
modified T cells for acute lymphoid leukemia. N Engl J Med. 2013; 368(16):1509-
18.
Investigator’s Brochure RO7172508.
Investigator’s Brochure tocilizumab.
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. 
J Natl Cancer Inst. 2009;101(10):708-720.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. 
Current concepts in the diagnosis and management of cytokine release syndrome. 
Blood. 2014;124(2):188-195.
Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy 
through the engineering of a new type II anti-CD20 antibody with enhanced 
direct and immune effector cell–mediated B-cell cytotoxicity. Blood. 
2010;115:4393-4402.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008;27(13):2420-2439.
Rogatko A, Schoeneck D, Jonas W, et al. Translation of Innovative Designs into phase I 
trials. J Clin Oncol. 2007;25(31):4982-4986.
Salles G, Morschhauser F, Lamy T, et al. Phase 1 study results of the type II 
glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab 
(GA101) in B-cell lymphoma patients. Blood. 2012;119:5126−5132.


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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. AnnOncol. 
2004;15(12):1816–1824.
Seymour L, Boggaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for 
use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):143-152.
Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a Cochrane 
systematic review. J Rheumatol. 2011;38(1):10-20.
Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after 
blinatumomab treatment related to abnormal macrophage activation and 
ameliorated with cytokine-directed therapy. Blood. 2013;121:5154-7.
Thompson JA, Grunert F, Zimmermann W. Carcinoembryonic antigen gene family: 
molecular biology and clinical perspectives. J Clin Lab Anal. 1991;5(5):344-366.
Tocilizumab (Actemra®) United States Package Insert. Available at: 
https://www.gene.com/download/pdf/actemra_prescribing.pdf, accessed on 17 
September 2017.
Woo P, Wilkinson N, Prieur AM, Southwood T, Leone V, Livermore P, Wythe H, 
Thomson D, Kishimoto T. Open label phase II trial of single, ascending doses of 
MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof 
of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and 
demonstration of prolonged clinical improvement. Arthritis Res Ther. 
2005;7(6):R1281-8.
Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, et al. Therapeutic efficacy of 
humanized recombinant anti-interleukin-6 receptor antibody in children with 
systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005 Mar;52(3):818-25.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
and Appendix 3 (procedures for recording AEs), Appendix 5 (contraceptive guidance 
and collection of pregnancy information). Additional study-related appendices are in 
order of appearance in the protocol.


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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/IEC by the Principal Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/IEC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/IEC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/IEC. Investigators are 
also responsible for promptly informing the IRB/IEC of any protocol amendments 
(Section 2.3.1 of this Appendix).
The Investigator should follow the requirements for reporting all adverse events 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/IEC, and archived in the site’s 
study file.
1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
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, 


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and the IRB/IEC or study 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/IEC submission. The 
final IRB/IEC‑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 Consent Forms 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 Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to take part. The final revised IRB/IEC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB/IEC policy) during their participation in the study. For any updated or revised 
Consent Forms, 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 Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms 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.
A participant who is re-screened is not required to sign another ICF unless a newer 
version is available or if the re-screening occurs beyond 60 days from the previous ICF 
signature date.


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Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The Investigator or authorized designee will explain to each 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 specimens 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 specimens. 
Participants who decline to participate will not provide a separate signature.
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 subject who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
For sites in the United States, each Consent Form may also include patient authorization
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/IEC) 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 specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a participant wishes to withdraw 
consent to the testing of his or her specimens, the Investigator must inform the Medical 
Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if the 
trial 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 trial is closed. A participant's withdrawal from Study BP40092 does not, 
by itself, constitute withdrawal of specimens from the RBR. Likewise, a participant’s 
withdrawal from the RBR does not constitute withdrawal from Study BP40092. Data 
already generated before time of withdrawal of consent to RBR will still be used.


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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. 
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.
Confidentiality for Research Biosample Repository
Data generated from RBR specimens 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 specimens is confidential and may 
only be disclosed to third parties as permitted by the Informed Consent Form (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 specimen 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 specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.


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Monitoring and Oversight Research Biosample Repository
Specimens 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 specimens as specified in this protocol and in the 
Informed Consent Form. Roche 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 Roche. The site will permit monitoring, audits, IRB/IEC 
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.


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2.1.2.
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, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
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/IEC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.3.
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.
2.2.
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 unless 
local regulations or institutional policies require a longer retention period. 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.


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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/IEC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and competent 
authorities 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/IEC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/IEC 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.
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.


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2.3.3.
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/IECs to inspect facilities and records relevant to this study.
3.
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.
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 patient or clinical investigation subject 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:

Any 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.

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. 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.
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.


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
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.

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 


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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 the 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 the Sponsor and/or Medical Monitor.
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.
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 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 1
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).
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 participants 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.
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 (where 
applicable).

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.


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For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS
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.
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 
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

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)

Accidental overdoses or medication errors (see Appendix 2, Section 5.2 for details 
on reporting requirements)
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.


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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 AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
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.
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.


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Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period, if the event 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.  All special situations associated with RO7172508, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations 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.


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For RO7172508 and tocilizumab 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; see Appendix 2, 
Section 5.1). For RO7172508, adverse events associated with special situations should 
be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

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.
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 using the following reference document:

RO7172508 Investigator's Brochure

Obinutuzumab/RO7172508 combination - RO7172508 Investigator's Brochure

Tocilizumab 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 adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
1.1.INFUSION/INJECTION-RELATED REACTIONS/CYTOKINE RELEASE 
SYNDROME
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study treatment infusion should be captured as a diagnosis
(as per CTCAE v.5.0) 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/Cytokine Release Syndrome 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/Cytokine Release Syndrome eCRF.
1.2.OTHER ADVERSE EVENTS
For adverse events other than infusion-related reactions, 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, adverse events 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:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
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 adverse events 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 adverse event 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 adverse event 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.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating 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.


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6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN or 3baseline value in combination 
with total bilirubin2ULN or 2baseline value.

Treatment-emergent ALT or AST3ULN or 3baseline value in combination 
with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 8.3) 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
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor. This includes 
death attributed to progression of disease.
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.


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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”).
9.
LACK OF EFFICACY OR WORSENING OF DISEASE
Medical occurrences or symptoms of deterioration that are anticipated as part of disease 
progression should be recorded as an adverse event if judged by the Investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time 
during the study. When recording an unanticipated worsening of disease on the Adverse 
Event eCRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g., “accelerated tumor growth/development”).
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 criteria (e.g., RECIST v1.1). In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration. 
However, every effort should be made to document progression 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 adverse event 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.


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization 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 unless otherwise 
specified.
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

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose, 
urea, creatinine, protein, albumin, phosphate, 
calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, urate, LDH, C-reactive 
protein, amylase, lipase. (Tryptase: safety only)
Coagulation

INR, aPTT, PT, Fibrinogen, D-Dimer.
Viral Serology (screening 
only)

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.
Quantitative 
Immunoglobulins

IgE (safety only)
Pregnancy Test

All women of childbearing potential (including those 
who have had a tubal occlusion) will have a blood 
pregnancy test at screening. Urine pregnancy tests 
will be performed at specified subsequent visits. If a 
urine pregnancy test is positive, it must be confirmed 
by a blood pregnancy test.
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood, ketones, 
bilirubin, urobilinogen, nitrite, and leukocyte esterase.

If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine will 
be sent to the laboratory for microscopy and culture. If 
there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no 
need to perform microscopy and culture.

Microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.
Other Tests

sCEA*
*will be performed centrally and locally


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The results of each test must be entered into the CRF.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most 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 
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, 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 each laboratory parameter. 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.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
i)
Pre-menarchal
j)
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.
k)
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.


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2.
CONTRACEPTION GUIDANCE

Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception 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

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User-Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
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). 
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.
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.


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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 and be withdrawn from the study.
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 a serious adverse event, recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5 of Appendix 2).
Elective abortion not associated with 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; see 
Section 8.3).


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Appendix 6
New Response Evaluation Criteria in Solid Tumors [RECIST] –
Version 1.1
Modified Excerpt from Original Publication with 
Addition of Supplementary Explanations [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, inammatory breast disease, lymphangitic involvement of skin or lung, 
peritoneal spread, and abdominal masses/abdominal organomegaly identied by physical exam 
that is 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 lms are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
conrm the presence or disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identiable 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 denition of 
measurability described above. 

Blastic bone lesions are non-measurable. 
Cystic lesions:

Lesions that meet the criteria for radiographically dened simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) because they are, 
by denition, simple cysts. 

‘Cystic lesions’ thought to represent cystic metastases, can be considered as measurable 
lesions if they meet the denition 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. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
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 
identied and reported lesion at baseline and during study. Imaging based evaluation should 
always be the preferred option. 
Clinical lesions: Clinical lesions will only be considered measurable when they are supercial and 
≥10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 


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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 dened 
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 dened measurability of lesions on CT scan on the 
basis of 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 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. 
Endoscopy, Laparoscopy, Tumor markers, Cytology, Histology: The utilization of these 
techniques for objective tumor evaluation cannot generally be advised but will be dependent on 
the study design. 
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 dened by the presence of at least one measurable lesion (as detailed in Section 1.1.1).
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 ve 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should 
be identied as target lesions and will be recorded and measured at baseline.


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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 on the basis of 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 nodes 
which are dened as measurable and may be identied 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 2 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 x 30 mm has a short axis of 
20 mm and qualies 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 characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identied 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’). 


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2.3 RESPONSE CRITERIA
This section provides the denitions 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 identied 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 dened 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 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 
denable 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). 


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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 denitions 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 specied 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. 
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’ on the basis of 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 on the basis of 
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 
trials 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 quantied (by denition: 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 


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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 specic criteria for the identication of 
new radiographic lesions; however, the nding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or ndings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or are 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. 
A lesion identied 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 conrm there is denitely 
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 specied 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 below. When participants have non-measurable 
(therefore non-target) disease only, Table 2 is to be used.


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Table 1
Time-Point Response – Target (w/wo non-target) Lesions
Abbreviations: w/wowith or without.
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 are 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. 


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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.
Table 3
Best Overall Response when Confirmation is Required
2.4.3
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 shown in Table 1 
and Table 2 of this Appendix.
For equivocal ndings of progression (eg, 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 conrmed, the date of progression should be the 
earlier date when progression was suspected. 


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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 tumors: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-247.


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Appendix 7
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 on the basis of 
investigator-assessed individual lesion data recorded in the eCRF.  
iRECIST response status is not a specific component of treatment discontinuation criteria, 
including decisions about whether to continue treatment beyond progression per RECIST v1.1. 
Investigators should instead take into account radiologic data and clinical status in making such 
decisions
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 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.
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.


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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" (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 (eg, 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 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).


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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.
Abbreviations: 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 a publication by Seymour et al. 
(2017).


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REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.  
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(9):850858.
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e152.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:74127420.


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Appendix 8
Supporting Statistical Documentation
1
MONOTHERAPY DOSE-ESCALATION
This appendix provides details of the design that will guide the monotherapy 
IV dose-escalation stage of this study and of its operating characteristics through 
simulations.
1.1
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 I 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 DLT rate, π(MTD), belongs to [0.2, 0.35] while keeping the probability of overdose 
P{p(MTD) 0.35} below 0.25.
1.2
STATISTICAL MODEL
A two-parameter logistic model with bivariate (log) normal priors will be used to fit the 
dose-toxicity relationship. The probability of DLT at dose dj, p(dj) is defined as
          exp(xj)
p(dj) -------------------------
         1 exp(xj)
where
 = 	(
∗) = 	(
∗)
and d* is the reference dose (in this case d* 100).
The model thus can be rewritten as: 
p(dj)
ln(-----------) xj
1 - p(dj)
where and log() are assumed to follow a bivariate normal distribution, 0 and 
1 log() are the parameters to be estimated.


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1.2.1
Model Prior
For the multiple participant cohort dose-escalation, the prior distribution will be a mixture 
of prior informative and minimally informative components. The informative component 
will be the posterior distribution of the CEA TCB (cibisatamab) monotheraphy toxicity 
data (without obitunuzumab pre-treatment), as of cutoff date 20 July 2017, approximated 
with a bivariate normal distribution. A minimally informative prior «neutral» component
will be constructed based on the assumed not toxic and toxic doses. The two 
components will be mixed in a 10/90% ratio (pi1 0.25) (informative prior component 
10%; minimally informative component 90%).
(, log())~ π1N1(1,1) (1-π1)N2(2,2)
1.2.2
Informative Component
The parameters of the informative component are listed below:
(-1.4199504, -0.7110435)
The minimally informative component makes the design robust against surprising 
deviations from the informative component.
A minimally informative prior component will be constructed based on the assumed not 
toxic and toxic doses. It is conservatively assumed that would be very unlikely (with a 60% 
confidence) that 10% or higher DLT rates are associated with the first dose of 
monotheraphy dose-escalation and that it would be very unlikely (with 90% confidence) 
that a 25% or lower DLT rates are associated with the dose of 400 mg.
The parameters of the minimal informative prior are listed below:
(-0.0983878, -0.4150429)
The plot of the prior distribution used for the study can be seen in Figure 1 and it will be 
the primary prior distribution used to determine the dose-escalation decisions.
0.173397         0.0023933
0.0023933   7.3526064 10-4

1.7525039         -0.0052047
-0.0052047          0.0185343



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Figure 1: Prior Plot
In black the informative, in blue the minimal informative and in red the mixture prior dose-toxicity
relationship.
1.2.3
Dose Grid
The following dose grid has been used: from 0.5, to 10 by 0.1, from 11 to 20 by 1, 25, 27, 
from 30 to 100 by 5, 120, 150 to 400 by 50.
1.2.4
Maximum Dose-Increments
The following rules for selecting the maximum allowed dose-increment will be applied.
Relative to DLT:
Until 1 DLT an increment of 100%, from 1 DLT an increment of 50% maximum are 
allowed.
The lower increment between the ones described above will then be chosen as 
maximum allowed dose-increment.
1.2.5
Stopping Rules
The trial will be halted if either at least 6 participants have been observed at a dose 
close to MTD (i.e., a dose differs by 20%) and the posterior probability that 


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[0.2 Prob(DLT | dose) 0.35] for the next best dose is above 40% or the maximum of 
60 DLT-evaluable participants is reached.
1.3
MODEL PERFORMANCE EVALUATION
To illustrate how the design will perform, different escalation scenarios are explored and 
results are tabulated in Table 1. Each row 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, NA indicates that the model would stop escalating and the trial would be halted.
Table 1: Dose-Escalation Mock Runs
Dose, mg
DLTs
Next Dose, mg
Stop
Increment
1.6
0
3.2
FALSE
100
1.6
1
2.4
FALSE
50
1.6
2
0.8
FALSE
-50
1.6
3
NA
TRUE
NA
3.2
0
6.4
FALSE
100
3.2
1
4.8
FALSE
50
3.2
2
3.1
FALSE
-3
3.2
3
1.3
FALSE
-59
6.4
0
12.0
FALSE
87
6.4
1
9.5
FALSE
48
6.4
2
6.4
FALSE
0
6.4
3
3.9
FALSE
-39
12.0
0
20.0
FALSE
67
12.0
1
18.0
FALSE
50
12.0
2
12.0
FALSE
0
12.0
3
8.3
FALSE
-31
20.0
0
40.0
FALSE
100
20.0
1
30.0
FALSE
50
20.0
2
25.0
FALSE
25
20.0
3
14.0
FALSE
-30
40.0
0
80.0
FALSE
100
40.0
1
60.0
FALSE
50
40.0
2
50.0
FALSE
25
40.0
3
27.0
FALSE
-32
80.0
0
150.0
FALSE
88
80.0
1
120.0
FALSE
50
80.0
2
90.0
FALSE
12
80.0
3
50.0
FALSE
-38
150.0
0
300.0
FALSE
100
150.0
1
200.0
FALSE
33
150.0
2
150.0
FALSE
0


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Dose, mg
DLTs
Next Dose, mg
Stop
Increment
150.0
3
95.0
FALSE
-37
300.0
0
400.0
FALSE
33
300.0
1
400.0
FALSE
33
300.0
2
250.0
FALSE
-17
300.0
3
150.0
FALSE
-50
1.4
SIMULATION STUDY
A simulation study is conducted to evaluate the operating characteristics for the chosen 
design parameters (priors, reference dose, 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.
1.4.1
Dose-toxicity Scenarios
In these simulations (Figure 2), the starting dose of 0.5 mg is assumed. Scenario 1 
reflects the current expected toxicity of this compound. The others are intermediate or 
extreme scenarios. The MTD (upper 35% DLT toxicity interval) ranges from 69 mg (low 
MTD) to 438 mg (illustrating a scenario for which toxicities are expected only at the 
highest dose).
Figure 2
Dose Toxicity Scenarios


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Table 2: Scenarios Parameters
Scenario
Target Dose Interval, mg
Parameters
1
48-75
alpha -0.11, beta 1.74
2
136-199
alpha -2, beta 2
3
247-299
alpha -5, beta 4
4
82-121
alpha -1, beta 2
5
375-438
alpha -8, beta 5
6
23-69
alpha -0.36, beta 0.7
1.4.2
Simulation Results
For each of the scenarios, 500 trials were simulated.
The design is evaluated using the following criteria: the MTD chosen, the number of 
participants treated at doses higher than the MTD, and the total number of participants 
treated. The result of the simulations is summarized in Table 3.
Table 3: Simulation Study Results Summary
Scenario
Target 
Dose 
Interval in 
True 
Scenario, 
mg
Overall N of 
Participants*
N 
Participants 
Treated 
above 
Target 
Toxicity 
Interval*
Proportions 
of DLTs in 
the Trials, %*
Doses 
Selected 
as MTD, 
mg*
Dose 
most 
often 
Selected 
as MTD, 
mg
1
48-75
29
(24, 36)
7 (0, 12)
16.4
(12.5, 21.2)
72.3
(44.5, 
100)
50
2
136-199
34
(30, 39)
6 (0, 12)
13
(10, 16.7)
186.7
(120, 250)
150
3
247-299
34
(30, 39)
6 (3, 9)
10.5
(6.7, 13.9)
290.3
(250, 350)
250
4
82-121
31
(27, 36)
4 (0, 9)
14.8
(11.1, 18.2)
111.7
(75, 150)
150
5
375-NA
37
(33, 45)
0 (0, 0)
7.3
(5.6, 9.5)
384
(350, 400)
400
6
23-69
28
(21, 36)
2 (0, 9)
18.1
(14.3, 22.2)
45.1
(14, 85)
25
* mean and 10 and 90 % quantiles.


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In addition, illustrated here separately for each true dose toxicity scenarios the true 
toxicity curve from the scenario with the average model fit from the 500 simulation runs.
Scenario 1: True MTD 74.64 Parameters alpha=-0.11, beta=1.74
Scenario 2: True MTD 199.47 Parameters alpha=-2, beta=2


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Scenario 3: True MTD 298.99 Parameters alpha=-5, beta=4 
Scenario 4: True MTD 120.98 Parameters alpha=-1, beta=2 


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Scenario 5: True MTD 437.62 Parameters alpha=-8, beta=5
Scenario 6: True MTD 69.07 Parameters alpha=-0.36, beta=0.7 


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2
BAYESIAN POSTERIOR PROBABILITY APPROACH TO 
THE EVALUATION OF LOSS OF EXPOSURE
This appendix provides the details of the approach that will be used during the 
course of the study to evaluate the impact of anti-drug-antibodies (ADAs) on 
exposure of RO7172508. If a significant number of participants experience a 
relevant loss of exposure to RO7172508 due to ADAs (LOE+ rate), then 
obinutuzumab pre-treatment will be implemented. The decision to implement 
obinutuzumab will be based on a Bayesian posterior probability approach.
All analyses were performed using the R statistical software R version 3.4.4 
(2018-03-15) (@baseR).
2.1 PRIOR DISTRIBUTION
In the Bayesian approach, it is assumed that the prior distribution of the true 
underling LOE+ rate, π(p) (between 0 and 1) , follows a two-parameters beta 
distribution β(a, b) with parameters a and b.
In this case, the parameters are assumed to be a=0.6667 and b=0.3333 and 
correspond to the prior shown in Figure 1. This prior, representing previous 
knowledge or belief of the LOE+ rate of the regimen, was based on results 
observed in participants treated with cibisatamab (CEA-TCB), where 14 out of 
21 (67%) in the flat dosing mono-therapy cohorts ≤20 mg had experienced loss 
of exposure due to ADAs (cibisatamab IB v5). This dose range was selected as it 
is expected to be similar to those administered in the current study. The CEA-
TCB data were appropriately down weighted in order to derive the current prior.


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Figure 1
Prior Distribution
2.2 POSTERIOR DISTRIBUTION AND DECISOPN CRITERIA
As new information from the RO7172508 dose escalation is collected, the prior 
distribution will be updated to generate the posterior probability distribution of 
the true LOE+ rate given the data observed. At each assessment, the posterior 
probability, with n participants who experienced a relevant loss of exposure out 
of n+m evaluable participants, will therefore follow a two-parameters beta 
distribution β(a+n, b+m).
At the time of the evaluation, if there is high confidence that the underlying true 
LOE+ rate is above a pre-defined target, the obinutuzumab pre-treatment will be 
introduced for all subsequent participants in the study. Otherwise, the dose 
escalation will proceed without obinutuzumab pre-treatment until the next 
assessment or the end of the dose escalation (whichever is reached first).
For a given target LOE+ rate, the posterior probability can be computed as:
PP = Prob(True LOE + Rate (Target LOE + Rate/Data, Prior))
Therefore, the decision rule for the implementation of obinutuzumab 
pretreatment at interim can be constructed as follows:
if PPӨH then implement obinutuzumab, otherwise continue. 


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The target LOE+ rate has been set to 50%. The posterior probabilities threshold,
ӨH, has been set to 80% based on acceptable probability of implementing 
obinutuzumab under different assumption for true underling LOE+ rates (see 
Section 1.3).
The first assessment will be conducted once RO7172508 PK data up to Cycle 3 
are available from at least 14 participants across both Part I and II and thereafter 
after each cohort PK RO7172508 data up to Cycle 3  are available and again at 
the end of the dose escalation.
At the end of the dose escalation, if the above criteria have not yet been met and, 
at the same time, there is low confidence (<70% confidence level) that the true 
underline LOE+ rate is less than 5%, the expansion cohorts at the OBD with 
and without obinutuzumab will be evaluated. The expansion cohorts will 
determine if the safety profile and pharmacodynamics effects of the regimens are 
acceptable with continued RO7172508 exposure.
2.3 OPERATING CHARACTERISTICS
The performance characteristics of the study design at the first interim are 
outlined below.
At the first evaluation, the posterior probability equal or higher than 80% 
(ӨH=0.8) that the true LOE+ rate is ≥ 50%, is equivalent to observe 9 or more 
participants with relevant loss of exposure out of 14 evaluable participants.
The probability of taking the decision to implement obinutuzumab for a given 
true underline LOE+ rate, based on 104 simulations, is illustrated in Figure 2.


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Figure 2
Probability of Implementing Obinutuzumab for Different True 
Underlining LOE+ rate at N= 14
If the true underline LOE+ rate is 60% then the decision to proceed exclusively 
with obinutuzumab pretreatment will be taken in 48.65% of the times. If instead, 
the true underline LOE+ rate is 40%, then this decision would be taken only in 
5.74% of the times.
The exact number of participants, with relevant loss of exposure, required to 
meet the criteria at subsequent evaluations will depend on the actual number of 
participants enrolled in each cohort and on the number of cohorts necessary to 
reach the end of the dose escalation.
For these reasons, an evaluation of the operating characteristics for a meaningful 
additional number of cohorts (9 cohorts), with constant cohort size 
(3 participants), is given in Figure 3 based on 104 simulations.
At final analysis with 41 participants the posterior probability equal or higher 
than 80% (ӨH= 0.8) that the true LOE+ rate is ≥ 50% is equivalent to observe 
24 or more participants with relevant loss of exposure out of 41 evaluable 
participants.
The posterior probability equal or higher than 70% (ӨL= 0.7) that the true LOE+ 
rate is 5% is equivalent to observe 1 or less participants with relevant loss of 
exposure due to ADAs out of 41 evaluable participants




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Appendix 9 Protocol Amendment History
PROTOCOL AMENDMENT VERSION 3 AND VERSION 4 SUMMARY OF 
CHANGES
Since the changes made under Protocol BP40092 version 3 and Protocol BP40092 
version 4 followed each other in quick succession and Protocol BP40092 version 3 was 
not submitted to any ethics committees or regulatory authorities, the Summary of 
Changes provided reflects all changes made under both Protocol BP40092 Version 3 
and Version 4. 
The protocol synopsis has been updated to reflect the changes of the protocol where
applicable.
Section 1.2 Schematic of Study Design
Figure 1 Overview of Study Design has been updated to include obinutuzumab 
pretreatment for dose escalation.
Section 1.3 Schedule of Activities
Table 1, Table 2, Table 3, Table 4, and Table 5 have been updated, including the footers.
Two new tables (Table 6 and Table 7) Table 6: Screening Schedule of Assessments with 
Obinutuzumab Pretreatment and Table 7: Schedule of Assessments Part II: Multiple 
Participant Cohorts SC Q3W have been added.
Section 2.1 Study Rationale
[…]
The development of anti-drug antibodies (ADAs) can result in a partial or complete loss 
of exposure and is thought to be mainly mediated by the stimulation of B-cells, which 
leads to generation of antibody-producing plasma cells. The use of obinutuzumab as a 
pre-treatment (if needed) to inhibit or attenuate ADA responses by depletion of B-cells 
has been implemented in this study and is supported by nonclinical and clinical studies 
further described in Section 2.2.2. For the benefit/risk assessment of obinutuzumab pre-
treatment, please refer to Section 2.3.
Section 2.2.2 Obinutuzumab
RO7172508 may induce the production of ADAs that could result in the complete or 
partial loss of exposure. Obinutuzumab, a humanized and glycoengineered Type II anti-
CD20 monoclonal antibody that recognizes the CD20 antigen present on normal and 
malignant B-cells. Obinutuzumab is approved for the use in untreated and 


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relapsed/refractory follicular lymphoma as well as untreated chronic lymphocytic 
leukemia. The use of obinutuzumab has demonstrated effective B-cell depletion 
following administration in cynomolgus monkeys (Mössner et al 2010) and patients 
with B-cell malignancies (Salles et al 2012; Cartron et al 2014 ). The use of 
obinutuzumab as a pre-treatment to inhibit or attenuate ADA responses in participants 
with solid tumors is supported by nonclinical and clinical studies. Pre-clinically, 
obinutuzumab pre-treatment resulted in strong suppression of de novo antibody 
responses while protective humoral memory responses remained intact both in human 
CD20 transgenic mice and cynomolgus monkeys. In Studies BP28920 (RO6895882; 
Phase I), BP29435 (RO6895882 + atezolizumab; Phase Ib) and BP29541 (cibisatamab; 
Phase I), obinutuzumab pre-treatment effectiveness was confirmed as pre-treated 
patients did not lose exposure of the investigational compounds. For the benefit/risk 
assessment of obinutuzumab pre-treatment, please refer to Section 2.3.
For more details on obinutuzumab, please refer to the obinutuzumab IB.
Section 2.3 Benefit/Risk Assessment
[…]
There is a potential risk for RO7172508 to induce the production of ADAs. ADA 
formation against RO7172508 can potentially reduce its efficacy by blocking CEA or 
CD3e targeting and/or potentially result in symptomatic hypersensitivity reactions, in 
particular immune complex reactions. Therefore, Part II of the BP40092 study allows 
obinutuzumab pretreatment to attenuate the formation of ADAs if a predefined number 
of patients experience a loss of exposure to RO7172508 (see Section 4.1.3). 
If obinutuzumab pretreatment is introduced as a way to mitigate ADA formation and 
subsequent loss of exposure, the safety profile of RO7172508 given after obinutuzumab 
will be carefully monitored. Only if the safety profile of RO7172508 after 
obinutuzumab pretreatment is shown to be acceptable and comparable to RO7172508 
alone (i.e., without obinutuzumab pretreatment if applicable) will the Sponsor consider 
investigating obinutuzumab pretreatment in further development.


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Section 3 Objectives and Endpoints
Table 8 Objectives and Endpoints has been updated:
Objectives
Endpoints
Primary

To determine the maximum-tolerated dose 
(MTD) and/or the optimal biological dose 
(OBD) for intravenous (IV) and 
subcutaneous (SC) administrations of 
RO7172508 as monotherapy and with 
obinutuzumab pre-treatment (if applicable)

Nature and frequency of dose-
limiting toxicities (DLTs) and other 
AEs, PD and PK profile

To assess the safety and tolerability 
profile of RO7172508 and with 
obinutuzumab pre-treatment (if applicable)

Incidence, nature and severity of
AEs graded according to the 
National Cancer Institute (NCI)
Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0
Secondary

To establish the IV and SC 
pharmacokinetics of RO7172508 given as 
monotherapy and with obinutuzumab pre-
treatment (if applicable)
The PK profiles and parameters 
derived for RO7172508 including 
where appropriate and when data 
allow, the parameters listed below:

Maximum concentration (Cmax)

Time of maximum concentration 
(Tmax)

Clearance (CL) or apparent 
clearance (CL/F) (dependent on 
route of administration)

Volume of distribution at steady state
(Vss)

Area under the curve (AUC)

Half-life (t1/2)

Other PK parameters may be 
determined, as deemed appropriate.

To assess the incidence of anti-drug 
antibodies (ADAs) against RO7172508
with obinutuzumab pre-treatment (if 
applicable)

Presence or absence and titer of 
ADAs 

To characterize PD effects and duration of 
PD response for multiple doses and 
schedules of RO7172508 administration

Changes in frequency, activation 
status and spatial distribution of 
tumor infiltrating lymphocytes (TILs).


RO7172508—F. Hoffmann-La Roche Ltd
191/Protocol BP40092, Version 4
Objectives
Endpoints

To assess preliminary anti-tumor activity 
of RO7172508.

Objective response rate (ORR)

Disease control rate (DCR); defined 
as rate of response (RR) + stable 
disease (SD)

Duration of response (DOR)

Progression-free survival (PFS) 
(on-treatment)
According to Response Evaluation 
Criteria in Solid Tumors (RECIST) 
Version 1.1 criteria by Investigator’s 
assessment:
[…]
Tertiary/exploratory

To further assess preliminary anti-tumor 
activity of RO7172508.

PFS, objective response, DOR, and 
DCR according to modified RECIST 
(mRECIST).

PFS, objective response, DOR, and 
DCR according to immune modified
RECIST (iRECIST)Overall survival 
(OS)

Overall survival (OS).

To assess ADA specificity

Development of ADAs directed 
against either the CEA or CD3 
binding moiety.

To make a preliminary assessment of the 
efficacy of tocilizumab 
(Actemra®/RoActemra®) in ameliorating 
the symptoms of severe CRS following 
RO7172508 treatment, if data allows.

Changes in the nature and severity 
of CRS following administration of 
tocilizumab for severe CRS.

To assess the incidence of anti-drug antibodies 
(ADAs) against obinutuzumab (if applicable)

Presence or absence and titer of ADAs 

Serum concentration of obinutuzumab
Section 4.1 Overall Design
An overview of the study design is provided in Section 1.2.
Study BP40092 is a first-in-human, open-label, multicenter, dose-escalation, Phase I 
clinical study to determine the maximum-tolerated dose (MTD) and/or the optimal 
biological dose (OBD) as well as the optimal schedule for intravenous (IV) and 
subcutaneous (SC) administrations of RO7172508 as monotherapy, with or without 
obinutuzumab pre-treatment, in participants with locally advanced and/or metastatic 
CEA-positive solid tumors who have progressed on SOC treatment, are intolerant to 
SOC, and/or are non-amenable to SOC. The study will be conducted in two parts.
[…]


RO7172508—F. Hoffmann-La Roche Ltd
192/Protocol BP40092, Version 4
PART II
Part II is a multiple participant cohort/multiple-ascending dose-escalation study to define 
the MTD and/or OBD of RO7172508 administered as single agent, IV or SC, in 
participants who have tumors with cytoplasmic and/or membranous CEA expression in 
20% of cells at intensities greater than at least IHC 1+ on archival material (or fresh 
biopsy when archival is not available). The starting-dose for the initiation of the IV 
dose-escalation will be determined by Part I and RO7172508 will be initially given Q3W. 
Dose-escalation will be undertaken based on safety until determination of the MTD or 
the highest safe dose if MTD is not reached.
Once the IV schedule has shown RO7172508 preliminary clinical activity, defined by 
partial response (PR) or better, according to RECIST (Appendix 6), or the MTD has 
been established and is greater than 6 mg, the QW SC multiple ascending dose finding 
cohorts will be initiated. SC dosing will initially be once a week (QW). The starting dose 
for SC administration will be proposed based on the evaluation of the safety and PK data 
observed following IV administration; however, due to practical considerations, a 
minimum dose of 2 mg is defined for a single SC administration. In addition, the QW SC 
starting dose will not exceed one third of the IV MTD or of the highest safe IV dose 
tested. Once the IV schedule has shown RO7172508 preliminary clinical activity, 
defined by partial response (PR) or better, according to RECIST v. 1.1(Appendix 6), or 
the MTD has been established and is equal to or above 2 mg, the SC multiple-ascending 
dose-finding cohorts could be initiated. The starting-dose and regimen (QW or Q3W) 
for SC administration will be proposed based on the evaluation of the safety and PK 
data observed following IV administration but will not exceed the highest safe dose 
tested in the IV Q3W dose escalation; however, due to practical considerations, a 
minimum dose of 2 mg is defined for a single SC administration. In addition, the QW 
SC starting-dose will not exceed one third of the IV MTD or of the highest safe IV dose 
tested.
Dose escalation in the SC treatment group will proceed until the SC MTD/OBD has been 
determined (see Section 4.1.2). If the SC treatment group is started Q3W at a dose <6 
mg, the QW schedule can be evaluated once the dose is ≥6 mg. Data from this treatment 
group will establish if the SC route of administration, which will have a lower Cmax than IV 
after first administration, can show comparable efficacy and/or comparable or improved 
safety profile of a TCB either QW and/or Q3W.
During the course of this study, the need for obinutuzumab pretreatment will be 
assessed based on loss of RO7172508 exposure and/or ADA-related safety events. 
Details, including decision criteria, are provided in Section 4.1.3 and Appendix 78.
[…]


RO7172508—F. Hoffmann-La Roche Ltd
193/Protocol BP40092, Version 4
If deemed necessary, at the end of dose escalation, to further characterize the safety, 
preliminary anti-tumor activity, PK, and/or PD profile of RO7172508 (IV and/or SC) with 
or without obinutuzumab pre-treatment, additional participants (up to approximately 
15 participants) may be enrolled at the doses already tested; or at doses that have not 
been explored for the determination of the MTD, but not higher than MTD; or the highest 
safe dose tested if MTD has not be determined. The additional patients could be
allocated to one or more doses; however, the total number will not exceed
15 participants across all doses. If new cohorts are opened at a dose equal to or lower 
than already explored, the cohorts will follow the same recruitment rules and safety 
windows as per dose escalation rules. Patients enrolled at dose levels that have already 
been assessed, will also be staggered as per dose escalation rules (i.e. at least one day 
between consecutive patients).  If DLT events are observed, the estimated MTD and the 
probability of overdosing at the current recruiting cohort, will be re-assessed with all 
available data. If the updated estimated MTD indicate that the current recruiting 
cohort is not safe, recruitment will be stopped.
Section 4.1.2.2 Part II: Multiple-Ascending Dose-Escalation (Multiple 
Participant Cohorts)
[…]
In Part II dose-escalation, a minimum of 3 participants per cohort will be enrolled who have
a baseline sCEA level 20 ng/ml. Participants within a cohort will be treated in a sequential 
manner with one week between the first and second participant, and at least one day 
between subsequent participants. However, if the first participant experiences a DLT 
within the first 7 days, then the time between the treatment of subsequent participants 
within the same cohort may be increased. The DLT evaluation window in Part II is 
defined as a period of 3 weeks after the first administration of RO7172508 in an IV Q3W 
schedule. Based on emerging data, the interval between dosing of each participant 
within a cohort or the DLT window may be adjusted if deemed appropriate by the 
Investigators and/or the Sponsor.
For each cohort, all participants will be followed through a 3-week DLT window 
(i.e., 21 days after the first dose of RO7172508). If fractionated dosing is implemented in 
Cycle 1 to improve tolerability, the DLT window will be extended to include the cycle 
where the planned target dose is administered in full i.e., Cycle 1 Day 1 until the end of 
Cycle 2. The DLT window will therefore be 6 weeks (42 days), or 8 weeks (56 days) if 
treatment has been delayed for no more than 14 days.


RO7172508—F. Hoffmann-La Roche Ltd
194/Protocol BP40092, Version 4
A new cohort can be opened when at least 3 evaluable participants of the previous 
cohort have completed the DLT window. At least 3 evaluable participants must have a 
baseline sCEA level of 20 ng/ml. If participants experience a DLT before completion of the 
last day of their DLT window, they will be considered as having completed their DLT 
window. Prior to opening a new cohort, the logistic regression model will be updated with 
the treatment outcome (i.e., the occurrence of DLT) and a new estimate of the MTD will 
be derived. 
Enrollment into the next cohort will only resume after the Sponsor and the Investigators 
have jointly decided on the next dose-escalation step. Subject to clinical judgment, a 
new cohort of participants will be dosed at the new estimate of the MTD or the highest 
allowable dose based on pre-specified safety constraints as described below, whichever 
is lower and as guided by the mCRM-EWOC model. The design will continue as 
described, assigning participants to the MTD as estimated from all of the DLT data 
cumulatively, until one of the pre-defined stopping criteria is satisfied (see Section 4.1.4) 
or the pre-determined sample size of 60 DLT-evaluable participants is reached, 
whichever comes first. Depending on emerging PK and safety data, the dose escalation may be 
evaluated taking into account sCEA levels at baseline in a sensitivity analysis (i.e. dose escalating 
more conservatively in case toxicity is associated with low baseline sCEA levels).
[…]

Dose-escalation to SC MTD
Once an MTD or OBD has been defined, or relevant clinical activity is seen (e.g., PR or 
better according to RECIST) for IV route of administration and schedule, SC 
administration will be tested. The starting dose and regimen for SC will be proposed 
based on the evaluation of the safety and efficacy data observed following IV 
administration; however, due to practical considerations, a minimum dose of 2 mg is 
defined for a single SC administration (Section 4.3). 
In the QW cohorts, RO7172508 will be administered three times per cycle (i.e. QW), 
with a maximum starting-dose of one third of the RO7172508 IV MTD dose or, in case 
MTD has not been reached, of the highest safe dose ≥6 mg tested in the IV 
dose-escalation part. For a Q3W regimen the starting dose will not exceed the highest 
safe dose tested in the IV Q3W dose escalation. 
The maximum allowed dose will be 160 mg QW or 400 mg Q3W (flat dose). Different 
dosing schedules (e.g., non-fractionated and/or fractionated dosing) may be tested.
[…]
The OBD (IV and SC) will be selected based on the overall clinical safety and activity, as 
well as available PK and PD data for RO7172508. Data will be listed and summarized by
dose group as described in the analysis section (see Section 9.4).


RO7172508—F. Hoffmann-La Roche Ltd
195/Protocol BP40092, Version 4
Once a schedule, route of administration and OBD has been selected, and in case 
efficacy is observed during dose-escalation, disease-specific expansions may be 
opened to confirm these efficacy signals. The protocol will be amended in this case to 
describe treatment of these cohorts. If one route of administration is not unequivocally 
superior, and a decision cannot be taken during or at the end of dose escalation, both routes of 
administration may be compared in disease specific expansions. Criteria for selection of a route of 
administration will then be added via the protocol amendment preceding the expansions, 
including endpoints.
Section 4.1.3 Obinutuzumab Pre-treatment
During the course of the study, the need for obinutuzumab pre-treatment will be 
assessed based on loss of RO7172508 exposure and/or ADA-related safety events. 
Previous experience with the combination of immunotherapy and obinutuzumab has 
shown the capacity of obinutuzumab to abrogate ADA formation, thereby maintaining 
exposure to the investigational compound as determined by PK analysis (see 
Section 2.2.2 and the RO7172508 investigator’s brochure for further references).
During the course of the dose escalation, the decision to implement obinutuzumab will 
be based on a Bayesian posterior probability approach (see Appendix 8 for further 
details). At the time of the evaluation, if there is high confidence (80% confidence level) 
that the underlying true rate of participants with relevant loss of exposure is above 
50% then obinutuzumab pre-treatment will be introduced for all subsequent 
participants in the study (see Section 6.1 and Appendix 8). If the criteria are not met, 
the dose escalation will proceed without obinutuzumab pre-treatment until the next 
assessment or the end of the dose escalation, whichever is reached first (see 
Appendix 8).
If obinutuzumab will be implemented during the course of the dose escalation, then the 
dose escalation will be run under the same condition as defined for Part II without 
obinutuzumab. The starting dose will be a dose that has been safely tolerated in Part II 
without obinutuzumab. Escalation, stopping rules and maximum number of 
participants applied to Part II will also apply to Part II with obinutuzumab pre-
treatment.  
The first assessment on the implementation of obinutuzumab will be conducted once PK 
data following 3 cycles of treatment are available from at least 14 participants across 
both Part I and II (see Appendix 8). Loss of exposure is defined as at least a 70% 
reduction in Cmax at Cycle 3 from Cycle 1 in a participant. This threshold may be 
adapted based on emerging PK data. Ongoing assessments of safety and PK data will be 
performed for each cohort and at the end of dose escalation, to continuously evaluate the 
criteria for implementation of obinutuzumab pre-treatment. In addition, the incidence 
and titer of ADAs will be assessed on an ongoing basis throughout the study.






RO7172508—F. Hoffmann-La Roche Ltd
198/Protocol BP40092, Version 4
sCEA level has been indicated for doses < 12 mg in Part I and Part II (dose escalation) 
to minimize the impact of RO7172508 binding to sCEA. Preliminary PK data from the 
current study suggest sCEA may also impact the clearance of RO7172508. In order to further 
explore this relationship, at least 3 patients in each cohort in Part II should have a baseline sCEA 
level of ≤20 ng/mL.
[…]
The recovery of RO7172508 at Cmax was calculated using the above parameters for 
predicted doses < 12 mg in Part I and Part II (dose escalation) (Figure 6).
[…]
Table 10
sCEA Concentrations Predicted to Result in 80% Recovery of 
RO7172508 at Part I Doses Less Than 12 mg
Dose (g)
65
160
400
800
1600
sCEA concentration (ng/mL)
22-24
28-31
44-49
70-78
123-137
Dose (mg) (g)
3.265
6.4160
12400
800
1600
sCEA concentration (ng/mL)
229-
25422 24
440-
48928 31
809-
89944
49
70 78
123 137
Section 4.3.1 RO7172508
[…]
A maximum dose of 400 mg Q3W of RO7172508 has been defined. The Cmax observed 
at Cycle 1 of 400 mg (MTD) cibisatamabRO6958688 was 113 g/mL. Assuming a
potency factor of 20, an equivalent RO7172508 Cmax of 5.6 g/mL is estimated to be 
achieved by 25 mg. The clinical potency may differ from the in vitro levels; therefore, a 
maximum dose of 400 mg has been defined to allow this to be tested. The 
dose-escalation will only take place once a full evaluation of safety data has taken place 
and the dose-increment levels may be reduced to ensure the participant’s safety. 
Dose-fractionation may also be implemented in Cycle 1 where a dose not exceeding 400 
mg will be administered over one cycle e.g., 40 mg on Day 1, 120 mg on Day 8 and 240 
mg on Day 15. The maximum SC dose administered QW will be 160 mg QW which is 
480 mg over a three- week period/cycle.  By applying a conservative bioavailability of 
~80% this would equate to 400 mg Q3W IV.


RO7172508—F. Hoffmann-La Roche Ltd
199/Protocol BP40092, Version 4
Section 4.3.2 Obinutuzumab
If required, during the course of this study, based on the incidence of ADA-induced loss 
of exposure or safety events, obinutuzumab will be administered as detailed in the SoA 
(Section 1.3). Obinutuzumab will be administered as pre-treatment for RO7172508 
either as 2000 mg of obinutuzumab IV on one day (Day -7) or as 1000 mg of 
obinutuzumab IV on 2 consecutive days (Day -7 and Day -6) as specified in the SoA as 
per the site’s choice. Details regarding the infusion process are provided in Section 6.1. 
ADA titers and PK of both RO7172508 and obinutuzumab will be monitored as 
described in Section 4.1.3. 
The interval between obinutuzumab and the start of treatment has been determined 
based on Study BP39365, which is exploring the clinical activity of RO6874281 (FAP-
IL2v) in combination with atezolizumab. Five patients were pretreated with 
obinutuzumab 7 days prior to the combination treatment. It could be confirmed that 
complete B cell depletion was observed at the start of the combination treatment seven 
days after obinutuzumab was administered. There was no evidence of ADA formation 
in these participants when assessing ADA titers for RO6874281 (FAP-IL2v) and 
atezolizumab (RO5541267) up to 32 weeks of treatment. One patient showed positive 
ADA titers after 32 weeks of RO6874281/atezolizumab combination, which correlated 
with the reconstitution of B cells. Another patient remains on study after 52 weeks with 
no evidence of ADA titers and B cells remain depleted. Without obinutuzumab 
pretreatment in Study BP39365, the incidence of ADAs is approximately 80%. The 
kinetics of B-cell depletion and repletion have also been studied in Study BO20999 and 
following the administration of obinutuzumab a rapid depletion of B-cells was observed 
by Study Day 8 in CLL patients (first measurement after administration).
Further details are provided in the obinutuzumab Investigator’s Brochure.
Section 5 Study Population
[…]
In Part I, approximately 5 participants will be enrolled. In Part II, up to approximately 
60 75 participants during each dose-escalation, including additional 15 participants 
(1520 participants total in both IV and SC) will be enrolled (Section 9.2). In case the 
OBD is evaluated with and without obinutuzumab, an additional 15 participants may 
be enrolled.


RO7172508—F. Hoffmann-La Roche Ltd
200/Protocol BP40092, Version 4
Section 5.1 Inclusion Criteria
[…]
4.
For Part I (single participant cohorts) and Part II (dose escalation) <12 mg dose
cohorts, serum CEA (sCEA) levels below a certain threshold is required as follows:

For dose cohorts 65-159 g, an sCEA level of 22 ng/mL.

For dose cohorts 160-399 g, an sCEA level of 28 ng/mL.

For dose cohorts 400-799 g, an sCEA level of 44 ng/mL.

For dose cohorts 800-1599 g, an sCEA level of 70 ng/mL.

For the dose cohort of 1.6 - 3.1 mg, an sCEA level of 123 ng/mL.

For the dose cohort of 3.2 - 6.3 mg, an sCEA level of 229 ng/mL.

For the dose cohort of 6.4 -11.9 mg, an sCEA level of 440 ng/mL.
If dose fractionation is implemented, the sCEA threshold for inclusion should 
correspond to the dose range of the first dose administered.
For Part II, at least 3 participants in each cohort should have a baseline sCEA level ≤20 ng/mL.
5.
For Part II, participants with locally advanced and/or metastatic solid tumor 
expressing cytoplasmic and/or membranous high-CEA or moderate/low-CEA on 
archival material (or fresh biopsy when archival is not available), who have 
progressed on a SOC therapy, are intolerant to SOC, and/or are non-amenable to 
SOC. Participants must have a lesion amenable to biopsy (except participants with 
NSCLC, which may be enrolled with archival tissue available only). For participants 
with colorectal cancer (CRC) only, the CEA assessment by IHC should be performed but the 
result is not required to enroll the participant.
•
High-CEA:20% of tumor cells with IHC 2+ and/or 3+.
•
LModerate/low-CEA: 20% 20% of tumor cells with the sum of any IHC 
intensity (1+ 2+ and 3+) and not considered CEA-Highof tumor cells with IHC 
2+ and/or 3+ and/or 20% of tumor cells with IHC 1+.
[…]
11. Adequate liver function: total bilirubin 1.5 the upper limit of normal (ULN; 
excluding Gilbert‘s Syndrome), aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) 2.5 ULN (in case of liver metastases, 5 ULN).
[…]


RO7172508—F. Hoffmann-La Roche Ltd
201/Protocol BP40092, Version 4
15. Male and female participants
[…]
b) Male Participants
During the treatment period and for at least 2 months after the last dose of study 
treatment}, agreement to:

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additionalor a contraceptive method that 
together result in a failure rate of1% per year, with partners who are WOCBP (as 
defined in Section 1 of Appendix 5).
[…]
Section 5.2 Exclusion Criteria
[…]
12. Presence of bilateral lung lesions with either 3 lesions per lung or 1 lesion per 
lung with a diameter 3 cm (only unequivocal lesions of >1 cm are to be counted 
for this criterion, unless there is miliary metastatic-type diffuse disease, then these 
participants are ineligible).
[…]
19. Other Exclusions
19. Known hypersensitivity to any of the components of RO7172508.
Specific Exclusion Criteria if Pre-treatment with Obinutuzumab is Implemented
20. Known HIV (HIV testing will be performed at screening if required by local 
regulations)
21. Positive test results for chronic HBV infection (defined as positive HBsAg 
serology), HBcAb indicating an active viral infection and positive test results for 
HCV (HCV antibody serology testing). 
22. Participants positive for HCV antibody are eligible only if polymerase chain 
reaction (PCR) is negative for HCV ribonucleic acid (RNA).
23. History of progressive multifocal leukoencephalopathy. 
24. Active TB requiring treatment within 3 years prior to baseline. 
25. Latent TB diagnosed during Screening. 
26. Positive test results for human T-lymphotropic virus 1 (HTLV 1).


RO7172508—F. Hoffmann-La Roche Ltd
202/Protocol BP40092, Version 4
27. HTLV testing is required in participants from endemic countries (Japan, countries 
in the Caribbean basin, South America, Central America, sub-Saharan Africa, and 
Melanesia) 
28. Known hypersensitivity to any of the components of obinutuzumab. 
Section 6 Treatments
[…]
The investigational medicinal products (IMP) required for completion of this study 
(RO7172508, obinutuzumab and tocilizumab) will be provided by the Sponsor. 
Administration of study treatment will be at the study centers under supervision of 
qualified site staff.
Section 6.1 Treatments Administered
[…]
Administration of Obinutuzumab
The obinutuzumab Drug Product will be supplied by the Sponsor as a 50 mL single 
dose glass vial containing 1000-mg liquid concentrate in 40 mL (25 mg/mL) for 
infusion. In addition to the drug substance, the liquid is also composed of 
histidine/histidine-HCl, trehalose and poloxamer 188 (see Table 12).
Obinutuzumab will be administered either as a single dose of 2000 mg 7 days (D-7) 
before the first dose of RO7172508 (C1D1) or two doses of 1000 mg over days 6 and 
7 days (D-6 and D-7) before the first dose of RO7172508 (C1D1).  
For information on the formulation and handling of obinutuzumab, refer to the 
pharmacy manual and Obinutuzumab Investigator’s Brochure.


RO7172508—F. Hoffmann-La Roche Ltd
203/Protocol BP40092, Version 4
Table 12
Obinutuzumab Summary of Treatment Administered
Study Treatment Name
Obinutuzumab
Dosage Formulation
Concentrate for solution for IV 
infusion
Unit Dose Strength(s)/Dosage Level(s)
25 mg/mL
Dose
2000 mg or split doses of 2x 1000 mg
Route of Administration
IV
Dosing Instructions
see Pharmacy Manual
Packaging and Labeling
Study treatment will be provided in a 
carton (one labeled vial per box). Each 
carton will be labeled as required per 
country requirement.
Section 6.1.1 Pre-medication
[…]
In the event that the change in the route of administration from IV to SC does not 
mitigate the tumor inflammatory events or IRRs, then the same steroid regimen may be 
implemented as described in Table 14 and Table 15. These regimens are based on the 
expected duration of inflammatory events and they may be reduced or modified based 
on emerging data. Also, they may be extended from Cycle 1 to subsequent cycles, in 
case tumor inflammation and/or IRR occur at later cycles. Pre-medication may also 
include 1000 ml saline, 50 mg indomethacin (or equivalent non-steroidal anti-
inflammatory [NSAID]), 10 mg metoclopramide (or equivalent anti emetic) and 50 mg 
diphenhydramine (or equivalent H1 antagonist).


RO7172508—F. Hoffmann-La Roche Ltd
204/Protocol BP40092, Version 4
Table 14
Steroid Use on Cycle 1 of RO7172508 Infusion to be implemented in 
the event of frequent IRR/CRS or gastrointestinal RO7172508-related toxicity
occurrence after first administration
Timing
Dose
C1D 1: 12 24 hours before RO7172508 infusion
1 mg/kg prednisone IV/PO
C1D1: up to 60 minutes 4 to 6 hours before RO7172508 
infusion
0.51 mg/kg 
methylprednisolonemethyl
prednisone IV*/PO
1 g paracetamol PO TID
2 mg loperamide PO
C1D1: approximately 2 hours after RO7172508 infusion
1 mg/kg prednisone IV/PO*
C1D2: approximately 24 hours post-RO7172508 EOI
0.51 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
2 mg loperamide PO**
C1D3: approximately 48 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
C1D4: approximately 72 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO*
1 g paracetamol PO TID
C: Cycle; D: Day; EOI: end of infusion; IV: intravenous; PO: oral; TID: 3 times a day.
* rounded up to next multiple of 10 mg (or equivalent doses of mid acting steroids) 
** subsequent treatment with loperamide only to be given as clinically indicated 


RO7172508—F. Hoffmann-La Roche Ltd
205/Protocol BP40092, Version 4
Table 15
Steroid Use on Cycle 1 of RO7172508 or gastrointestinal RO7172508-
related toxicity to be implemented in the event of frequent IRR/CRS persisting 
despite dose fractionation
Timing
Dose
C1D 1: 12 24 hours before RO7172508 infusion
0.5 mg/kg prednisone IV/PO
C1D1: up to 60 minutes 4 to 6 hours before RO7172508 
infusion
0.51 mg/kg 
methylprednisolonemethyl
prednisone IV*/PO
1 g paracetamol PO TID
2 mg loperamide PO
CD1D1: approximately 2 hours post-RO7172508 EOI
0.5 1 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D27: approximately 12 24 hours before post-RO7172508
EOI infusion
0.51 mg/kg prednisone IV/PO
C1D8: up to 60 minutes before RO7172508 infusion
0.51 mg/kg 
methylprednisolonemethyl
prednisone IV*/PO
1 g paracetamol PO TID
2 mg loperamide PO**
C1D89: approximately 2 hours post-RO7172508 infusionEOI
0.5 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D914: 12 approximately 24 hours before post-RO7172508
EOI infusion
0.5 mg/kg prednisone IV/PO
C1D15: up to 60 minutes before RO7172508 infusion
0.51 mg/kg 
methylprednisolonemethyl
prednisone IV*/PO
1 g paracetamol PO TID
2 mg loperamide PO **
C1D156: approximately 2 hours post-RO7172508 EOI
0.51 mg/kg prednisone IV/PO
1 g paracetamol PO TID
C1D16: approximately 24 hours post-RO7172508 EOI
0.5 mg/kg prednisone IV/PO
C: Cycle; D: Day; EOI: end of infusion; IV: intravenous; PO: oral; TID: 3 times a day.
* rounded up to next multiple of 10 mg (or equivalent doses of mid acting steroids) 
** subsequent treatment with loperamide only to be given as clinically indicated 
In addition to the above mentioned premedication regimens, additional premedication may be 
implemented after agreement between Sponsor and Investigators for prophylaxis of RO7172508-
related toxicity at cycle 1 and/or at subsequent cycles:

From 30 to 60 minutes before administration of RO7172508, 5-HT3-receptor antagonist 
administration (preferably a long acting antagonist such as palonosetron 500 µg); 

Budesonide 9mg daily to start 3 days before first RO7172508 and to be continued up to 7 
days after first RO7172508 administration.


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Subsequent RO7172508 Infusions
Participants who experienced a Grade 2 IRR or other RO7172508-related toxicity within 24 
hours of RO7172508 administration on a previous infusion should be pre-medicated for 
subsequent infusions. The regimen indicated in Table 14 will be recommended for subsequent 
cycles, however in lieu of IV methylprednisolone administration, an equal oral dose of 
methylprednisolone (or equivalent) can be used. Similarly, the additional premedication regimens 
may be moved to subsequent cycles to prevent recurrence of the toxicity that occurred in Cycle 1. 
Premedication regimens for subsequent cycles may be reduced or omitted in case of ≤ Grade 1 
events in the previous cycle.

Paracetamol (500 1000 mg oral [PO] or IV) and diphenhydramine (25 50 mg PO or 
IV; or an alternative histamine H1/2 antagonist at an adequate dose). If a participant 
experienced a Grade 3 IRR, the same will apply in addition to corticosteroid 200 mg 
hydrocortisone IV (or equivalent dose of another corticosteroid).
[…]
For participants who experience an IRR-like reaction with a single and isolated symptom, 
such as fever that occurs within 24 hours after the study treatment infusion was 
completed, the use of pre-medication such as paracetamol, anti-histamine, and 
corticosteroids is not foreseen prior to subsequent RO7172508 administrations. The 
event will be reported as a single AE (e.g., fever). Pre-medication with corticosteroids of 
those participants at subsequent infusions needs approval from the Sponsor and the 
treatment and management at the time of an event is at the discretion of the Investigator.
Pre-medication may be changed based on emerging data and the regimens described above 
should be considered as the maximum suggested regimens. After collecting information on the 
effectiveness of the above mentioned premedication regimens scheduling and dose intensities may 
be reduced but not increased.
Premedication Prior to Obinutuzumab Administration
The use of corticosteroids, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) 
and/or antihistamines is required to minimize expected IRR reactions associated with 
the administration of obinutuzumab. Pre-medication must be administered prior to
obinutuzumab administration. A list of the mandatory pre-medications is provided in
Table 16.
Hypotension may occur as a result of an IRR adverse event. Therefore, it is 
recommended that antihypertensive drugs not be given on the morning of, and 
throughout the infusion of obinutuzumab, even if clinically indicated. Patients with a 
history of cardiac disease should be monitored closely.


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Table 16
Premedication Requirements for Obinutuzumab
Pre-Medication
Timing of Administration
Prednisolone 100 mg administered by IV 
infusion (or equivalent)
At least 60 minutes prior to the 
obinutuzumab infusion
Analgesic/anti-pyretic (e.g., paracetamol/oral 
acetaminophen 500 1000 mg) administered 
orally or by IV infusion
At least 30 minutes prior to the 
obinutuzumab infusion
Antihistamine (e.g., oral diphenhydramine 
50 100 mg) administered orally or by IV 
infusion (or an alternative anti-histamine at 
an adequate dose)
At least 60 minutes prior to the 
obinutuzumab infusion
Section 6.6 Dosage Modification
[…]
If a participant experiences obinutuzumab-related toxicity on Day -7 that requires the 
subsequent administration of obinutuzumab on Day -6 to be delayed, administration of 
obinutuzumab up to Day -5 is acceptable. Any obinutuzumab-related toxicity should 
resolve to NCI CTCAE Grade ≤ 2 for hematological toxicities or ≤ 1 for non-
hematological toxicities before RO7172508 administration. The first RO7172508 
administration can be delayed for of up to 1 week and if toxicity persists, the start of 
RO7172508 treatment will need to be agreed with the Medical Monitor.  
Section 8.1.1 Tumor and Response Evaluations
[…]
The data collected for RECIST v1.1 (Appendix 6) and mRECIST  will be used by the 
Sponsor to calculate programmatically time-point responses for iRECIST (Appendix 7), 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).
Section 8.2 Safety Assessments
Planned time-points for all safety assessments are provided in the SoA (Section 1.3). In 
order to better understand related adverse events, if any unscheduled assessments are 
performed during the study as part of standard of care, such as biopsies at the time of 
inflammation, these samples and/or results can be shared with the Sponsor for further 
analysis. 


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Section 8.3.8 Management of Specific Adverse Events
Guidelines for the management of participants who experience specific AEs to the IMPs 
other than RO7172508 (obinutuzumab and tocilizumab) are provided in the 
obinutuzumab and tocilizumab Investigator's Brochure and local prescribing 
information. Guidelines for the management of participants who experience AEs 
associated with RO7172508 are provided in Table 17, Table 18, and Table 19. For cases in 
which management guidelines are not covered in this protocol or in the 
obinutuzumab/tocilizumab Investigator's Brochure and local prescribing information, 
toxicities should be treated as deemed appropriate by the Investigator according to best 
medical judgment and local medical guidelines. Please see the RO7172508 
Investigator’s Brochure for the further details of the safety profiles of the management of 
specific AEs.
Section 8.3.8.1 Infusion-Related Reactions/Cytokine Release Syndrome
Administration of RO7172508 may cause a spectrum of infusion-related adverse events 
that typically occur during, shortly after, or within 24 hours after the infusion and 
could be associated with an IRR or CRS. 
IRRs are typically seen with the first two cycles and without symptoms of hypoxia 
and/or hypotension. In contrast, CRS is more likely to occur with the symptoms of 
hypoxia and/or hypotension at any cycle and with any symptom following from the 
third cycle onward. IRR events are therefore defined as taking place in association with 
the first two infusions and without symptoms of hypotension and/or hypoxia.
Given the overlap in signs and symptoms, IRRs may be indistinguishable from CRS, 
defined as a disorder characterized by nausea, headache, tachycardia, hypotension, rash, 
shortness of breath, and renal, coagulation, hepatic, and neurologic disorders (Lee et al. 
2014). Severe CRS may be associated with other clinical sequelae, such as disseminated 
intravascular coagulation and capillary leak syndrome.
Given that IRRs may be indistinguishable from CRS based on symptomatology, single-
treatment management guidelines are being recommended for both IRRs and CRS, 
during or up to 24 hours after infusion of RO7172508. The approach to have single-
treatment management guidelines for IRR and CRS will continue to be reviewed as 
additional safety data accumulate.
Table 17 provides guidelines for management of infusion-related reactions/ cytokine 
release syndrome.


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Table 17 Recommendations for Management of IRRs and CRS considered related 
to RO7172508a
Symptoms
Guidance
Grade 1
Fever, 
constitutional 
symptoms
–
If RO7172508 infusion is ongoing, slow infusion to ≤50% or interrupt infusion
–
Symptomatic treatment and supportive care
–
Monitor fluid balance and administer IV fluids as clinically indicated
–
At next cycle administer pre-medications that may include antihistamine, 
antipyretics/NSAIDS, antiemetic, and corticosteroids (See Table 14 and Table 15 &)
Grade 2
Hypotension:
responds to
fluids 
OR
Hypoxia*: 
requires <40% 
FiO2 (or ≤5 
L/min of 100% 
O2) to 
maintain 
adequate 
hemoglobin 
oxygen 
saturation
–
Follow all Grade 1 recommendations
–
Hold further RO7172508 treatment until symptoms completely resolved
–
At the restart of the infusion, Sslow down the rate of infusion to 25% of original rate
–
If event occurred during infusion, and symptoms recur with the same or greater 
severity following interruption of RO7172508 infusion, the infusion must be stopped 
immediately.  Consider to manage as a Grade 3 event. No further RO7172508 will be 
administered for the cycle.e; if hypotension or hypoxia recurs manage as grade 3 
event
–
Monitor cardiac and other organ functions closely
–
Hemodynamic support as indicated and oxygen for hypoxia
–
Admit to ICU as appropriate
–
Consider administering a single dose of tocilizumab IV 8 mg/kg
–
If no improvement within 24 hours:
a)
Notify Medical Monitor
b)
Administer IV corticosteroids (e.g., methylprednisolone [2 mg/kg/day] or 
dexamethasone 10 mg if neurologic symptoms are present)
–
Additional monitoring and evaluation:
–
Consider 24 hour hospitalization
–
Work up for organ functions (e.g. liver, cardiac) based on clinical assessment of 
the Investigator
–
May receive RO7172508 in next cycle if symptoms resolve to Grade ≤1 with the 
approval of the Medical Monitor including considerations for dose reduction 
and/or reduction of infusion rate at the next administration. 
–
At next cycle administer pre-medications that may include antihistamine, 
antipyretics/NSAIDS, antiemetic, and corticosteroids 
Grade 3
Hypotension: 
requires 
vasopressor 
support   
OR
Hypoxia*: 
requires >40%
FiO2 or >5 
L/min O2 to 
maintain 
adequate 
hemoglobin 
oxygen 
saturation
–
If RO7172508 infusion is ongoing, stop infusion immediately
–
No further RO7172508 will be administered for the cycle
–
Cardiopulmonary and organ function monitoring in ICU
–
Closely monitor and maintain fluid balance; and other supportive care as clinically 
indicated
–
Vasopressor support for hypotension with high and repeated doses if required
–
Notify Medical Monitor
–
Initiate IV corticosteroids (e.g., methylprednisolone [2 mg/kg/day] or dexamethasone 
10 mg if neurologic symptoms are present)
–
Administer tocilizumab 8 mg/kg  IV 
–
If no clinical improvement within 24 h: repeat dose of tocilizumab 8 mg/kg
–
Additional monitoring and evaluation:
–
Hospitalize patient for 24 hours


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Symptoms
Guidance
–
Work up for organ functions (e.g. liver, cardiac) based on clinical assessment of 
the Investigator
–
Permanently discontinue RO7172508 and follow the Schedule of Assessments 
(Table 5)
Grade 4
Hypoxia:
Mechanical
ventilation 
required
–
Follow all Grade 3 guidelines
–
Permanently discontinue RO7172508
a Grading of events is based on CTCAE V5.0 
* Isolated hypoxia (without hemodynamic instability) requiring oxygen support in a patient with tumor 
(primary or metastatic) in the lung should be managed as per tumor inflammation guidelines (Table 18) and 
not per CRS guidelines (Table 17). 
Section 8.3.8.2 Suspected Tumor Inflammation
Adverse events associated with tumor inflammation have been reported with T-cell 
engaging therapies and are consistent with the mechanism of action of such therapies 
that lead to influx of T-cells into tumor sites. Tumor inflammation is driven by influx 
of T cells and it is dependent on the mechanism of action of RO7172508. Along with 
the volume increase dependent on the influx of T cells, there may be an additional 
volumetric component possibly dependent by local inflammation. Events involving 
tumor inflammation, including tumor flare, have been reported in studies with in-class 
agent cibisatamabRO6958688. These events tend to occur with a short time to onset 
following administration and may present with varying degrees of severity. 
In addition, depending on tumor size and anatomic location, events associated with 
tumor inflammation may potentially result in mass effects on vital structures, 
including airways, major blood vessels, and/or major organs. Depending on the nature 
of the tumor inflammation, further medical and/or surgical management may be 
necessary (e.g. anti-inflammatory agents, airway management, decompression, cardiac 
function monitoring in terms of ejection fraction). Participants with tumors involving 
critical anatomic locations should be closely monitored for tumor inflammation and 
prospective consideration for preventive or interventional measures may need to be 
considered or planned prior to dosing. The treating physician/study investigator should 
contact the Medical Monitor to discuss risk assessment and mitigation strategies prior 
to initiating RO7172508 treatment in case participants present disease closed to vital 
structures. 
For further safety information, refer to the RO7172508 Investigator Brochure.
[…]


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Table 18
Management of Suspected Tumor Inflammation
Event
Initial Management 
Recommendation
Action to be Taken with 
RO7172508
Respiratory toxicities
Supportive measures, e.g., oxygen support and intubation, as indicated.
Grade 1
Monitor participant closely.
Continue treatment.
Grade 2
Monitor participant closely.
If no resolution to Grade 1 within 
48 hours, administer 1 mg/kg/day of 
IV methylprednisolone or equivalent 
followed by tapering with oral 
steroids until Grade 1.
Hold until resolution to 
Grade 1.
Grade 3
Administer 2 mg/kg/day of IV 
methylprednisolone or equivalent 
followed by tapering with oral 
steroids until resolution to Grade 1 
or baseline.
Ensure participant access to an 
intensive care unit is available
Hold until resolution to 
Grade 1.
Grade4
Consider permanent 
discontinuation after discussion 
with Medical Monitor.
Toxicities in other organs systems
(e.g., colitis, enteritis, increased liver enzymes)
Grade 1 or 2
Monitor participant closely
Continue if Grade 1 event (for 
Grade 2 events, hold until 
resolution to Grade 1).
Grade 3
Administer 1 mg/kg/day of IV 
methylprednisolone or equivalent 
followed by tapering with oral 
steroids until Grade 1 or baseline 
(consider escalating next day to 2 
mg/kg/day if no improvement, or 
escalate to 2 mg/kg directly if event 
occurs during prophylactic treatment 
with steroids).
Ensure participant access to an 
intensive care unit is available.
Hold until resolution to 
Grade 1. For grade ≥3 
toxicity and duration ≥5 days 
permanent discontinuation 
(including liver enzyme 
elevations).Hold until resolution 
to Grade 1.Exceptions may 
be warranted after discussion 
of benefit/risk profile of a 
specific patient with Medical 
Monitor
Grade 4
Administer 2 mg/kg/day of IV 
methylprednisolone or equivalent 
until Grade 1 or better.
Ensure participant access to an 
intensive care unit is available.
Consider permanent 
discontinuation after discussion 
with Medical Monitor.
Section 8.3.8.3 Management of Diarrhea/Colitis
[…]


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Table 19
Management of Diarrhea/Colitis
Event 
Management Recommendations
Grade 1

Continue treatment with RO7172508.

Initiate anti-diarrheal treatment (e.g., loperamide) as 
soon as possible.

Monitor the participant closely.

Ensure appropriate fluid intake.

If symptoms persist despite optimal anti-diarrheal 
treatment for more than 5 days, perform 
gastrointestinal (GI) work up*.
Grade 2

Withhold treatment with RO7172508.

Initiate anti-diarrheal treatment (e.g., loperamide) as 
soon as possible

Monitor the participant closely, perform GI work up*.

Ensure appropriate fluid intake

If symptoms do not improve to Grade 1 despite 
optimal anti-diarrheal treatment within 2 days, consider 
treatment with IV or oral corticosteroids (1mg/kg/day 
oral prednisolone or equivalent).

If diarrhea does not improve after 48 hours of 
corticosteroid treatment of 1mg/kg/day, increase dose 
to 2mg/kg/day.

If symptoms do not resolve despite corticosteroid 
treatment, consider referring the participant to GI 
specialist 

RO7172508 can be re-started if symptoms resolve to 
Grade 1.
Grade 3

Withhold treatment with RO7172508.

Refer the participant to GI specialist for diagnostic 
procedures (stool culture, endoscopy) and appropriate 
treatment.

Initiate corticosteroid treatment IV (2mg/kg/day IV 
methylprednisolone or equivalent).

Ensure appropriate fluid intake.

RO7172508 can be re-started if symptoms resolve to 
Grade 1.

If no improvement after 24 hours, consider treatment 
as per Grade 4 guidelines
Grade 4

Permanently discontinue treatment with RO7172508.

Refer the participant to GI specialist for diagnostic 
procedures (stool culture, endoscopy) and appropriate 
treatment.

Manage all symptoms by aggressive symptomatic 
treatment.

Initiate corticosteroid treatment IV.

If the there is no improvement for more than 48 hours, 
immunosuppressive treatment might be considered 
(such as infliximab).
* GI work up for further evaluation (e.g. endoscopy) and includes stool culture (in case of positive results 
e.g., Clostridium difficile, enteric bacteria, cytomegalovirus treat with antibiotics if appropriate). If the results 
of stool culture are negative, consider referring the participant to GI specialist for further evaluation 
(endoscopy).


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Section 8.3.8.4 Management of Immunogenicity
Administration of therapeutic antibodies may cause the formation of ADAs and 
immunogenicity is a potential risk for RO7172508. There is currently no evidence of 
ADAs in participants treated with RO7172508, with the limitation that only a low 
number of participants have been exposed. However, severe AEs (including two fatal 
events) associated with ADA formation were observed during clinical development of in 
class agent cibisatamab. 
All participants will be monitored at regular intervals for the development of ADAs 
against RO7172508 (see Section 8.5.1 for details). In case of emergence of AEs (in 
particular hypersensitivity reactions and CRS) possibly related to the development of 
ADAs against RO7172508, management will follow guidelines as summarized in
Table 17. In all cases of AEs associated with the development of ADAs, treatment 
discontinuation should be immediately considered even if the event is low grade after 
discussion with Medical Monitor. 
As an additional mitigation strategy, obinutuzumab pre-treatment will be initiated if 
there is evidence of ADA mediated hypersensitivity reactions or other safety signals 
that are likely related to ADAs (see Section 4.1.3 for details). In such instance, 
obinutuzumab will be implemented for all subsequent participants and the enrollment 
of participants without obinutuzumab will be stopped.
Section 8.5 Pharmacokinetics
Serum samples will be collected for RO7172508 PK analyses for both IV and SC 
administrations.
[…]
Serum samples will be collected for obinutuzumab PK analyses in those participants 
who receive obinutuzumab as pre-treatment.
Section 8.5.1 Immunogenicity Assessments
[…]
Antibodies to RO7172508 will be evaluated in blood samples collected from all 
participants according to the SoA (Section 1.3). Additional ADA samples should also be 
collected at the time of treatment discontinuation or at the safety follow-up visit and in 
participants who experience a Grade3 IRR and in participants with clinical signs of 
hypersensitivity reaction, in particular immune complex reaction. In each case, for each 
collected ADA sample, a corresponding PK sample will be collected at the same 
time-point for the determination of the RO7172508 concentration. Participants 
experiencing a Grade 3 toxicity potentially related to ADAs will not be further treated 
with RO7172508 (see Section 7.1).
[…]


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Antibodies to obinutuzumab will be evaluated in all participants who receive 
obinutuzumab as pre-treatment according to the SoA.
Section 8.6 Pharmacodynamics
[…]

Serum and/or plasma samples: PD biomarkers such as cytokines and 
inflammation markers (including but not limited to TNF, IFN, IL-6, Macrophage 
Inflammatory Protein [MIP], etc.) will be analyzed. Because these measurements are 
also safety measure assessments during any IRRs, they will be examined in 
participants enrolled in both Part I and Part II of the study. Disease-monitoring 
markers that include but are not limited to sCEA will also be assessed.

Archival tissue and fresh tumor biopsy: If archival is not available, fresh biopsy 
collected at baseline will be used. Study enrollment will be based on CEA status 
assessed on archival tissue (with the exception of participants with CRC). iIf 
archival is not available, fresh biopsy collected at baseline will be used). Mandatory 
tumor biopsy samples obtained in Part II for all participants (including participants 
with CRC) at baseline and on-treatment (Cycle 2 Day 8; see SoA, Section 1.3) will 
be assessed for changes in immune cell numbers and activation characteristics as 
well as changes in tumor markers such as PD-L1. These analyses will be performed 
by flow cytometry, molecular and/or immunohistochemistry methods with respect to 
changes in the characteristics of lineage (CD4+ T-cells, CD8+ T-cells, NK cells, 
monocytes, T-regulatory cells, and B-cells), activation (including but not limited to 
CD25, CD69, etc.), differentiation (including but not limited to Ki67, PD1, TIM3, 
ICOS, etc.), and TCR Vrepertoire.
Whole blood, serum/plasma, and tissue samples will be collected at time-points 
specified in the SoA (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.
Section 8.8 Biomarkers
[…]
In particular, aArchival tumor tissue is to be obtained from all participants, if available, in 
order to perform CEA assessment for participant eligibility except for participants with 
CRC (refer to the Laboratory Manual). Both archival and fresh tumor biopsy specimens 
will be analyzed with respect to changes as described (Section 8.6) including but not 
limited to immune and tumor cell characteristics, TCR Vrepertoire etc.


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Section 9.2 Sample Size Determination
Part I will enroll up to approximately 5 participants. The sample size is determined by the 
dose-increment steps implemented in this part.
In Part II, it is anticipated that a maximum of approximately 60 evaluable participants will 
be enrolled in each dose-escalation phase (IV and SC) (up to approximately 
75 participants if one or several cohorts are expanded). In case the OBD dose cohort is 
expanded both with and without obinutuzumab, an additional 15 participants may be 
enrolled. 
The probability of observing at least one event out of 15 participants for a true 
underline rate of 10% is 79% while out of 5 patients is 41%. Probabilities of the 
occurrence of 1 or more events for different ranges of true underline rates and different 
participant numbers are summarized in Table 20.
The exact sample size for the dose-escalation part cannot be pre-determined and 
depends on the number of cohorts needed to reach the MTD (or highest safe dose if 
MTD is not reached).
Table 20 Probabilities for Observing Adverse Events 
Total N of 
Participants
True AE 
Probability
Probability 
that AE ≥ 1
Probability 
that AE ≥ 2
Probability 
that AE ≥ 3
15
0.1
0.79
0.45
0.18
0.2
0.96
0.83
0.60
0.3
1.00
0.96
0.87
0.4
1.00
0.99
0.97
0.5
1.00
1.00
1.00
10
0.1
0.65
0.26
0.07
0.2
0.89
0.62
0.32
0.3
0.97
0.85
0.62
0.4
0.99
0.95
0.83
0.5
1.00
0.99
0.95
5
0.1
0.41
0.08
0.01
0.2
0.67
0.26
0.06
0.3
0.83
0.47
0.16
0.4
0.92
0.66
0.32
0.5
0.97
0.81
0.50


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Section 9.3 Populations for Analyses
Table 21
Analysis Populations
Population
Description
Efficacy
All participants who received at least one dose of 
RO7172508.
Safety
All participants enrolled in the study who received at least 
one dose of study treatment (RO7172508 and/or 
obinutuzumab if applicable) will be included in the safety 
population. Unless otherwise specified, the safety population 
will be the default analysis set used for all analyses.
[…]
Section 9.4 Statistical Analyses
The data will be analyzed by the Sponsor and/or designated Contract Research 
Organization (CRO). 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, 
pharmacokinetic and biomarker measurements. Data will be summarized by cohort and 
regimen within each part and CEA level where applicable,. including the additional 
participants that may be enrolled in expanded cohorts (see Section 4.1.2.2). Participants who 
receive only obinutuzumab but no dose of RO7172508 will be summarized separately.
The baseline value of any variable will be defined as the last available value prior to the 
first administration of study treatment (RO7172508 or obinutuzumab (if applicable) as 
appropriate).
The following endpoints may be used to select a route of administration for further development: 
PD parameters including T-cell activation in blood and in the tumor; pharmacokinetic 
parameters such as AUC, Cmax and half-life; tolerability and safety; as well as incidence of ADAs 
and their effect on exposure. Clinical efficacy will be considered, but is not expected to be a key 
criterion, as efficacy will likely be affected by parameters which cannot be controlled for in such 
small cohorts. Data will be listed and summarized by dose group as described in this analysis 
section. Analyses are exploratory in nature and no formal hypothesis testing will be performed.  
If one route of administration is not unequivocally superior, and a decision cannot be taken 
during or at the end of dose escalation, both routes of administration will be compared in disease 
specific expansion. Criteria for selection of a route of administration will then be added via the 
amendment preceding the expansions, including endpoints. 


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Section 9.4.2 Efficacy Analyses
[…]

ORR and DCR are both determined as the rate of participants with an observed 
tumor response of CR or PR (ORR) or CR, PR or SD (DCR). ORR and DCR will be 
derived for both RECIST v1.1 and mRECIST.
Section 9.4.3 Safety Analyses
Unless otherwise specified, the safety population will be the default analysis set used for 
all analyses. Those participants who receive only obinutuzumab, but withdraw from the 
study before receiving RO7172508, will be summarized separately.
DLT evaluable participants will be used in the determination of the MTD.
The safety endpoints and appropriate analyses are summarized in Table 23.
Table 23
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Incidence, nature, 
and severity of 
AEs
The original terms recorded on the eCRF by the Investigator for AEs 
will be coded by the Sponsor. For classification purposes, preferred 
terms will be assigned by the Sponsor to the original terms entered on 
the eCRF. AEs will be graded according to guidelines provided in 
Section 3.1 of Appendix 2.
AEs will be summarized by mapped term and appropriate thesaurus 
level. Toxicity grade, seriousness and relationship to study treatment 
will be presented, as well as listings of deaths, AEs leading to death 
and premature withdrawal from study treatment. Glossary of AEs, 
medication and procedures will be provided. AE occurring between 
obinutuzumab pre-treatment (if applicable) and the first 
administration of RO7172508 will be summarized separately. 
Section 9.4.4 Pharmacokinetic Analyses
[…]
Individual and mean serum obinutuzumab concentration versus time data will be 
tabulated.
Section 9.4.5 Immunogenicity Analyses
[…]


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Antibodies to obinutuzumab will be evaluated in blood samples using appropriate 
assays from all participants who receive obinutuzumab as pre-treatment.
Section 10 References
Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in 
relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 
GAUGUIN study. Blood. 2014;124:2196−2202.
[…]
Flynn JM, Byrd JC, Kipps TJ, et al. Obinutuzumab (GA101) 1,000 mg versus 2,000 mg 
in patients with chronic lymphocytic leukemia (CLL): results of the phase II 
GAGE (GAO4768g) trial. 2014. ASCO 
[https://meetinglibrary.asco.org/recod/92456/abstract]
[…]
Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy 
through the engineering of a new type II anti-CD20 antibody with enhanced 
direct and immune effector cell–mediated B-cell cytotoxicity. Blood. 
2010;115:4393-4402.
[…]
Salles G, Morschhauser F, Lamy T, et al. Phase 1 study results of the type II 
glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab 
(GA101) in B-cell lymphoma patients. Blood. 2012;119:5126−5132.
Appendix 2 Section 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 using the following reference document:

RO7172508 Investigator's Brochure 

Obinutuzumab/RO7172508 combination - RO7172508 Investigator's Brochure

Tocilizumab Investigator's Brochure

RO7172508 Investigator's Brochure



RO7172508—F. Hoffmann-La Roche Ltd
219/Protocol BP40092, Version 4
Appendix 4 Clinical Laboratory Tests
[…]
Table 1
Protocol-Required Safety Laboratory Assessments
[…]
Other Tests

sCEA*
*will be performed centrally and locally
Appendix 6 New Response Evaluation Criteria in Solid Tumors [RECIST] –
Version 1.1 (Modified Excerpt from Original Publication with Addition of 
Supplementary Explanations) was replaced with the new company standard text.
Appendix 7 : Modified RECIST v1.1 for Immune-Based Therapeutics (iRECIST)
was added.