Clinical trial NCT03708328
Conditions: Solid Tumors Metastatic Melanoma Non-small Cell Lung Cancer (NSCLC) Small Cell Lung Cancer (SCLC) Esophageal Squamous Cell Carcinoma (ESCC)
Sponsor: Hoffmann-La Roche
Start date: 2018-10-15; Completion date: 2024-07-09
Enrollment: 134 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose (MAD) study of single agent lomvastomig (RO7121661), an anti PD-1 (programmed death-1) and TIM-3 (T-cell immunoglobulin and mucin domain 3) bispecific antibody, for participants with advanced and/or metastatic solid tumors. The study consists of 2 parts: Dose Escalation (Part A) and Expansion (Parts B1, B2, B3, B4, and B5). The Dose Escalation part will be conducted first to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) based on safety, tolerability, pharmacokinetic, and/or the pharmacodynamic profile of escalating doses of lomvastomig. The Expansion part will enroll tumor-specific cohorts to evaluate anti-tumor activity of the MTD and/or RDE of lomvastomig from Part A (Q2W) and to confirm safety and tolerability in participants with selected tumor types.

Detailed description:

Arms: arm 1: Lomvastomig will be administered in treatment cycles once every 2 weeks (Q2W). Dose escalation will be carried out according to a modified continual reassessment method (mCRM) with escalation with overdose control (EWOC) design. arm 2: This cohort will comprise participants with checkpoint inhibitor (CPI) experienced, second line and beyond metastatic melanoma. The starting dose of lomvastomig for Expansion will be derived from the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) and the best dosing schedule determined during Dose Escalation. arm 3: This cohort will comprise participants with CPI and platinum experienced, second or third line PD-L1 positive non-small cell lung cancer (NSCLC). The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. arm 4: This cohort will comprise participants with PD-L1 high, cancer immunotherapy (CIT) naïve first line NSCLC. The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.

This cohort was not initiated and no participants were enrolled in it. arm 5: This cohort will comprise participants with CPI naïve small cell lung cancer (SCLC) with prior failure of, progression on, or intolerance to, standard therapy. The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation. arm 6: This cohort will comprise participants with CPI-naïve esophageal squamous cell carcinoma (ESCC). The starting dose of lomvastomig for Expansion will be derived from the MTD/RDE and the best dosing schedule determined during Dose Escalation.
Interventions: intervention 1: Lomvastomig
Intervention descriptions: intervention 1: Lomvastomig will be administered intravenously (IV) with a flat dose on the schedule described for each study arm.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: 
An Open Label, Multicenter, Dose Escalation and Expansion, Phase 1 
Study to Evaluate Safety, Pharmacokinetics, and Preliminary Anti 
Tumor Activity of RO7121661, a PD-1/TIM-3 Bispecific Antibody, in 
Patients with Advanced and/or Metastatic Solid Tumors 
NCT Number: 
NCT03708328 
Document Date: 
Protocol Amendment Version 5: 07-September-2021 


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. 
RO7121661—F. Hoffmann-La Roche Ltd 
Protocol NP40435, Version 5 
PROTOCOL 
TITLE: 
AN OPEN LABEL, MULTICENTER, DOSE 
ESCALATION AND EXPANSION, PHASE 1 STUDY 
TO EVALUATE SAFETY, PHARMACOKINETICS, 
AND PRELIMINARY ANTI TUMOR ACTIVITY OF 
RO7121661, A PD-1/TIM-3 BISPECIFIC ANTIBODY, 
IN PATIENTS WITH ADVANCED AND/OR 
METASTATIC SOLID TUMORS 
PROTOCOL NUMBER: NP40435 
VERSION: 
5 
EUDRACT NUMBER: 
2018-000982-35 
IND NUMBER: 
142844 
TEST PRODUCT: 
RO7121661 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1: 27 June 2018 
DATE AMENDED: 
Version 2: 12 June 2019 
Version 3: 02 October 2019 
Version 4: 04 June 2020 
Version 5: See electronic date stamp below 
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
07-Sep-2021 12:46:59


RO7121661—F. Hoffmann-La Roche Ltd 
2/Protocol NP40435, Version 5 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
AN OPEN LABEL, MULTICENTER, DOSE 
ESCALATION AND EXPANSION, PHASE 1 STUDY 
TO EVALUATE SAFETY, PHARMACOKINETICS, 
AND PRELIMINARY ANTI TUMOR ACTIVITY OF 
RO7121661, A PD-1/TIM-3 BISPECIFIC ANTIBODY, 
IN PATIENTS WITH ADVANCED AND/OR 
METASTATIC SOLID TUMORS 
PROTOCOL NUMBER: NP40435 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2018-000982-35 
IND NUMBER: 
142844 
TEST PRODUCT: 
RO7121661 
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. 


RO7121661—F. Hoffmann-La Roche Ltd
3/Protocol NP40435, Version 5
PROTOCOL AMENDMENT, VERSION 5
RATIONALE
Protocol NP40435 has been amended to enable participants, who are benefitting from
the therapy with RO7121661 at the end of the treatment period, to remain on treatment 
beyond the initial 24 months. Changes to the protocol, along with a rationale for each 
change, are summarized below.

Section 2.3 and Section 6.5.1 were updated to add Covid-19 benefit/risk 
assessment and vaccine information.

The Schedule of Assessment Table 1 (footnotes only), Section 4.1, Section 7.1, 
and Section 8.10.4 have been updated to add language to prolong the treatment 
period for participants who benefit from treatment.

Medical Monitor language was updated in Section 5.1, Section 5.2, Section 5.4,
Section 6.1.2, Section 6.5.1, Section 6.6, Section 7.1.1, Section 7.1.2, Section 
8.3.8.1, Section 8.4, and Appendix 6 to reflect new guidelines on medical 
monitoring in accordance with ICH E6(R2) 4.3.1.

In Appendix 6, the dose modification and treatment interruption sections have been 
removed to avoid redundancy with Sections 6.6 and 7.1.1. Information on 
immune-mediated myocarditis, Grade 1-2 has been removed from the 
management guidelines Table 6 to align with updates in the atezolizumab 
Investigator’s Brochure. A section on hemophagocytic lymphohistiocytosis and 
macrophage activation syndrome was added to align language with other protocols 
studying in-house checkpoint inhibitors (including RO7121661).
Additional minor changes have been made to improve clarity and consistency. New 
information appears in Book Antiqua italics. This amendment represents cumulative 
changes to the original protocol.




RO7121661—F. Hoffmann-La Roche Ltd
5/Protocol NP40435, Version 5
4.3.2
Rationale for Biomarker Assessments................................... 57
4.4
Dose Justification .................................................................. 58
4.5
End of Study Definition .......................................................... 60
5.
STUDY POPULATION................................................................................ 60
5.1
Inclusion Criteria.................................................................... 60
5.2
Exclusion Criteria................................................................... 66
5.3
Lifestyle Considerations......................................................... 70
5.4
Screen Failures ..................................................................... 71
5.5
Recruitment Procedures........................................................ 72
6.
TREATMENTS............................................................................................ 72
6.1
Treatments Administered....................................................... 72
6.1.1
RO7121661 ........................................................................... 72
6.1.2
Pre-medication ...................................................................... 73
6.2
Preparation/Handling/Storage/Accountability ........................ 74
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 75
6.3.1
Method of Treatment Assignment.......................................... 75
6.4
Treatment Compliance .......................................................... 75
6.5
Concomitant Therapy ............................................................ 75
6.5.1
Permitted Therapy................................................................. 75
6.5.2
Prohibited Therapy ................................................................ 76
6.6
Dosage Modification .............................................................. 77
6.7
Treatment after the End of the Study..................................... 78
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 78
7.1
Discontinuation of Study Treatment....................................... 78
7.1.1
Temporary Interruption .......................................................... 80
7.1.2
Resumption of Study Treatment............................................ 80
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 81
7.3
Lost to Follow-Up................................................................... 81
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 82
8.1
Efficacy Assessments............................................................ 82


RO7121661—F. Hoffmann-La Roche Ltd
6/Protocol NP40435, Version 5
8.1.1
Tumor and Response Evaluations......................................... 82
8.1.2
Photography of Cutaneous Lesions....................................... 83
8.2
Safety Assessments .............................................................. 84
8.2.1
Physical Examinations........................................................... 84
8.2.2
Royal Marsden Hospital Risk Score ...................................... 84
8.2.3
Eastern Cooperative Oncology Group 
Performance Status............................................................... 84
8.2.4
Vital Signs.............................................................................. 84
8.2.5
Electrocardiograms................................................................ 85
8.2.6
Clinical Safety Laboratory Assessments................................ 86
8.2.7
Medical History and Demographic Data ................................ 87
8.3
Adverse Events and Serious Adverse Events ....................... 87
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 87
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 88
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 88
8.3.3.1
Investigator Follow-Up........................................................... 88
8.3.3.2
Sponsor Follow-Up ................................................................ 88
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 89
8.3.4.1
Emergency Medical Contacts................................................ 89
8.3.5
Pregnancy ............................................................................. 89
8.3.6
Non-Serious Adverse Events of Special Interest................... 90
8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs ............................ 90
8.3.8
Management of RO7121661 Specific Adverse 
Events.................................................................................... 90
8.3.8.1
Infusion-Related Reactions.................................................... 91
8.3.8.2
Immune-mediated adverse events ........................................ 93
8.4
Treatment of Overdose.......................................................... 93
8.5
Pharmacokinetics .................................................................. 94
8.5.1
Immunogenicity Assessments ............................................... 94


RO7121661—F. Hoffmann-La Roche Ltd
7/Protocol NP40435, Version 5
8.6
Pharmacodynamics/Exploratory Biomarkers......................... 95
8.6.1
Blood Samples ...................................................................... 96
8.6.2
Tissue Samples..................................................................... 97
8.6.2.1
Archival Tumor Samples........................................................ 97
8.6.2.2
Fresh Tumor Biopsies............................................................ 97
8.7
Genetics ................................................................................ 98
8.7.1
Whole Genome/Exome/Targeted DNA Analysis ................... 98
8.8
Samples for Research Biosample Repository ....................... 99
8.8.1
Overview of the Research Biosample Repository.................. 99
8.8.2
Sample Collection................................................................ 100
8.9
Health Economics................................................................ 101
8.10
Timing of Study Assessments ............................................. 101
8.10.1
Screening and Pre-treatment Assessments ........................ 101
8.10.2
Assessments during Treatment........................................... 102
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................. 102
8.10.4
Follow-Up Assessments ...................................................... 102
8.10.4.1
Post-Study Safety Follow-up ............................................... 102
8.10.4.2
Post-study Survival Follow-up ............................................. 102
8.10.5
Assessments at Unscheduled Visits.................................... 102
9.
STATISTICAL CONSIDERATIONS .......................................................... 103
9.1
Statistical Hypotheses ......................................................... 103
9.2
Sample Size Determination ................................................. 103
9.3
Populations for Analyses ..................................................... 104
9.4
Statistical Analyses.............................................................. 104
9.4.1
Demographics and Baseline Characteristics ....................... 104
9.4.2
Efficacy Analyses ................................................................ 105
9.4.3
Safety Analyses................................................................... 106
9.4.4
Pharmacokinetic Analyses................................................... 108
9.4.5
Immunogenicity Analyses.................................................... 108
9.4.6
Pharmacodynamic Analyses ............................................... 108
9.5
Interim Analyses .................................................................. 109
9.6
Summaries of Conduct of Study.......................................... 109




RO7121661—F. Hoffmann-La Roche Ltd
9/Protocol NP40435, Version 5
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
BSA
Body surface area
BsAb
Bispecific antibody
CIT
Cancer immunotherapy
CLss
Clearance
Cmax
Maximum concentration
CNS
Central nervous system
COA
Clinical outcome assessments
CPI
Checkpoint inhibitor
CRCL
Creatinine clearance
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
DCR
Disease control rate
DLCO
Diffusion capacity
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
EC
Ethics Committee
ECG
Electrocardiogram
eCOA
Electronic clinical outcome assessment
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EGFR
Epidermal growth factor receptor
EOI
End of infusion
EOO
End of observation


RO7121661—F. Hoffmann-La Roche Ltd
10/Protocol NP40435, Version 5
Abbreviation
Definition
ESCC
Esophageal squamous cell carcinoma
ESF
Eligibility screening form
EU
European Union
EWOC
Escalation with overdose control
FDA
Food and Drug Administration
FFPE
Formaldehyde fixed-paraffin-embedded 
FNA
Fine-needle aspiration
FSH
Follicle-stimulating hormone
HBcAb
Total hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoproteins
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HR
Heart rate
HRT
Hormonal replacement therapy
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
imAE
Immune-mediated adverse event
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
iRECIST
Immune-related response evaluation criteria in solid 
tumors
IRR
Infusion-related reaction
IUD
Intrauterine device
IV
Intravenous


RO7121661—F. Hoffmann-La Roche Ltd
11/Protocol NP40435, Version 5
Abbreviation
Definition
IRT
Interactive response technology system
JMC
Joint Monitoring Committee
LAG-3
Lymphocyte-activation gene 3
LDL
Low-density lipoproteins
LPLV
Last participant, last visit
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MABEL
Minimum anticipated biological effect level
MAD
Multiple-ascending doses
mCRM
Modified continual reassessment method
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NGS
Next generation sequencing
NK
Natural killer
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Pharmacodynamic
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PGIC
Patient global impression of change
PK
Pharmacokinetic
PT
Prothrombin time
QW
Every week
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QT
QT interval
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RBR
Research biosample repository


RO7121661—F. Hoffmann-La Roche Ltd
12/Protocol NP40435, Version 5
Abbreviation
Definition
RDE
Recommended dose for expansion
RECIST
Response evaluation criteria in solid tumors
RNA
Ribonucleic acid
RO
Receptor occupancy
RR
Response rate
SAE
Serious adverse event
SD
Stable disease
SDR
Stable disease rate
SEB
Staphylococcal enterotoxin B superantigen-induced
SoA
Schedule of activities
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
T1/2
Half-life
TB
Tuberculosis
TCR
T-cell receptor
TIL
Tumor infiltrating lymphocytes
TIM-3
T-cell immunoglobulin and mucin domain 3
TKI
Tyrosine kinase inhibitor
TLR
Toll like receptor
Tmax
Time of maximum concentration
TMB
Tumor mutational burden
TMDD
Target-mediated drug disposition 
TPS
Tumor proportion score
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
WBC
White blood cell
WES
Whole exome sequencing
WGS
Whole genome sequencing
WOCBP
Woman of childbearing potential


RO7121661—F. Hoffmann-La Roche Ltd
13/Protocol NP40435, Version 5
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
AN OPEN LABEL, MULTICENTER, DOSE ESCALATION AND 
EXPANSION, PHASE 1 STUDY TO EVALUATE SAFETY, 
PHARMACOKINETICS, AND PRELIMINARY ANTI TUMOR 
ACTIVITY OF RO7121661, A PD-1/ TIM-3 BISPECIFIC ANTIBODY, 
IN PATIENTS WITH ADVANCED AND/OR METASTATIC SOLID 
TUMORS
SHORT TITLE
DOSE ESCALATION AND EXPANSION STUDY OF PD-1/TIM-3 
BISPECIFIC ANTIBODY IN PATIENTS WITH ADVANCED AND/OR 
METASTATIC SOLID TUMORS
PROTOCOL NUMBER:
NP40435
VERSION:
5
TEST PRODUCT:
RO7121661
PHASE:
I
RATIONALE
RO7121661, an anti-programmed death-1 (PD-1) / T-cell immunoglobulin and mucin domain 3 
(TIM-3) bispecific antibody (BsAb), was designed to target dysfunctional tumor antigen-specific 
T lymphocytes (expressing PD-1 and TIM-3) in order to establish or re-establish an effective 
anti-tumor immune-response in cancer patients with high unmet medical need. This may result 
in improvement in the therapeutic response over currently available therapies and/or 
overcoming of primary resistance or emerging resistance against PD-1/programmed death-
ligand 1 (PD-L1) checkpoint blockade in patients previously treated with PD-1 or PD-L1 
checkpoint inhibitors (CPI experienced). 


RO7121661—F. Hoffmann-La Roche Ltd
14/Protocol NP40435, Version 5
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

Dose Escalation: Safety, tolerability, 
maximum-tolerated dose (MTD) and/or 
recommended dose for expansion 
(RDE)

Nature and frequency of dose-limiting 
toxicities (DLTs) and other adverse 
events (AEs), pharmacodynamic (PD) 
and pharmacokinetic (PK) profile.

Incidence, nature and severity of AEs 
graded according to the National 
Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events 
(CTCAE) v5.0.

Expansion: Assessment of the anti-
tumor activity of RO7121661.

According to Response Evaluation 
Criteria in Solid Tumors (RECIST) 
Version 1.1 criteria:
o
Objective response rate (ORR).
o
Disease control rate (DCR); 
defined as (ORR) stable disease 
rate (SDR).
o
Duration of response (DoR).
o
Progression free survival (PFS) 
defined as the time from the first 
study treatment (Day 1) to the first 
occurrence of progression per 
Investigator assessment or death 
from any cause, whichever occurs 
first.
Secondary

To characterize the immunogenicity 
profile of RO7121661 (Part A and B).

Incidence of anti-drug antibodies 
(ADAs).

To explore potential PD-1, TIM-3 and 
PD-1/TIM-3 specific PD biomarkers
(Part B).

Examine the profile and status of T cell 
proliferation/activation in tumor biopsies 
and peripheral blood.

To investigate the single and multiple 
dose PK of RO7121661 (Part A and B).

PK profiles and parameters derived for 
RO7121661.

To explore degree of target binding of 
RO7121661 (in association with PK/PD) 
via receptor occupancy (RO).

Evaluate RO via ex-vivo assay.

To evaluate the safety and tolerability of 
RO7121661 (Part B).

To explore preliminary anti-tumor 
activity of RO7121661 (Part A).

Incidence, nature and severity of AEs 
graded according to the NCI CTCAE 
v5.0.

According to RECIST Version 1.1 
criteria:
–
Objective response rate (ORR).
–
Disease control rate (DCR).
–
Progression-free survival (PFS).
–
Duration of response (DoR).


RO7121661—F. Hoffmann-La Roche Ltd
15/Protocol NP40435, Version 5
OVERALL DESIGN
Study NP40435 is a first-in-human, open-label, multicenter, Phase I multiple-ascending dose 
(MAD) study of single agent RO7121661.
Study Design
The study consists of 2 parts (A and B):
Part A (RO7121661 Dose Escalation): To determine the MTD and/or RDE based on safety, 
tolerability, PK, and/or the PD profile of escalating doses of RO7121661 every 2 weeks (Q2W). 
If for specific cleared cohort(s) the safety, PK and/or RO and/or the biomarker profile need to be 
further characterized, additional participants, potentially enriched in certain indications and/or 
characteristics, may be enrolled.
Part B (RO7121661 Tumor-Specific Expansion Cohorts): To evaluate anti-tumor activity of the 
RDE of RO7121661 from Part A (2.1 g Q2W) and to confirm safety and tolerability in 
participants with selected tumor types. B1, B2, B4 and B5 expansions may be staggered, 
sequential or concurrent. Part B3 will not proceed prior to generation of data from the initial CPI 
experienced indication(s):

Part B1: CPI experienced second line and beyond metastatic melanoma

Part B2: CPI and platinum experienced second or third line PD-L1 positive NSCLC

Part B3: PD-L1 positive, CPI naïve, first line NSCLC

Part B4: CPI-naïve SCLC with prior failure of, progression on, or intolerance to standard 
therapy

Part B5: CPI-naïve ESCC
Treatment Groups and Duration
The investigational medicinal product (IMP) is RO7121661.
Part A
RO7121661 will be administered IV with a flat dose. The starting dose will be 70 mg and the 
maximum dose explored will be 2.1 g. Since RO7121661 will be administered Q2W in Part A, 
the cycle length will be defined as 14 days.
This part of the study will enroll participants with solid tumors who have progressed on a cancer 
therapy or who are not amenable to standard of care. At least  DLT evaluable participants will 
be enrolled in each cohort during the dose escalation. Dose escalation will be carried out 
according to a modified continual reassessment method (mCRM) with escalation with overdose 
control (EWOC) design, with the aim of identifying the MTD/RDE of RO7121661. 
The maximum total number of participants in the dose escalation portions of Part A will be 
approximately 
 DLT evaluable participants. A dose cohort can be extended to enroll 
additional participants, potentially enriched in certain tumor types and/or characteristics 
(approximately 
) to confirm safety, PK and/or RO data.  
Part B
Part B1 and/or B2 and/or B4 and/or B5 may commence upon completion of Part A. The starting 
dose of RO7121661 for Part B is 2.1 g as derived from the RDE in Part A determined by safety, 
PK and/or RO and/or the biomarker profile. Part B3 will not proceed prior to generation of data 
from the initial CPI experienced indication(s).
Patients enrolled in Part B expansions have more specific limitations of prior therapies for 
inclusion than during the dose escalation. Patients enrolled in Part B1 (CPI experienced 
melanoma) must have had treatment with approved anti-PD-L1/anti-PD-1 checkpoint inhibitors. 
Patients enrolled in Part B2 (CPI and platinum experienced, PD-L1 expression 1% NSCLC) 
must have had a checkpoint inhibitor and platinum chemotherapy. Patients enrolled in Part B3 
(untreated, CIT naïve NSCLC with PD-L1 expression 50%) should not have had any prior 
therapy. Patients enrolled in Part B4 (CPI naïve SCLC) and B5 (CPI-naïve ESCC) should not 
have had any prior checkpoint inhibitor therapy but may have had chemotherapy. Specific 
details for Part B Expansions are included in the Inclusion and Exclusion Criteria.
In Part B (tumor specific expansion cohorts) approximately 
 participants will be included per 
indication. Part B cohorts may run in parallel staggered or sequentially.


RO7121661—F. Hoffmann-La Roche Ltd
16/Protocol NP40435, Version 5
Parts A and B
Participants will be treated with RO7121661 until disease progression, unacceptable toxicities, 
or withdrawal of consent. Participants may continue treatment with RO7121661 for 24 months
or longer if the participant is still benefitting from treatment at the time of the last visit at 
the end of the two-year period. As with other immunotherapies, treatment beyond progressive 
disease according to RECIST Version 1.1 can be considered after consultation and agreement 
between the Sponsor and Investigator.
Length of Study
The duration of the study for each participant will be up to 27 months (Parts A and B), divided 
as follows:
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 (7) days after last treatment with RO7121661 for Part A; 90 (.7) days 
after last treatment with RO7121661 for Part B.
Survival follow-up: 90 (7) days after last treatment with RO7121661; then every 3 months (2 
weeks) for total 24-month study period after initial dose.
The treatment period may be prolonged past month 24 if the participant is still benefitting 
from treatment at the time of the last visit at the end of the two-year period. Participants may 
extend treatment within the ongoing study whether they are on treatment or are on a 
treatment pause at the 24-month time point. During the extended treatment period, the 
participant follows the schedule of assessments as indicated for “Subsequent Cycles.” 
Participants will be treated until disease progression, unacceptable toxicities, or withdrawal 
of consent. For participants who extend their treatment, the safety follow-up will be 
performed 60 (7) days for Part A or 90 (7) days for Part B after the last treatment with 
RO7121661 and survival follow-up every 3 months (2 weeks) thereafter for a total of 48 
months after initial dose, or end of the study.
End of Study
The end of the study is defined as the last participant’s last visit (LPLV) per protocol (includes 
the safety follow-up visit 60 days (Part A) or 90 days (Part B) after last dose of study drug) or 
the date at which the last data point from the last participant required for statistical analysis is 
received (last participant, last observation), whichever is the latest date. Because of the 
exploratory nature of this clinical study, any part of its conduct can be discontinued at any time 
at the discretion of the Sponsor.
Data Monitoring Committee: In Part A, ongoing medical data review will be performed and 
regular teleconferences with participation of investigators and key representatives of the 
Sponsor will be scheduled. In Part B, a Joint Monitoring Committee (JMC) will monitor 
participants’ safety. The JMC will consist of designated Sponsor personnel and independent 
clinical expert(s) (i.e., expert[s] independent from the Sponsor).
PARTICIPANT POPULATION
The study population consists of male and female participants with advanced and/or metastatic 
solid tumors.
Inclusion Criteria
General Inclusion Criteria for Parts A and B
Participants are eligible to be included in the study only if all of the following criteria apply prior 
to dosing on Cycle 1, Day 1.
Informed Consent
1.
Signed written informed consent and ability to comply with the study protocol according to 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and local regulations.


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Age
2.
Age 18 years.
Type of Participants and Disease Characteristics
3.
For Part A only: Patients with advanced and/or metastatic solid tumors who have 
progressed on a cancer therapy, for whom no effective standard therapy exists, or who 
decline treatment with approved therapies.
4.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and a life 
expectancy of 12 weeks.
5.
Adequate cardiovascular function:

New York Heart Association (NYHA) Heart Failure Stage 2.

Baseline-corrected QT (QTcF) interval 470 ms.

Resting systolic blood pressure 150 mmHg and diastolic blood pressure 100 
mmHg (average of 3 readings on 2 sessions with short break between 
sessions) (no clinically significant hypertension).

Resting heart rate (HR) between 45-100 bpm (no clinically significant tachycardia).
6.
Adverse events from any prior radiotherapy, chemotherapy, or surgical procedure must have 
resolved to Grade 1, except alopecia (any grade), vitiligo, endocrinopathy managed with 
replacement therapy and Grade 2 peripheral neuropathy.
7.
Adequate hematological function: neutrophil count of 1.5 109 cells/L (1500/l), platelet 
count of 100 109/L (100,000/L), hemoglobin 9 g/dL (90 g/L), lymphocyte count 
of 0.5 109 cells/L (500/L).

Hemoglobin must be stable for at least a week without need for packed red blood 
cell transfusion.
8.
Adequate liver function: total bilirubin 1.5 ULN; aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), and alkaline phosphatase 2.5 ULN; with the following 
exceptions:

Participants with known Gilbert disease or hepatocellular carcinoma: serum 
bilirubin level 3 ULN.

Participants with documented liver metastases: AST and ALT 5 ULN.

Participants with documented liver or bone metastases: ALP 5 ULN.
9.
Adequate renal function: serum creatinine 1.5 ULN or creatinine clearance by 
Cockcroft-Gault formula 50 mL/min for participants in whom, in the Investigator‘s judgment, 
serum creatinine levels do not adequately reflect renal function. Cockcroft-Gault glomerular 
filtration rate estimation:
(140 age) (weight in kilograms) (0.85 if female)
72 (serum creatinine in mg/dL)
10. Additional adequate laboratory parameters obtained: 
o
Serum albumin 25 g/L (2.5 g/dL).
o
For participants not receiving therapeutic anticoagulation: Prothrombin time (PT) 
and activated partial thromboplastin time (aPTT) 1.5 ULN or 2 ULN for 
participants with HCC.
o
For participants receiving therapeutic anticoagulation: stable anticoagulant 
regimen.
11. Negative HIV test at screening.
12. Negative hepatitis B surface antigen (HBsAg) test at screening.
13. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb 
test followed by a negative hepatitis B virus (HBV) DNA test at screening.


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
The HBV DNA test will be performed only for participants who have a positive total 
HBcAb test.
14. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test 
followed by a negative HCV RNA test at screening.
The HCV RNA test will be performed only for participants who have a positive HCV 
antibody test.
15. Diagnosis of locally advanced and/or metastatic solid tumors with radiologically measurable 
disease according to RECIST v1.1.

Previously irradiated lesions should not be counted as target lesions unless clearly 
progressed after the radiotherapy.

Participants must have at least one measurable lesion (target lesion [TL]) not 
intended to be biopsied. Lesions that are intended to be biopsied should not be 
counted as target lesions.
Contraception
16. Male and/or 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, symptom-thermal, 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, not breastfeeding, and at 
least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP).

WOCBP, who:

Agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of 1% per year during the 
treatment period and for at least 4 months after the final dose of RO7121661.

Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal occlusion, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and 
copper intrauterine devices.

Have a negative pregnancy test (blood) within the 7 days prior to the first study 
RO7121661 administration.
b). Male Participants

During the treatment period and for at least 4 months after the final dose of RO7121661, 
agreement to: 
o
Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that 
together result in a failure rate of 1% per year, with partners who are women of 
childbearing potential.

With pregnant female partners, remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures such as a 
condom to avoid exposing the embryo.
o
Refrain from donating sperm during this period.


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Specific Inclusion Criteria for Biopsies
17. Participants who are enrolled on the parts of the study where fresh biopsies are requested 
(i.e. biomarker cohort(s) and expansion cohorts B1, B2, B3, B4 and B5) must have at least 
one non-target tumor lesion accessible to biopsy per clinical judgment of the treating 
physician and consent to undergo mandatory fresh baseline and on-treatment biopsy. 
Participants in Part B, presenting with only one target lesion and no non-target lesions that 
can be biopsied may omit mandatory biopsies. In such cases, the Medical Monitor is 
available to the Investigator to advise and answer any questions in this regard. A lesion 
with evidence of progression by imaging (or measurement for cutaneous lesions) is 
preferred if it can be assessed accurately. Bone lesion biopsies, bronchoscopy/trans-
bronchial biopsies, and cytology fine needle aspirates are not acceptable.
Specific Inclusion Criteria for Part B Expansion in CPI Experienced Patients
CPI experienced patients are defined in this study as those who have had prior treatment with 
an anti-PD-1 or anti-PD-L1 agent.  Participants must meet the following additional criteria to be 
eligible for inclusion in Part B of the study if they are CPI experienced.
18. Participants with advanced and/or metastatic malignancies who have progressed on an 
anti-PD-L1/anti-PD-1 agent.
19. Participants who are considered to be deriving benefit from treatment beyond progression, 
as per clinical judgment, are not considered eligible. Screening tumor assessment should 
confirm progression.
20. Prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may have been 
administered as indicated for the respective indications, with the exception of adjuvant 
therapy.
Melanoma Cohort (CPI-Experienced; Part B1)
21. Participants with histologically confirmed advanced or metastatic melanoma previously 
treated with approved anti-PD-L1/anti-PD-1 agents with or without approved anti-CTLA-4 
therapy and up to one additional treatment regimen.

Eligibility of participants receiving previous treatment with non-approved anti PD-1 or 
anti-PD-L1 inhibitors or combination treatment with other non-approved agent(s) may be 
discussed with the Medical Monitor prior to enrollment. The decision to enroll the 
patient in the study is the responsibility of the Investigator.
22. Participants whose tumors have a known BRAFV600 mutation must also have experienced
disease progression (during or after treatment) or intolerance with BRAF inhibitor(s) and/or 
MEK inhibitor(s) if treatment is available. Participants with BRAFV600 mutation but refusing 
such inhibitor(s), or not available to them, will be eligible.
23. Enrollment will be managed so that:

No more than approximately 10% of participants in this cohort will be participants with 
ocular (uveal) melanoma.

Up to 10 patients with primary resistance to CPI will initially be enrolled. This may be 
expanded if efficacy and or biomarker assessments for proof of mechanism warrant 
further exploration.
–
Primary resistance is defined as Investigator assessed best overall response of 
progressive disease within the first 10 weeks of anti-PD-L1/anti-PD-1 treatment.

If a scan within the first 10 weeks exists and shows progressive disease 
the patient is considered primary resistant (i.e. the scan result cannot be 
overruled by investigator assessment of clinical benefit). 

Should a subsequent scan for the same line of treatment show clinical 
benefit after initial radiographic progression (i.e. pseudoprogression) the 
patient is not considered primary resistant.


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20/Protocol NP40435, Version 5
NSCLC Cohort (CPI-Experienced; Part B2)
24. Participants with histologically confirmed advanced NSCLC previously treated with 
approved PD-L1/PD-1 inhibitors and platinum based chemotherapy, either sequentially or 
concurrently.

Eligibility of participants receiving previous treatment with non-approved anti PD-1 or 
anti-PD-L1 inhibitors or combination treatment with other non-approved agent(s) may be 
discussed with the Medical Monitor prior to enrollment. The decision to enroll the 
patient in the study is the responsibility of the Investigator.
25. Patients must be PD-L1 () defined as 1% PD-L1 expression based on 
immunohistochemistry using antibody clone 22c3, sp263 or 28-8. Expression will be 
determined in a fresh tumor biopsy collected during study screening or a possibly available 
archival sample, provided that the latter is not older than 12 months and has been obtained 
after failure of last CPI treatment line and prior to receiving study treatment.
26. Participants must have experienced Investigator assessed initial clinical benefit (stable 
disease or better) from most recent CPI therapy for at least 4 months. 

If a scan within the first 4 months exists and shows progressive disease the patient is 
not eligible (i.e. the scan result cannot be overruled by Investigator assessment of 
clinical benefit). 

Should a subsequent scan for the same line of treatment show clinical benefit after 
initial radiographic progression (i.e. pseudoprogression) the patient is eligible.
27. Patients should have had only one CPI and one platinum based regimen, whether 
sequentially or concurrently. The acceptable sequences are:

Platinum-based chemotherapy (1L) CPI treatment (1L); i.e., study treatment is 
second line therapy

Platinum-based chemotherapy (1L) CPI treatment (2L); i.e., study treatment is third 
line therapy

CPI treatment (1L) Platinum-based chemotherapy (2L); i.e., study treatment is third 
line therapy
–
Adjuvant chemo-radiation treatment with anti-PD-1/PD-L1 inhibitors or 
consolidation treatment with anti-PD-1/PD-L1 after definitive chemo-radiation 
therapy is allowed but participants do require an additional line of anti-PD-1/PD-L1 
treatment in the metastatic setting. 
Specific Inclusion Criteria for Part B3 Expansion in PD L1 High, CPI Naïve, First Line
NSCLC Cohort
28. Participants with histologically confirmed advanced NSCLC with PD-L1 high defined 
as 50% PD-L1 expression based on immunohistochemistry using antibody clone 22c3, 
sp263 or 28-8. Expression will be determined in a fresh tumor biopsy collected during study 
screening or a possibly available archival sample, provided that the latter is not older than 
12 months and has been obtained after failure of last CPI treatment line and prior to 
receiving study treatment.
Specific Inclusion Criteria for Part B4 Expansion in CPI-Naïve SCLC Cohort
29. Participants must have histologically confirmed SCLC.
30. Participants may have had prior chemotherapy, radiation therapy or declined approved 
therapies for SCLC.


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Additional Inclusion Criteria for Part B5: CPI Naïve Esophageal Squamous Cell 
Carcinoma
31. Participants whose major lesion was histologically confirmed squamous cell carcinoma or 
adenosquamous cell carcinoma of the esophagus.
32. Patients who have previously received not more than 1 prior lines of treatment for 
metastatic disease prior to enrolling to the study. The prior line must be a fluoropyrimidine 
and platinum-based regimen and patients must have experienced progressive disease.
33. Patients who underwent a radical resection (R0 resection confirmed) in conjunction with 
chemotherapy with fluoropyrimidine and platinum-based drugs including neo-
adjuvant/adjuvant therapy and chemo-radiation (including patients who underwent chemo-
radiation followed by salvage surgery) are allowed. 

If recurrence was confirmed by imaging within 24 weeks after the last dose of the 
treatment, the therapy should be counted as equivalent to metastatic treatment. Such 
patients are eligible and do not require an additional line of therapy in the metastatic 
setting.

If recurrence occurred later than 24 weeks after the completion of the initial neo-
adjuvant/adjuvant therapy the patients need to be exposed to an additional line of 
fluoropyrimidine and platinum-based drugs in the metastatic setting to be eligible for the 
study - unless the investigator considers the patient not eligible for the re-exposure with 
fluoropyrimidine and platinum-based drugs.
Exclusion Criteria
General Exclusion Criteria for Parts A and B
Participants are excluded from the study if any of the following criteria apply prior to dosing on 
Cycle 1, Day 1:
1.
Pregnancy, lactation, or breastfeeding.
2.
Known hypersensitivity to any of the components of RO7121661, including but not limited to 
hypersensitivity to Chinese hamster ovary cell products or other recombinant human or 
humanized antibodies.
Medical Conditions
3.
Known symptomatic central nervous system (CNS) metastases.

Participants with previously treated brain metastases may participate provided they:

Are stable (without evidence of progression by CT or MRI for at least 4 weeks prior to 
Cycle 1/Day 1).

Have no evidence of new or enlarging brain metastases within at least 4 weeks from 
Cycle 1/Day 1.

Are off systemic steroids for at least 28 days prior to Cycle 1/Day 1
4.
Spinal cord compression not definitively treated with surgery and/or radiation or without 
evidence that disease has been clinically stable for 2 weeks before Cycle 1/Day 1.
5.
Active or history of carcinomatous meningitis/leptomeningeal disease. Known asymptomatic
CNS primary tumors or metastases if they have requirement for steroids or 
enzyme-inducing anticonvulsants in the last 28 days prior to Cycle 1/Day 1 screening.
6.
Participants with an active second malignancy. Concurrent malignancy exceptions include: 
curatively treated carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of 
the breast, basal- or squamous-cell skin cancer, Stage I melanoma, or low-grade, 
early-stage localized prostate cancer and any previously treated early stage non-
hematological malignancy that has been in remission for at least two years.
7.
Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results, including diabetes mellitus, history of relevant 
pulmonary disorders, and known autoimmune diseases or immune deficiency, or other 


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disease with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, 
neurofibromatosis, palmar/plantar fibromatosis, etc.).
8.
Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
9.
Severe dyspnea or requiring supplemental oxygen therapy at rest.
10. Significant cardiovascular/cerebrovascular vascular disease within 6 months prior to Day 1 
of study drug administration, including any of the following:

hypertensive crisis/encephalopathy

unstable angina

transient ischemic attack/stroke

congestive heart failure (for NYHA classification, refer to inclusion criteria)

serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, 
paroxysmal supraventricular tachycardia)

history of thromboembolic events (such as myocardial infarction, stroke or pulmonary 
embolism)
11. Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited 
to tuberculosis [TB] and typical mycobacterial disease), parasitic, or other infection 
(excluding fungal infections of nail beds) or any major episode of infection requiring 
treatment with IV antibiotics or hospitalization (relating to the completion of the course of 
antibiotics, except if for tumor fever) within 4 weeks prior to the start of drug administration.
12. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease.
13. Major surgical procedure or significant traumatic injury (excluding biopsies) within 28 days 
prior to Cycle 1, Day 1 (i.e., first RO7121661 infusion), or anticipation of the need for major 
surgery during the course of the study.
14. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
render the participant at high risk from treatment complications.
15. Dementia or altered mental status that would prohibit informed consent.
16. Uncontrolled pleural effusion (with the exception of participants with indwelling catheters, 
e.g. PleurX), pericardial effusion, or ascites requiring recurrent drainage procedures 
(expected to occur once monthly or more frequently). 
17. Active or history of autoimmune disease or immune deficiency, including, but not limited to, 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple 
sclerosis, with the following exceptions:

Participants with a history of autoimmune-mediated hypothyroidism or endocrinopathy 
who are on thyroid-replacement hormone or appropriate replacement therapy are 
eligible for the study.

Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study.

Participants with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met:

Rash must cover 10% of body surface area

Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids


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
No occurrence of acute exacerbations of the underlying condition requiring psoralen 
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin 
inhibitors, or high-potency or oral corticosteroids within the previous 12 months
Prior/Concomitant Therapy
18. Vaccination with live vaccines within 28 days prior to the start of treatment.
19. For Part A Part B1 (CPI experienced melanoma patients) and B2 (CPI and platinum 
experienced NSCLC patients), prior treatment with CPIs, immunomodulatory monoclonal 
antibodies (mAbs), and/or mAb-derived therapies is allowed, with the following exceptions:

4 weeks have elapsed between the last dose of prior anti-PD-1 and the proposed 
Cycle 1, Day 1

5 half-lives or 28 days (whichever is shorter) have elapsed from prior treatment with 
specific immunomodulators, TLR agonists, inhibitors of IDO/TDO, or agonists (e.g., 
OX40)

Prior treatment with adoptive cell therapies, such as CAR-T therapies is not permitted
20. Prior treatment with a TIM-3 inhibitor is prohibited.
21. Concurrent therapy with any other investigational drug (defined as treatment for which there 
is currently no regulatory authority-approved indication) 28 days or 5 half-lives of the 
drug, whichever is shorter, prior to the first RO7121661 administration on Cycle 1, Day 1 is 
prohibited.
22. Immuno-modulating agents:

Last dose with any of the following agents, for example, etanercept, infliximab, 
tacrolimus, cyclosporine, mycophenolic acid, alefacept, or efalizumab (or similar 
agents) 28 days prior to Cycle 1, Day 1 is prohibited.

Regular immunosuppressive therapy (i.e., for organ transplantation, chronic 
rheumatologic disease) is prohibited.
23. Chronic use of steroids (excluding topical and inhaled) and concurrent high doses of 
systemic corticosteroids will not be allowed. Participants receiving baseline corticosteroid 
therapy (10 mg prednisone/day or equivalent) within 1 week prior to the first dose of study 
drug are excluded.
24. Radiotherapy within the last 4 weeks before start of study drug treatment is not allowed, 
with the exception of limited palliative radiotherapy.
25. Enrollment of participants who require blood transfusion (before and after the start of the 
study) is at the discretion of the Investigator. The Medical Monitor/Sponsor is available 
to the Investigator to advise and answer any question as needed.
Specific Exclusion Criteria for Part B1 and Part B2 Expansion cohorts (CPI experienced 
patients)
26. Any history of an immune-mediated Grade 4 adverse event attributed to prior cancer 
immunotherapy (other than endocrinopathy managed with replacement therapy or 
asymptomatic elevation of serum amylase or lipase)
27. Any history of an immune-mediated adverse event attributed to prior CIT (other than 
endocrinopathy managed with replacement therapy or asymptomatic elevation of serum 
amylase or lipase) that resulted in permanent discontinuation of the prior 
immunotherapeutic agent.
28. All immune-mediated adverse events related to prior immunomodulatory therapy (other 
than endocrinopathy managed with replacement therapy or stable vitiligo) must have 
resolved completely to baseline. Participants treated with corticosteroids for immune-
mediated adverse events except for corticosteroids replacement therapy for adrenal 
insufficiency (provided that the patient receives 10 mg prednisone/day or equivalent), 


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must demonstrate absence of related symptoms or signs for 4 weeks following 
discontinuation of corticosteroids.
Specific Exclusion Criteria for Part B3 Expansion (1st line CIT naïve patients)
29. Prior therapy for metastatic disease is not permitted i.e., treatment with any immune CPIs 
(such as anti PD L1/PD 1, CTLA 4), immunomodulatory mAbs, other immunomodulator 
therapies, chemotherapy or TKIs.
30. Adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed. Adjuvant chemotherapy is 
permitted as long as treatment was administered 6 months prior to Cycle 1, Day 1.
Specific Exclusion Criteria for NSCLC patients (Part B2)
31. NSCLC patients with the following mutations, rearrangements, translocations are not 
eligible for Part B2: EGFR; ALK; ROS1, BRAFV600E, NTRK
Specific Exclusion Criteria for Part B4 Expansion (CPI-naïve SCLC patients)
32. Prior therapy with any immune CPIs (such as anti-PD-L1/PD-1, anti-CTLA-4), is not 
permitted.
Specific Exclusion Criteria for Part B5: CPI Naïve Esophageal Squamous Cell Carcinoma
33. Prior therapy with any immunomodulatory agents including CPIs (such as anti-PD-L1/PD-1, 
anti-CTLA-4), is not permitted.
NUMBER OF PARTICIPANTS
The maximum planned enrollment for this study is approximately 270-280 participants for both 
Parts A and B.
For the dose escalation stage in Part A, up to 
 DLT evaluable participants are planned for the 
Q2W schedule with an additional 
 participants if confirmation of safety, PK, RO and/or 
biomarkers are needed prior to opening Part B cohorts. The exact sample size cannot be pre-
determined and depends on the number of cohorts needed to reach the MTD/RDE with the 
maximum planned dose set at 2.1 g.
Up to approximately 
participants may be enrolled in the expansion stages across the 
indication-specific cohorts in Part B.
CONCOMITANT MEDICATIONS
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 can advise if there are any questions regarding concomitant or 
prior therapy.
All concomitant medications or vaccines should be reported to the Investigator and recorded on 
the Concomitant Medications electronic Case Report Form (eCRF). All therapy and/or 
medication administered to manage adverse events should be recorded on the Adverse Event 
eCRF.
Radiotherapy 
The use of limited field palliative radiotherapy is allowed at any time during the study, except 
for: 

Days where RO7121661 is administered. 

During the DLT evaluation window. 
–
If radiotherapy is administered during the DLT evaluation window, the participant will 
not be evaluable. 


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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 and therapy for pre-existing conditions, unless the 
rationale for exception is discussed and clearly documented.
Use of the following therapies is prohibited during the study and for at least 28 days or 
5 half-lives of the drug, whichever is shorter, prior to initiation of study treatment, unless 
otherwise specified below:
Investigational or unlicensed/unapproved agents 
Immunotherapy/radio-immunotherapy 
Chemotherapy / targeted therapy
Radiotherapy (with the exception of limited field palliative radiotherapy). 
Biologic agents (e.g., bevacizumab, cetuximab). 
Chronic use of steroids (inhaled and topical steroids are permitted) at baseline of 10 mg of 
prednisone/day (or equivalent). Concurrent high doses of systemic corticosteroids will not be 
allowed.
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.




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Table 1
Schedule of Activities: Q2W regimen for Part A and B1, 2, 3, 4, and 5
Q2W regimen Cycle length 14 days
Screening
Subsequent 
cycles
Study 
Completion/Early 
Termination Visit12
 Safety Follow up Visit Survival Follow up Visit13
 Unscheduled Safety  
Day
Up to 28 
Days
1
2
3
5
(+/- 1)
1
2
5
(+/- 1)
1
28 (+/-7) days after 
last dose
60 (+/-7) days (Part A), 
90 (+/- 7) days (Part B) 
post last dose
90  (+/-7) days post last 
dose, then every
3 months (+/- 2wks)
e.g. In the event of an IRR 
or hypersensitivity event 
≥G2 or AE leading to dose 
reduction or delay
Time Relative (h)
0
24
48
96
0
24
96
0
***
***
***
***
Assessments
Informed Consent 1
x
Review Eligibility Criteria
x
Demography
x
Medical History
x
Royal Marsden Risk Score
x
Previous and Concomitant Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
Cancer History
x
Physical Exam 2,4
x
x
x
x
x
x
x
Vital Signs 2, 14
x
x
x
x
x
x
x
x
x
x
x
x
ECOG Performance Status2
x
x
x
x
x
x
Triplicate ECG 12-Lead 2 . 3
x
x
x
x
x
x
x
Adverse Events 5
x
x
x
x
x
x
x
x
x
x
x
x
x
RO7121661 administration 
x
x
x 
Tumor Assessment 6
x
x6
x6
Local Laboratory Assessments 2
Coagulation 9
x
x
x
x9
x
x
x
Immunology 15
x
TSH, free T3 (or total T3), and free T4 16
x
x16
x
Auto Antibody Panel 7
x
x7
x
Viral Serology 8
x
Hematology
x
x
x
x
x
x
x
x
x
x
x
x
Blood chemistry
x
x
x
x
x
x
x
x
x
x
x
x
Lipid Panel 10
x
x
x10
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
Pregnancy Test 11
x
x
x11
x
x
Central Laboratory Assessments
PK RO7121661
ADA to RO7121661
Receptor Occupancy 
PD Plasma
PD Serum
IgE/Tryptase
PD Whole Blood Flow Cytometry
Whole Blood RNA
bTMB
ctDNA
Archival Tumor Sample
Fresh Tumor Biopsy 
RBR Sample (Saliva DNA)
Refer to Hourly Schedule of Assessments for specific Sample Collection Timepoint Details
Cycle 1
Cycles 2


RO7121661—F. Hoffmann-La Roche Ltd
28/Protocol NP40435, Version 5
Table 1
Schedule of Activities: Q2W regimen for Part A and B1, 2, 3, 4, and 5 (cont.)
1.
Informed consent must be obtained before any study-specific procedures. (Note: A separate consent form is required for RBR testing). 
Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be 
used and such tests do not need to be repeated for screening.
2.
If indicated assessments are performed within 72 hours before dosing days, the assessments do not have to be repeated on the first day 
of that cycle. If performed on the day of study drug administration they must be done PRIOR to study drug administration.  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.
3.
Triplicate 12-lead ECG recordings (i.e., 3 qualitatively acceptable ECGs without artifacts) must be obtained at screening, at pre-infusion, 
end of infusion (EOI) and within windows provided at each specified time-point. Patients should be resting and in a supine position for at 
least 10 minutes prior to each ECG collection.  Unscheduled 12-lead ECGs are ONLY REQUIRED as clinically indicated, e.g. there is 
evidence of QT prolongation on previous ECG assessments. In addition, single ECGs will be recorded in the case of an IRR. Recording 
must be done prior to PK sampling.  
4.
Complete physical exam (including weight and height at screening only) must be performed during screening, Day 1 of each treatment 
cycle before study treatment administration, at any unscheduled safety visit, and at study treatment discontinuation, and at the 60-day
(Part A) / 90-day (Part B) safety follow‑up. At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Any abnormality identified at baseline should be recorded on the General Medical History and 
Baseline Conditions eCRF. 
5.
Adverse Events: After initiation of study drug, all AEs and SAEs, regardless of attribution, must be reported until study completion or 
patient discontinuation, whichever is later. After this period, investigators should report only SAEs that are believed to be related to prior 
treatment with study drug.  Serious adverse events occurring after signature of informed consent but prior to the first infusion of study 
treatment are reportable according to local regulations. Serious adverse events related to study procedures are reportable following 
signature of informed consent. For serious adverse events (SAEs) prior to first dose, a corresponding AE page should also be completed.
6.
Tumor assessments will include contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) of the chest, 
abdomen, and pelvis as well as the site of the primary tumor (if applicable). Measurable lesions will be assessed at Screening and then 
every 8 weeks ( 7 days) after Cycle 1, Day 1 for the first year; and every 12 weeks ( 7 days) thereafter until disease progression or 
treatment discontinuation (whichever occurs last), initiation of a new line of therapy or death.  Tumor assessments performed as standard 
of care prior to obtaining informed consent and within 28 days of Cycle 1, Day 1 may be used as the screening tumor assessment rather 
than repeating the scans. Evaluation of tumor response will be based on RECIST v1.1 criteria (see Appendix 7). Every time a tumor
assessment is done, a PD Serum sample should be collected. 


RO7121661—F. Hoffmann-La Roche Ltd
29/Protocol NP40435, Version 5
Table 1
Schedule of Activities: Q2W regimen for Part A and B1, 2, 3, 4, and 5 (cont.)
7.
The auto-antibody panel will be assessed at Screening, pre-dose Cycles 3 and 9, and every 6 cycles thereafter. In participants who 
develop signs and/or symptoms suggestive of auto-immune disease while on-treatment, the auto-antibody panel (anti-nuclear antibody, 
anti−double-stranded deoxyribonucleic acid (DNA), circulating anti-neutrophil cytoplasmic antibody [cANCA], and perinuclear anti 
neutrophil cytoplasmic antibody [pANCA]) should be repeated. Patients with confirmed positive serology of at least one of the auto-
antibody panel during the course of the study should be discussed between Sponsor and Investigators, and if judged clinically relevant, 
could be referred to a specialist to exclude an underlying auto-immune disease.
8.
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 RO7121661.
9.
Coagulation sampling (including prothrombin time [PT], international normalized ratio [INR], and activated partial prothrombin time [aPTT]) 
will be performed at the specified time-points (prior to dosing). After Cycle 6, coagulation sampling will be performed at every visit when
tumor assessment is performed. Additional coagulation parameters (i.e., anti-thrombin III, fibrinogen, PT, fibrin degradation products, D-
dimer) maybe be assessed according to clinical judgment.
10. Lipid panel is to be obtained at Screening, Cycle 1, Day 1 and then every 8 weeks (7 days) after Cycle 1/Day 1 and at indicated time-
points.
11. Serum pregnancy test at screening, within 7 days prior to first dose, every cycle (urine or serum), discontinuation visit, and at the safety 
follow-up visit; a urine or serum pregnancy test will be performed. If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. Results must be obtained and reviewed prior to administration of RO7121661.  Unscheduled pregnancy test (urine or 
serum) can be done anytime during the study if clinically indicated. 
12. Participants who discontinue will be asked to return to the clinic for an early termination visit within 28 ( 7) days after the last dose.  In 
some instances, the visit at which a response assessment shows progressive disease may be used as the early termination visit. 
Alternatively, the study completion visit may be completed at the end of study if a participant remains on a treatment pause to that day.
13. Survival follow-up visit to be performed 90 ( 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 up to 24 months (48 months for the extended treatment period) from 1st dose 
for overall survival. For participants in Part B, the safety follow-up visit will occur on the same day as the first survival follow-up visit. Post-
study anti-cancer therapies should be collected and reported as appropriate in the electronic case report form (eCRF).


RO7121661—F. Hoffmann-La Roche Ltd
30/Protocol NP40435, Version 5
Table 1
Schedule of Activities: Q2W regimen for Part A and B1, 2, 3, 4, and 5 (cont.)
14. Vital signs include measurements of heart rate, respiratory rate, systolic and diastolic blood pressures (while the patient is in a supine 
position), and temperature. For each visit, only those vital signs that are obtained prior to study drug administration or that constitute an 
adverse event (e.g., temperature for event of fever) or a primary manifestation of an adverse event (e.g., blood pressure associated with 
an infusion-related reaction or heart rate associated with an arrhythmia) should be recorded in the eCRF.
15. At Screening, an immunology sample will be taken for quantitative immunoglobulins (Ig): IgA, IgG, IgM, and IgE.
16. TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 3 and 
every three cycles thereafter (i.e., Cycle 6/ Day 1; Cycle 9/ Day 1; Cycle 12, Day 1; Cycle 15, Day 1; Cycle 18, Day 1; etc.). An 
endocrinologist should be consulted if an endocrinopathy is suspected.


RO7121661—F. Hoffmann-La Roche Ltd
31/Protocol NP40435, Version 5
Table 2
Schedule of Activities: Q2W regimen for Part A; hourly
Q2W regimen 
Cycle length 14 
days
Day
Scheduled 
Time (h)a
Time 
Window
Vital Signsb
Triplicate 
ECG - 12 
Leadc
Hematology
Blood 
Chemistry
PK 
Sampled
ADA 
RO7121661e
Receptor 
Occupancy 
PD 
Serum l
PD 
Plasma 
IgE/ 
Tryptaseg
WGS k
Archival 
Tumor 
Samplef
Fresh Tumor 
Biopsy h
RBR Saliva 
DNA 
Optional i
Screening
x
x
x
x
x
x
PreDose
-4h
x
x
x
x
x
x
x
x
x
x
x
1/2 EOI
+/- 5 min
x
x
EOI
+ 10  min
x
x
x
x
x
x
x
0.5
+/- 10 min
x
2
+/- 15 min
x
x
x
4
+/- 1 h
x  
x
x
8
+/- 1 h
x
x
x
Day 2
24
+/- 2 h
x
x
x
x
x
x
Day 3
48
+/- 2 h
x
x
x
x
x
Day 5
96
+/- 24 h
x
x
x
x
x
Day 8
168
+/- 24 h
x
x
x
x
Day 12
264
+/- 24 h
x
x
PreDose
-4h
x  
x
x
x
x
x
x
x
x
EOI
+ 10  min
x  
x
x
4
+/- 1 h
x
x
Day 2
24
+/- 2 h
x
x
x
x
Day 5
96
+/- 24 h
x
x
x
x
PreDose
-4h
x  
x
x
x
x
x
x
x
x
x
EOI
+ 10  min
x 
x
x
EOO
+/- 15 min
x
PreDose
-4h
x  
x
x
x
x
x
x
EOI
+ 10  min
x  
x
x
EOO
+/- 15 min
x
PreDose
-4h
x  
x
x
x
x
x
x
x
x
1/2 EOI
+/- 5 min
x
EOI
+ 10  min
x  
x
x
x
2
+/- 15 min
x
Day 2
24
+/- 2 h
x
x
Day 5
96
+/- 24 h
x
Day 8
168
+/- 24 h
x
x
x
Cycle 4
Day 1
Day 1
Cycle 3
Day 1
Cycle 2
Day 1
Cycle 1
Cycle 5
Day 1


RO7121661—F. Hoffmann-La Roche Ltd
32/Protocol NP40435, Version 5
Table 2
Schedule of Activities: Q2W regimen for Part A; hourly (cont.)
a)
Assessments should be performed relative to RO7121661 infusion. When not specified, assessments should be performed relative to the end
of the RO7121661 infusion.
b)
Vital signs include measurements of heart rate, respiratory rate, systolic and diastolic blood pressures (while the participant is in a seated or 
supine position), and temperature. For the first infusion of RO7121661, measure vital signs within 60 minutes before the infusion, every 15 
( 5) minutes during the infusion and at the time-points specified or if clinically indicated. For subsequent infusions, measure vital signs within 
60 minutes before the infusion, during the infusion if clinically indicated and at the time-points specified or if clinically indicated. For each visit, 
only those vital signs that are obtained prior to study drug administration or that constitute an adverse event (e.g., temperature for event of 
fever) or a primary manifestation of an adverse event (e.g., blood pressure associated with an infusion-related reaction or heart rate associated 
with an arrhythmia) should be recorded in the eCRF. Vital signs to be taken on Day 2 of Cycle 6 through Cycle 9 as noted on Main SOA Table.
c)
Triplicate 12-lead ECG recordings (i.e., 3 qualitatively acceptable ECGs without artifacts) must be obtained at screening, at pre-infusion, EOI
and at the time-points specified. Three individual ECG tracings should be obtained as closely as possible in succession, but no more than 5 
minutes apart. Additional unscheduled ECG assessments should be performed in case of abnormalities and if clinical symptoms occur. 
Recording must be done prior to PK sampling.
d)
Blood for PK of RO7121661 and for PD should be drawn at the indicated time-points relative to the end of the RO7121661 infusion. During the 
course of the study, PK/PD sampling time-points may be modified based on emerging data to ensure the PK/PD of RO7121661 can be 
adequately characterized. When more than one blood draw assessment at the same time point is required it should be taken in the order of 
safety, PK, ADA, then PD.
Q2W regimen 
Cycle length 14 
days
Day
Scheduled 
Time (h)a
Time 
Window
Vital Signsb
Triplicate 
ECG - 12 
Leadc
Hematology
Blood 
Chemistry
PK 
Sampled
ADA 
RO7121661e
Receptor 
Occupancy
PD 
Serum
PD 
Plasma
IgE/ 
Tryptaseg
WGS k
Archival 
Tumor 
Samplef
Fresh Tumor 
Biopsy h
RBR Saliva 
DNA 
Optional i
PreDose
-4h
x  
x
x
x
x
x
x j
x l
x j
EOI
+ 10  min
x  
x
x
EOO
+/- 15 min
x
In the event of 
an IRR or 
hypersensitivity 
event ≥G2 or AE 
leading to dose 
reduction or 
delay
x
x
x
x
x
x
x
x
Study 
Completion/Early 
Termination Visit
At Visit
x
x
x
x
x
x
x
x
x
 Safety Follow 
up Visit (60d Part 
A; 90d Part B)
At Visit
x
x
x
x
x
x
x
x
x
Unscheduled 
Visits
At Visit
x
x
x
x
x
x
x
Subsequent 
Cycles
Day 1


RO7121661—F. Hoffmann-La Roche Ltd
33/Protocol NP40435, Version 5
Table 2
Schedule of Activities: Q2W regimen for Part A; hourly (cont.)
e)
Blood for ADA determination of RO7121661 should be taken at indicated time-points up to Cycle 5. Thereafter, blood for ADA determination of 
RO7121661 will be taken at Cycle 7, Day 1, and every 6 cycles afterwards (Cycle 13, Cycle 19, Cycle 25, etc.). Blood for ADA determination 
should always be taken pre-dose.
f)
Participants with confirmed availability of representative archival tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks 
(preferred) or unstained slides, with an associated pathology report.
g)
IgE and tryptase samples will be collected for central and local analysis if a participant experiences a Grade 2 IRR for the first time with the 
second or subsequent study drug infusion or with clinical signs of hypersensitivity reaction at any time of the conduct of the study. A second 
sample for central IgE/tryptase analysis will be collected approximately 48 hours after onset of the reaction.
h)
No biopsies are required in Part A dose escalation. If dose cohort is extended in Part A to confirm safety, PK and/or RO and/or the biomarker 
profile, then fresh tumor biopsies are mandatory for these additional participants, unless otherwise specified by the Sponsor. Screening sample 
should be collected after eligibility is confirmed. Post dose sample to be collected 2/1 day[s] from scheduled timepoint. 
i)
Samples for RBR DNA saliva will be collected on Day 1 from all participants who signed RBR ICF prior to study drug (RO7121661) infusion.  If 
the RBR DNA saliva sample is not collected during the scheduled visit, it may be collected at any time during the conduct of the clinical study.
j)
Drug RO and PD-Plasma samples will be collected at Cycles 9, 22, 35 and 48.
k)
If sample is missed on Cycle, 1 Day 1, it can be collected at any time during the conduct of the study.
l)
After Cycle 5 the PD Serum sample should be collected every time a tumor assessment is done (every 8 weeks (7 days) thereafter for the 
first year; and every 12 weeks (7 days) thereafter until disease progression, treatment discontinuation or death).


RO7121661—F. Hoffmann-La Roche Ltd
34/Protocol NP40435, Version 5
Table 3
Schedule of Activities: Q2W regimen for Part B1, 2, 3, 4 and 5; hourly
Q2W regimen 
Cycle length 14 
days
Day
Scheduled 
Time (h)a
Time 
Window
Vital Signsb
Triplicate 
ECG - 12 
Leadc
Hematology
Blood 
Chemistry
PK 
Sampled
ADA 
RO7121661e
PD 
Serum m
PD 
Plasma 
IgE/ 
Tryptaseg
Whole Blood 
Flow Cytometry h
Whole 
Blood 
RNA 
bTMB 
ctDNA 
WGS l
Archival 
Tumor 
Sample f
Fresh 
Tumor 
Biopsy j
RBR Saliva 
DNA 
Optional i
Screening
x
x
x
x
xk
xk
x
x
PreDose
-4h
x  
x
x
x
x
x
x
x
x
x
x
x
1/2 EOI
+/- 5 min
x
x
EOI
+ 10  min
x
x
x
x
x
x
0.5
+/- 10 min
x
2
+/- 15 min
x
x
x
4
+/- 1 h
x
x
x
8
+/- 1 h
x
x
x
Day 2
24
+/- 2 h
x
x
x
x
x
x
x
Day 3
48
+/- 2 h
x
x
x
x
x
Day 5
96
+/- 24 h
x
x
x
x
x
Day 8
168
+/- 24 h
x
x
x
x
Day 12
264
+/- 24 h
x
x
PreDose
-4h
x
x
x
x
x
x
x
x
x
EOI
+ 10  min
x
x
x
4
+/- 1 h
x
x
Day 2
24
+/- 2 h
x
x
x
x
Day 5
96
+/- 24 h
x
x
x
x
PreDose
-4h
x
x
x
x
x
x
x
x
x
xk
xk
xk
x
EOI
+ 10  min
x
x
x
EOO
+/- 15 min
x
PreDose
-4h
x
x
x
x
x
x
x
EOI
+ 10  min
x
x
x
EOO
+/- 15 min
x
PreDose
-4h
x
x
x
x
x
x
x
x
x
x
x
1/2 EOI
+/- 5 min
x
EOI
+ 10  min
x
x
x
2
+/- 15 min
x
Day 2
24
+/- 2 h
x
x
x
Day 5
96
+/- 24 h
x
Day 8
168
+/- 24 h
x
x
x
Cycle 4
Day 1
Day 1
Cycle 5
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 1


RO7121661—F. Hoffmann-La Roche Ltd
35/Protocol NP40435, Version 5
Table 3
Schedule of Activities: Q2W regimen for Part B1, 2, 3, 4 and 5; hourly (cont.)
a)
Assessments should be performed relative to RO7121661 infusion. When not specified, assessments should be performed relative to the end
of the RO7121661 infusion.
b)
Vital signs include measurements of heart rate, respiratory rate, systolic and diastolic blood pressures (while the participant is in a seated or 
supine position), and temperature. For the first infusion of RO7121661, measure vital signs within 60 minutes before the infusion, every 15 
( 5) minutes during the infusion and at the time-points specified or if clinically indicated. For subsequent infusions, measure vital signs within 
60 minutes before the infusion, during the infusion if clinically indicated and at the time-points specified or if clinically indicated. For each visit, 
only those vital signs that are obtained prior to study drug administration or that constitute an adverse event (e.g., temperature for event of 
fever) or a primary manifestation of an adverse event (e.g., blood pressure associated with an infusion-related reaction or heart rate associated 
with an arrhythmia) should be recorded in the eCRF. Vital signs to be taken on Day 2 of Cycle 6 through Cycle 9 as noted on Main SOA Table.
c)
Triplicate 12-lead ECG recordings (i.e., 3 qualitatively acceptable ECGs without artifacts) must be obtained at screening (within 7 days before 
first dose of RO7121661), at pre-infusion, EOI and at the time-points specified. Three individual ECG tracings should be obtained as closely as 
possible in succession, but no more than 5 minutes apart. Additional unscheduled ECG assessments should be performed in case of
abnormalities and if clinical symptoms occur. Recording must be done prior to PK sampling.
d)
Blood for PK of RO7121661 and for PD should be drawn at the indicated time-points relative to the end of the RO7121661 infusion. During the 
course of the study, PK/PD sampling time-points may be modified based on emerging data to ensure the PK/PD of RO7121661 can be 
adequately characterized. When more than one blood draw assessment at the same time point is required it should be taken in the order of 
safety, PK, ADA, then PD.
Q2W regimen 
Cycle length 14 
days
Day
Scheduled 
Time (h)a
Time 
Window
Vital Signsb
Triplicate 
ECG - 12 
Leadc
Hematology
Blood 
Chemistry
PK 
Sampled
ADA 
RO7121661e
PD 
Serum
PD 
Plasma 
IgE/ 
Tryptaseg
Whole Blood 
Flow Cytometry h
Whole 
Blood 
RNA
bTMB k
ctDNA k
WGS l
Archival 
Tumor 
Sample f
Fresh 
Tumor 
Biopsy j
RBR Saliva 
DNA 
Optional i
PreDose
-4h
x
x
x
x
x
x
x m
x h
x h
EOI
+ 10  min
x
x
x
EOO
+/- 15 min
x
In the event of an 
IRR or 
hypersensitivity 
event ≥G2 or AE 
leading to dose 
reduction or delay
x
x
x
x
x
x
x
x
Study 
Completion/Early 
Termination Visit
At Visit
x
x
x
x
x
x
x
x
x
 Safety Follow up 
Visit (60d Part A; 
90d Part B)
At Visit
x
x
x
x
x
x
x
x
x
Unscheduled 
Visits
At Visit
x
x
x
x
x
x
x
x
x
Day 1
Subsequent 
Cycles


RO7121661—F. Hoffmann-La Roche Ltd
36/Protocol NP40435, Version 5
Table 3
Schedule of Activities: Q2W regimen for Part B1, 2, 3, 4 and 5; hourly (cont.)
e)
Blood for ADA determination of RO7121661 should be taken at indicated time-points up to Cycle 5. Thereafter, blood for ADA determination of 
RO7121661 will be taken at Cycle 7, Day 1, and every 6 cycles afterwards (Cycle 13, Cycle 19, Cycle 25, etc.). Blood for ADA determination 
should always be taken pre-dose.
f)
Participants with confirmed availability of representative archival tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks 
(preferred) or unstained slides, with an associated pathology report.
g)
IgE and tryptase samples will be collected for central and local analysis if a participant experiences a Grade 2 IRR for the first time with the 
second or subsequent study drug infusion or with clinical signs of hypersensitivity reaction at any time of the conduct of the study. A second 
sample for central IgE/tryptase analysis will be collected approximately 48 hours after onset of the reaction.
h)
PD-Plasma and blood flow cytometry samples will be collected at Cycles 9, 22, 35 and 48.
i)
Samples for RBR DNA saliva will be collected on Day 1 from all participants who signed RBR ICF prior to study drug (RO7121661) infusion.  If 
the RBR DNA saliva sample is not collected during the scheduled visit, it may be collected at any time during the conduct of the clinical study.
j)
Screening sample should be collected after eligibility is confirmed unless the fresh biopsy sample is needed to confirm patient eligibility. Post 
dose sample to be collected 2/ 1 day[s] from scheduled timepoint. If the patient progresses and discontinues treatment before the 
scheduled biopsy timepoint, the biopsy should be collected at time of treatment discontinuation. Additional biopsy at time of PR, SD, PD or any 
other timepoint of interest based on participants’ course of disease may be taken after discussion between the Investigator and the Sponsor. 
k)
bTMB and ctDNA should be collected on the same day as the tumor biopsy sample.
l)
If sample is missed on Cycle 1, Day 1, it can be collected at any time during the conduct of the study.
m) After cycle 5 the PD Serum sample should be collected every time a tumor assessment is done every 8 weeks (± 7 days) thereafter for the first 
year; and every 12 weeks (± 7 days) thereafter until disease progression, treatment discontinuation or death).


RO7121661—F. Hoffmann-La Roche Ltd
37/Protocol NP40435, Version 5
2.
INTRODUCTION
2.1
STUDY RATIONALE
RO7121661, an anti-programmed death-1 (PD-1) / T-cell immunoglobulin and mucin 
domain 3 (TIM-3) bispecific antibody (BsAb), was designed to target dysfunctional tumor 
antigen-specific T lymphocytes (expressing PD-1 and TIM-3) in order to establish or re-
establish an effective anti-tumor immune-response in cancer patients with high unmet 
medical need. This may result in improvement in the therapeutic response over currently 
available therapies and/or overcoming of primary resistance or emerging resistance 
against PD-1/programmed death-ligand 1 (PD-L1) checkpoint blockade in patients 
previously treated with PD-1 or PD-L1 checkpoint inhibitors (CPI experienced). 
Exploration of activity in patients without prior CPI exposure (i.e., CPI naïve) is also 
planned. 
NP40435 is a first in human, open label, multicenter, Phase I study to determine the 
maximum tolerated dose (MTD) and/or a recommended dose for expansion (RDE) that 
will allow exploration of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and 
preliminary anti-tumor activity of RO7121661.
The rationale for the study design is provided in Section 4.3.
2.2
BACKGROUND
Cancer remains a major cause of death worldwide despite several new agents providing 
survival benefits to patients. Many cancer indications have a poor prognosis, and the 
management of most advanced solid tumors remains challenging because of the high 
rate of tumor recurrence or the development of distant metastases. 
2.2.1
Non-Small Cell Lung Cancer Patients: Checkpoint Inhibitor 
Experienced and Naïve
Treatment of patients with advanced non-small cell lung cancer (NSCLC) has undergone 
significant changes with the development of immune CPI monoclonal antibodies (mAbs)
to anti-PD-1/PD-L1 e.g., pembrolizumab, nivolumab or atezolizumab or durvalumab (see 
recent reviews: Hashimoto et al 2018; Thommen and Schumacher 2018; Zappasodi et al 
2018) now commonly used in patients without mutations or rearrangements in the 
EGFR, ALK and ROS genes. Initial approval was in patients who had prior platinum 
based chemotherapy.  Pembrolizumab approval was supported by the KEYNOTE-001 
Phase I trial in patients with 50% PD-L1 (Garon et al 2015) and extended by the 
KEYNOTE-010 Phase III trial in patients with1% PD-L1 (Herbst et al 2016). Nivolumab 
was approved in patients regardless of PD-L1 status, initially in advanced squamous 
NSCLC (Brahmer et al 2015) and subsequently in non-squamous NSCLC (Borghaei et 
al 2015). Atezolizumab was approved in patients independent of PD-L1 status and 
histology (squamous and non-squamous) based on the POPLAR Phase II 
(Fehrenbacher et al 2016) and the OAK Phase III trials (Rittmeyer et al 2017). 


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Pembrolizumab has also received approval for treatment-naïve patients with advanced 
NSCLC without driver mutations and with tumor proportion score (TPS) 50% or high 
tumor PD-L1 expression, based on the KEYNOTE-024 Phase III study (Reck et al 2016). 
Pembrolizumab also received accelerated approval in combination with platinum and 
pemetrexed in first line treatment-naïve non-squamous patients irrespective of PD-L1 
status based on Phase II results in KEYNOTE-021 (Langer et al 2016) and confirmed in 
the Phase III KEYNOTE-189 study (Gandhi et al 2018). Recent results from CheckMate 
227, a Phase III trial in patients with chemotherapy-naïve stage IV or recurrent NSCLC 
demonstrates improvement in PFS with first-line nivolumab plus ipilimumab than with 
chemotherapy among patients with a high tumor mutational burden (TMB), irrespective 
of PD-L1 expression level. (Hellmann et al 2018) supporting a potential role for the use 
of TMB as a selection marker for treatment. Furthermore, durvalumab was approved for 
patients with unresectable Stage III NSCLC based on Phase III results in the PACIFIC 
study (Antonia et al 2017).
2.2.2
Small Cell Lung Cancer Patients: Checkpoint Inhibitor Naïve
In 2012, the World Health Organization (WHO) estimated the worldwide incidence of 
new lung cancer cases was 1.8 million, resulting in approximately 1.6 million deaths and 
accounting for about 13% of total cancer diagnoses (Ferlay et al 2012). In the Western 
World, approximately 13% of the lung cancers that are diagnosed are small cell lung 
cancer (SCLC). SCLC occurs primarily in patients with a history of tobacco use and 
originates from neuroendocrine cell precursors. It is characterized by rapid growth, high 
response rates to both chemotherapy and radiotherapy, and the development of 
treatment resistance in patients with metastatic disease (Frü h et al 2013).
Although SCLC is more responsive to chemotherapy and radiation therapy than other 
types of lung cancer, a cure is difficult to achieve because SCLC has a greater tendency 
to be widely disseminated by the time of diagnosis (NIH National Cancer Institute 2016). 
At the time of diagnosis, approximately 30% of patients with SCLC will have tumors 
confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph 
nodes. These patients are designated as having limited-stage disease (LD), where the 
treatment goal is curative (Frü h et al 2013). Patients with tumors that have spread 
beyond the supraclavicular areas are said to have extensive-stage disease (ED). The 
prognosis of SCLC strongly depends on the tumor stage, which is evaluated by the new 
tumor-node-metastasis (TNM) version 7 staging system according to the Union for 
International Cancer Control (UICC) (Frü h et al 2013).
In the last 30 years, multiple therapeutic agents and strategies, including dose 
intensification, have been explored, but with marginal improvement in PFS, and 
significant toxicity. The most important advances have improved the precision of 
radiation therapy and have introduced better supportive care measures, such as more 
effective antiemetic regimens.


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The generally accepted standard for first-line systemic therapy is etoposide combined 
with either cisplatin or carboplatin. Initial objective response rates of 60 to 80% are seen 
in patients without substantive co-morbid conditions. However, almost all patients with 
ED and most patients with LD experience disease progression within months of 
completing first-line therapy.
There is only one approved therapy for SCLC that has progressed on a platinum and 
etoposide combination regimen: topotecan, a topoisomerase 1 inhibitor. 
Recurrent/refractory SCLC is substantially less responsive to therapy than primary 
disease. Response rates for topotecan are approximately 25% for relapses occurring at 
least 3 months after completion of first-line therapy, and as low as 3 to 6% for 
progressive disease occurring at the time of or shortly after completion of first-line 
therapy. Objective responses to a third line of chemotherapy are uncommon.
Recent data demonstrates activity of checkpoint inhibitors in the treatment of SCLC.  
Two agents, pembrolizumab and atezolizumab, have recently demonstrated activity in 
both the monotherapy setting in recurrent SCLC and in combination with platinum and 
etoposide in untreated patients (Chung et al 2018, Ott et al 2017, Horn et al 2018). 
Monotherapy pembrolizumab demonstrated an ORR of 18.7% in unselected but 
previously treated SCLC patients and an ORR of 33-35.7% in the PD-L1 positive 
population (Chung et al 2018, Ott et al 2017).  Addition of atezolizumab to platinum 
chemotherapy as initial therapy has shown a 2 month improvement in overall survival 
(Horn et al 2018). Although these initial checkpoint inhibitors have demonstrated activity, 
SCLC remains a major cause of morbidity and mortality worldwide with a significant 
unmet need for new effective and safe treatments.
2.2.3
Melanoma Patients: Checkpoint Inhibitor Experienced
Ipiliumumab was the first checkpoint inhibitor approved for use in unresectable or 
metastatic melanoma based on significant improvement in overall survival shown in a 
pivotal randomized double-blind Phase III study (Hodi et al 2010). Subsequent to this, 
nivolumab was approved in advanced melanoma patients without BRAF mutation 
(Robert et al 2015). Pembrolizumab was approved for treatment of patients with 
advanced or unresectable melanoma who progressed after ipilimumab and/or BRAF
therapy (Ribas et al 2015; Robert et al 2015). 
The combination of ipilumumab and nivolumab has recently received approval in 
previously untreated patients with unresectable or metastatic melanoma (Robert et al 
2015), although toxicity may be more prominent with the combination therapy. An 
analysis involving patients with a PD-L1 expression level of more or less than 1%, 
suggests that this biomarker may determine the best option for individual patients, as 
monotherapy may provide sufficient results in terms of survival with less toxicity (Larkin 
et al 2015; Wolchok et al 2017). 


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2.2.4
Esophageal Squamous Cell Carcinoma Patients: Checkpoint 
Inhibitor Naïve
Treatment in esophageal squamous cell carcinoma (ESCC) patients without distal 
metastases is aimed at a radical cure by methods appropriate for their stage of cancer. 
Meanwhile, for patients with distal metastases or those with a postoperative distant 
recurrence, combination therapy with platinum based chemotherapy and 5-FU (FP 
therapy) is recommended as the standard treatment. In the second-line setting, single-
agent chemotherapy is an established option based on patient benefit-risk assessment 
(Lordick et al 2016, Muro et al 2019, National Comprehensive Cancer Network 2019, 
Kitagawa et al 2019). Although second-line treatments with docetaxel and paclitaxel are 
used for patients with advanced ESCC that has progressed after first-line chemotherapy, 
they are associated with hematological, gastrointestinal, and neurological toxicities 
(Jimenez et al 2011) and with poor long-term survival (Kato et al 2011, Muro et al 2004). 
More recently pembrolizumab has been approved for second-line therapy for ESCC, 
with PD-L1 expression levels by CPS of 10. Similarly, nivolumab has shown positive 
Phase III data in second-line ESCC independent of PD-L1 expression (Kato et al 2019) 
which has led to the approval of nivolumab for the treatment of patients with 
unresectable advanced or recurrent esophageal cancer that has progressed following 
chemotherapy in Japan.
2.2.5
Targeting PD-1 and TIM-3 Antigens
Although patients with advanced NSCLC and melanoma can benefit from CPI therapy, 
many patients will progress. Therefore, new agents are needed to increase the 
proportion of responding patients, and ultimately improve survival. Several hypotheses 
exist for mechanisms of acquired resistance, such as acquisition of mutations which 
make tumors less susceptible to T-cell mediated killing through a loss of interferon 
gamma (IFNresponse elements or MHC Class I (Zaretsky et al 2016). PD-1 is a 
checkpoint inhibitor that identifies activated and/or exhausted T-cells including tumor 
infiltrating CD8T-cells that recognize mutated tumor antigens (neo-antigens) through 
their T-cell receptor (TCR). Up-regulation of additional inhibitory surface membrane 
immune checkpoint proteins has been described following anti-PD-1 treatment. TIM-3 
represents one such molecule co-expressed with PD-1 and induced by PD-1 blockade. 
PD-1 and TIM-3 expression correlate with the degree of impairment of tumor infiltrating 
lymphocytes (TILs), effector functions and, consequentially, with a poor prognosis. 
TIM-3 is an emerging checkpoint inhibitory molecule involved in the regulation of 
antitumor immunity that is expressed on T-cells and innate immune cells (e.g., 
macrophages, dendritic, and natural killer (NK) cells), where it has been shown to 
suppress their responses upon interaction with their ligands (Anderson et al 2016; Das 
et al 2017). Recently, the results of a Phase I study of TSR-022, an antiTIM-3 mAb, 
were reported for patients with advanced solid tumors (Weiss et al 2017).  Overall, TSR-
022 monotherapy was well tolerated across multiple dose levels.  Adverse events were 
manageable and consistent with the safety profiles of other CPIs.


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The role of the co-expression of PD-1 and TIM-3 has been found on TILs in inflamed 
tumors with an ongoing antigen-specific immune response against the tumor, including 
melanoma and NSCLC (Gros et al 2014; Thommen et al 2015). PD-1 and TIM-3 can be 
found up-regulated upon treatment with T-cell BsAbs. In mouse models, combined 
targeting of the PD-1 and TIM-3 pathways has been shown to be more effective in 
controlling tumor growth of syngeneic mouse tumors than targeting either pathway alone 
(Sakuishi et al 2010).  Similarly, during chronic viral infection, the dual blockade of PD-1 
and TIM-3 enhanced the function of exhausted virus-specific CD8 T-cells 
(Jin et al 2010). Indeed, preclinical experiments in PD-1resistant tumors and analysis of 
patient tumor samples showed that TIM-3 can act as a marker and seems to have a role 
in the mechanism to evade immune response to antiPD-1/PD-L1 therapy 
(Koyama et al 2016).  Nevertheless, despite evidence in the literature, the exact 
mechanism for how TIM-3 interferes with anti-tumor immune response and the 
interaction with its putative ligands (e.g., Galectin-9, CEACAM-1, HMGB1 or 
phosphatidylserine) is not fully understood.
2.2.6
Description of RO7121661
RO7121661 is a novel, Fc-silent IgG1-based BsAb in the 11 format that incorporates 
monovalent binding to each of both checkpoint receptors, PD-1 and TIM-3. Use of a 
natural IgG-like monovalent heterodimeric IgG1 format allows avidity for simultaneous 
binding to PD-1 and TIM-3 when both receptors are co-expressed. RO7121661 binds 
with monovalent high affinity to a glycopeptide-epitope on PD-1, and with low affinity to 
TIM-3 to induce an avidity driven selectivity effect for binding to T-cells in the tumor 
microenvironment that co-express both PD-1 and TIM-3 or to T-cells expressing PD-1 
alone. This preferential binding avoids the targeting of other TIM-3 expressing cells such 
as myeloid or NK cells. 
An additional feature of RO7121661 is the specifically engineered IgG1-based Fc-region 
that prevents binding to FcRs by introduction of PGLALA mutations (Kabat et al 1991; 
Schlothauer et al 2016). This may avoid tumor-associated macrophage resistance 
mechanisms, which have been observed with IgG4-based PD-1 antibodies such as 
pembrolizumab and nivolumab (Arlauckas et al 2017). A schematic of the antibody is
shown in Figure 2.
A detailed description of the chemistry, pharmacology, and safety of RO7121661 is 
provided in the RO7121661 Investigator’s Brochure (IB).


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Figure 2
Schematic Representation of the RO7121661 Bispecific Antibody
Crossed PD-1 heavy chain (HC1A), crossed PD-1 light chain (LC1C), uncrossed TIM-3 light 
chain (LCD), and TIM-3 heavy chain (HC2B). PD-1 programmed death-1; TIM-3T-cell
immunoglobulin and mucin domain 3.
2.3
BENEFIT/RISK ASSESSMENT
Benefit from cancer immunotherapy (CIT) with CPI mAbs, such as those targeting PD-1/
PD-L1, is predominantly observed in a subset of patients with inflamed tumor 
phenotypes. However, response is not guaranteed even in this patient subset due to 
either primary or acquired resistance mechanisms. Upregulated TIM-3 expression on 
T-cells is associated with T-cell dysfunction potentially resulting in baseline or acquired 
resistance to anti-PD-1/PD-L1 therapies (Koyama et al 2016). Therefore, TIM-3 
blockade may overcome or prevent resistance mechanisms to anti-PD-1/PD-L1 and help 
restore cytotoxic T-cell proliferation and enhance T-cell function. RO7121661, a novel 
IgG1-based BsAb that targets the CPI receptors PD-1 and TIM-3, may serve to 
overcome such resistance through ligand blockade and subsequent T-cell re-invigoration 
and/or potentially prevent or delay the development of resistance.
Compared to monospecific PD-1/PD-L1 directed antibodies, one might expect a similar 
safety profile, but better efficacy primarily coming from targeting both PD-1 and TIM-3 
mediated immune resistance mechanisms. The reduction of drug internalization may 
also result in improved clinical pharmacology characteristics compared to monospecific 
antibodies. Compared to monospecific PD-1/PD-L1 and TIM-3 antibody combinations or 
other PD-1/TIM-3 bi-specifics, one anticipates similar efficacy in the context of better 
safety due to the preferential targeting of TILs, sparing of the myeloid compartment with 
avoidance of a peripheral sink, and lack of effector function due to the PGLALA mutation 
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As the mechanisms for optimal targeting of immune regulation in the tumor environment 
are still under exploration, rational new approaches to increase response rates to first 
line CPI therapy are warranted. Untreated NSCLC patients who demonstrate TPS or 
PD-L1 50%, which has clearly demonstrated sensitivity to PD-1 targeting, may benefit 
from first line treatment with a PD-1/TIM-3 BsAb if in fact the additional targeting of 
TIM-3 leads to additive antitumor activity beyond that expected of PD-1 targeting alone.
RO7121661 has demonstrated single-agent activity in Part A of this study. As of 1 March 
2020, objective responses with long-lived partial remissions were achieved in one 
participant with metastatic ESCC and one participant with metastatic non-small cell lung 
adenocarcinoma. Of note, the non-small cell lung adenocarcinoma participant was 
previously treated with a PD-L1 inhibitor and had PD as best overall response on this 
treatment. Further, disease control with disease stabilization or minor response was 
achieved in other solid tumor types with an overall disease control rate (DCR) of 35.9% 
(14/39 patients). 
RO7121661 was well tolerated in the patients dosed in Part A of this study. No specific 
safety concerns were identified and no MTD was identified although 1 DLT (Grade 3 
Troponin T increased, unresolved at the time of the publication of this version of 
protocol) was observed at 1.2 g dose level. 
Precaution against general risks for patients have been taken into account in the safety 
measures for this study, which include the definition of the inclusion/exclusion criteria 
(Section 5), dose-limiting toxicities (DLTs; Section 4.1.3), and rules for treatment 
interruption and withdrawal from study (Section 7).
The re-invigorating action of RO7121661 on immune effector cells, particularly given the 
TIM-3 modulation, might bear the risk of exaggerated immune cell activation that may 
result in the occurrence of enhanced, untoward, immune-mediated adverse events 
(imAEs) and an increase in cytokine release-mediated toxicities. Recommendations for 
the prophylaxis and the management of specific and known PD-1/PD-L1-mediated 
adverse events (AEs) can be found in Section 8.3.8 and Appendix 6.
Administration of therapeutic antibodies may cause infusion-related reactions (IRRs), 
which may include symptoms such as fever, chills, hypotension, shortness of breath, 
skin rash, headache, nausea, and vomiting.  Such reactions typically occur during or 
shortly after the infusion, predominantly the first infusion. The incidence and severity 
typically decrease with subsequent infusions.  Based on in vitro data, the risk of 
pro-inflammatory cytokine mediated IRRs upon first administration of RO7121661 as 
single agent is considered low. The recommended management of IRRs is detailed in 
Section 8.3.8.1.
Administration of therapeutic antibodies may cause the formation of ADAs, which may 
negatively affect the safety of the therapeutic (e.g., allergic reactions, immune 


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complex-mediated diseases).  In the non-GLP DRF PK/PD study and the 4-week GLP 
study in cynomolgus monkeys, ADA development was observed independently of the 
dose groups (RO7121661 IB Section 4.2.2.1 and Section 4.2.3.1). No adverse findings 
were observed; no toxicity related to ADA formation was observed.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected adverse events of RO7121661 is provided in the
RO7121661 IB.
Based on the considerations above, currently available data from Part A of this study
and the planned safety monitoring and management guidance, the proposed study 
treatment is considered to have an appropriate benefit/risk profile for the population 
included in this study.
COVID-19 Benefit/Risk Assessment
In the setting of the coronavirus disease (COVID-19) pandemic, patients with 
comorbidities (including those with cancer) are a more vulnerable population. Infection 
with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses. It is unclear how immunotherapy affects the incidence or 
severity of COVID-19. It is not anticipated that treatment with RO7121661 will 
increase the risk of infection with SARS-CoV-2. Severe COVID-19 is associated with a 
cytokine release syndrome (CRS) involving the inflammatory cytokines IL-6, IL-10, IL-
2, and interferon-gamma. RO7121661 has a low risk of CRS and, while it is not known, 
there may be a potential for an increased risk of an enhanced inflammatory response if a 
participant develops SARS CoV-2 infection while receiving RO7121661. At this time, 
there is insufficient evidence for causal association between RO7121661 and an 
increased risk of severe outcomes from COVID-19.
There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and SARS-CoV-2 vaccination, and it is recognized that 
human immune responses are highly regulated and that immune-modifying therapies 
may positively or negatively impact the efficacy and safety of SARS-CoV-2 vaccination 
(Society for Immunotherapy for Cancer [SITC] 2020).
Per recommendations of the National Cancer Comprehensive Network (NCCN) 
COVID-19 Vaccination Advisory Committee, SARS-CoV-2 vaccination is 
recommended for all patients with cancer receiving active therapy (including immune 
checkpoint inhibitors), with the understanding that there are limited safety and efficacy 
data in such patients (NCCN 2021). Given the lack of clinical data, currently no 
recommendations can be made regarding the optimal sequence of SARS-CoV-2 
vaccination in patients who are receiving cancer immunotherapy (SITC 2020). For 
patients enrolling in this study and receiving RO7121661, a decision to administer the 


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vaccine to a patient should be made on an individual basis by the Investigator in 
consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving RO7121661 to receive SARS-CoV-2 
vaccination include the following: the risk of SARS-CoV-2 infection and potential 
benefit from the vaccine, the general condition of the patient and potential 
complications associated with SARS-CoV-2 infection, underlying disease, and the 
severity of COVID-19 outbreak in a given area or region.
SITC and NCCN recommendations along with institutional guidelines should be used 
by the Investigator when deciding on administering SARS-CoV-2 vaccines. When 
administered, SARS-CoV-2 vaccines must be given in accordance with the approved or 
authorized vaccine label. Receipt of the SARS-CoV-2 vaccine is considered a 
concomitant medication and should be documented as such (see Section 6.5).
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints provided in Table 4, apply to:

Part A: RO7121661 single agent dose escalation phase

Part B: RO7121661 single agent expansion in selected indications


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Table 4
Objectives and Endpoints
Objectives
Endpoints
Primary
Dose Escalation: Safety, tolerability, MTD
and/or RDE.
Nature and frequency of DLTs and other 
AEs, PD and PK profile.
Incidence, nature and severity of AEs 
graded according to the National Cancer 
Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.
Expansion: Assessment of the anti-tumor 
activity of RO7121661.
According to Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 
criteria:
o
Objective response rate (ORR).
o
Disease control rate (DCR); defined 
as ORRstable disease rate (SDR).
o
Duration of response (DoR).
o
Progression free survival (PFS) 
defined as the time from the first 
study treatment (Day 1) to the first
occurrence of progression per 
Investigator assessment or death 
from any cause, whichever occurs 
first.
Secondary
To characterize the immunogenicity profile 
of RO7121661 (Part A and B).
Incidence of anti-drug antibodies (ADAs).
To explore potential PD-1, TIM-3 and 
PD-1/TIM-3 specific PD biomarkers (Part 
B).
Examine the profile and status of T cell 
proliferation/activation in tumor biopsies and 
peripheral blood.
To investigate the single and multiple dose 
PK of RO7121661 (Part A and B).
PK profiles and parameters derived for 
RO7121661.
To explore degree of target binding of 
RO7121661 (in association with PK/PD) 
via RO (Part A).
Evaluate RO via ex-vivo assay.
To evaluate the safety and tolerability of 
RO7121661 (Part B).
Incidence, nature and severity of AEs graded 
according to the NCI CTCAE v5.0.
To explore preliminary anti-tumor activity of 
RO7121661 (Part A).
According to RECIST Version 1.1 criteria:
–
Objective response rate (ORR).
–
Disease control rate (DCR).
–
Progression-free survival (PFS).
–
Duration of response (DoR).


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Table 4
Objectives and Endpoints (cont.)
Objectives
Endpoints
Tertiary/Exploratory
To make a preliminary assessment of the 
anti-tumor activity of RO7121661 using 
immune-related RECIST (iRECIST) (Part A 
and B).
Investigator-determined assessment using 
iRECIST:
o
ORR.
o
DCR; defined as response rate 
(RR)stable disease (SD).
o
DoR.
o
PFS defined as the time from the first 
study treatment (Day 1) to the first
occurrence of progression per 
Investigator assessment or death 
from any cause, whichever occurs 
first.
To make a preliminary assessment of 
overall survival from RO7121661 (Part A 
and B).
Overall survival (OS), defined as the time 
from first study treatment to death from any 
cause (if data mature at the time of 
analysis).
To explore and identify potential PD 
biomarkers in association with exposure 
kinetics (Part A and B).
Examine PD changes in the following 
compartments:
o
Tumor Microenvironment (preand
on-treatment tumor biopsies): 
Measure changes in degree and 
extent of T-cell infiltration and 
inflammatory gene expression 
profiles/signatures.
o
Peripheral Blood: Serial sampling to 
assess kinetic changes in select 
T-cell subsets, inflammatory 
cytokines, soluble factors, gene 
signatures and monitoring tumor 
burden.
Correlation of anti-tumor activity of 
RO7121661 to PK, PD and safety (Part A 
and B).
Compare anti-tumor activity by RECIST 
with PK parameters, PD changes and 
safety events. 
ADAs anti-drug antibodies; AEs adverse events; ctDNAcirculating tumor DNA; 
DCRDisease control rate; DLTs dose-limiting toxicities; DoRDuration of response; 
iRECIST immune-related RECIST; IVintravenous; MTDmaximum-tolerated dose; NCI 
CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events v5.0; 
ORRObjective response rate; OSOverall survival; PDpharmacodynamics; 
PFSProgression free survival; PKpharmacokinetic; RDErecommended dose for 
expansion; RECIST Response Evaluation Criteria in Solid Tumors; ROreceptor occupancy; 
RRresponse rate; SDstable disease; SDRstable disease rate; TMBtumor mutational 
burden.


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4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.
Study NP40435 is a first-in-human, open-label, multicenter, Phase I multiple-
ascending dose (MAD) study of single agent RO7121661. The study consists of 2 parts 
(A and B):

Part A (RO7121661 Dose Escalation): To determine the MTD and/or RDE based on 
safety, tolerability, PK, and/or the PD profile of escalating doses of RO7121661
every 2 weeks (Q2W). If for specific cleared cohort(s) the safety, PK and/or RO 
and/or the biomarker profile need to be further characterized, additional participants, 
potentially enriched in certain indications and/or characteristics, may be enrolled.

Part B (RO7121661 Tumor-Specific Expansion Cohorts): To evaluate anti-tumor 
activity of the RDE of RO7121661 from Part A (2.1 g Q2W) and to confirm safety 
and tolerability in participants with selected tumor types. B1, B2, B4 and B5
expansions may be staggered, sequential or concurrent. Part B3 will not proceed 
prior to generation of data from the initial CPI experienced indication(s):
–
Part B1: CPI experienced second line and beyond metastatic melanoma
–
Part B2: CPI and platinum experienced second or third line PD-L1 positive 
NSCLC
–
Part B3: PD-L1 positive, CPI naïve, first line NSCLC 
–
Part B4: CPI-naïve SCLC with prior failure of, progression on, or intolerance to 
standard therapy
–
Part B5: CPI-naïve ESCC
Part A of the study will enroll participants with solid tumors who have progressed on a 
cancer therapy or who are not amenable to standard of care. At least  DLT evaluable 
participants will be enrolled in each cohort during the dose escalation (see
Section 4.1.3). Dose escalation will be carried out according to a modified continual 
reassessment method (mCRM) with escalation with overdose control (EWOC) design, 
with the aim of identifying the MTD/RDE of RO7121661.
Since RO7121661 will be administered Q2W in Part A, the cycle length will be defined 
as 14 days. The maximum total number of participants in the dose escalation portions of 
Part A1 will be approximately 
 DLT evaluable participants on a Q2W schedule. A dose 
cohort can be extended to enroll additional participants (approximately 
), potentially 
enriched in certain tumor types and/or characteristics to confirm safety, PK and/or RO
and/or the biomarker profile. 
Part B1 and/or B2 and/or B4 and/or B5 may commence upon completion of Part A. The 
starting dose of RO7121661 for Part B is 2.1 g Q2W as derived from the RDE in Part A 


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determined by safety, PK and/or RO and/or the biomarker profile. Part B3 will not 
proceed prior to generation of data from the initial CPI experienced indication(s).
Patients enrolled in Part B expansions have more specific limitations of prior therapies 
for inclusion than during the dose escalation. Patients enrolled in Part B1 (CPI 
experienced melanoma) must have had treatment with approved anti-PD-L1/anti-PD-1 
checkpoint inhibitors.  Patients enrolled in Part B2 (CPI and platinum experienced, PD-
L1 expression 1% NSCLC) must have had a checkpoint inhibitor and platinum 
chemotherapy. Patients enrolled in Part B3 (untreated, CIT naïve NSCLC with PD-L1 
expression 50%) should not have had any prior therapy. Patients enrolled in Part B4 
(CPI naïve SCLC) and B5 (CPI-naïve ESCC) should not have had any prior checkpoint 
inhibitor therapy but may have had chemotherapy. Specific details for Part B Expansions 
are included in the Inclusion and Exclusion Criteria (Section 5.1 and Section 5.2).
In Part B (tumor specific expansion cohorts) approximately 
 participants will be 
included per indication. Part B cohorts may run in parallel, staggered or sequentially.
Participants will be treated with RO7121661 until disease progression, unacceptable 
toxicities, or withdrawal of consent. Participants may continue treatment with 
RO7121661 (Part A and B) for 24 months or longer if the participant is still benefitting 
from treatment at the time of the last visit at the end of the two-year period. As with 
other immunotherapies, treatment beyond progressive disease according to RECIST 
Version 1.1 can be considered after consultation and agreement between the Sponsor 
and Investigator.
4.1.1
Length of the Study
The duration of the study for each participant will be up to 27 months (Parts A and B), 
divided as follows:

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 (7) days after last treatment with RO7121661 for Part A; 
90 ( 7) days after last treatment with RO7121661 for Part B.

Survival follow-up: 90 (7) days after last treatment with RO7121661; then every 3 
months (2 weeks) for total 24-month period after initial dose.
The treatment period may be prolonged past month 24 if the participant is still 
benefitting from treatment at the time of the last visit at the end of the two-year period. 
Participants may extend treatment within the ongoing study whether they are on 
treatment or are on a treatment pause at the 24-month time point. During the extended 
treatment period, the participant follows the SoA as indicated for “Subsequent Cycles.”
Participants will be treated until disease progression, unacceptable toxicities, or 


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withdrawal of consent. For participants who extend their treatment, the safety follow-
up will be performed 60 (7) days for Part A or 90 (7) days for Part B after the last 
treatment with RO7121661 and survival follow-up every 3 months (2 weeks) 
thereafter for a total of 48 months after initial dose, or end of the study. 
4.1.2
Dose-Escalation Decision Criteria
For Part A, RO7121661 dose-escalation will be carried out according to a mCRM with 
EWOC design and will be based on the occurrence of DLTs. The dose-toxicity 
relationship is described by a 2-parameter logistic regression model, where the
probability of DLT is expressed as a function of dose. The model is continuously updated 
as additional participant information becomes available (for further information see 
Appendix 10).
A minimum of  participants per cohort will be enrolled and treated in a sequential
manner with one week between the first and second participant and at least 2 days 
between subsequent participants. However, if the first participant experiences a DLT 
within the first week, then the time between the treatment of subsequent participants 
within the same cohort may be increased. 
A new cohort can be opened when at least  participants per cohort are considered DLT 
evaluable, i.e., if they received 2 doses and either:

experienced a DLT within the DLT period

cleared the DLT period without a DLT
The DLT period is 21 days from Day 1/Cycle 1 to Day 7/Cycle 2. If there is a delay in 
Cycle 2 treatment the DLT period should be adjusted to cover Day 7/Cycle 2 up to a 
maximum of 35 days, since the maximum dose delay allowed is 14 days.
Once at least  participants per cohort are DLT-evaluable, the logistic regression model 
will be updated with the treatment outcome (i.e., the occurrence of DLT). Thus, a new 
estimate of the MTD (defined as the dose with the highest probability that the DLT rate is 
within the target of 20-35% and a relatively low probability 25% that the DLT rate is 
above 35%) will be derived. In addition, the model will recommend a dose for the new 
cohort of participants, with the EWOC recommendation being either the new estimate of 
the MTD or the highest allowable dose based on pre-specified safety constraints (e.g.,
maximum increments), whichever is lower. 
Built in safety constraints are in place to prevent exposing participants to undue risk of 
toxicity. For instance, in the absence of DLT, the maximum allowable dose-increment 
will be 200% (i.e., next dose could be as high as 3-fold the previous dose) for 
dose-levels 700 mg and 100% (i.e. 2-fold) for dose-levels 700 mg. In addition, in 
case of one event meeting DLT criteria in a dose-level, the maximum allowable dose 


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increment becomes 100% (i.e. 2-fold); while in the presence of 2 DLTs an increment of 
50% is allowed (i.e. 1.5-fold). For further information see Table 1 in Appendix 10.
The dose escalation decision and selection of the dose for the next cohort, guided by the 
mCRM EWOC recommendation, will also take into account an overall review of safety
and available PK and/or PD data as well as any additional data. Subject to clinical 
judgment, and upon agreement between the Sponsor and the Investigators on the next 
dose-escalation step, the new cohort can then be opened for enrollment. 
The design will continue as described, until one of the pre-defined stopping criteria is 
satisfied (see Section 4.1.4), or the RDE has been defined, whichever comes first.
4.1.3
Dose Limiting Toxicities
For the purpose of this study, a DLT will be defined as any of the following events 
attributed to RO7121661 (i.e., related to RO7121661) and occurring during the DLT 
window:
A DLT is defined as a clinically significant AE (classified according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.5.0, 
as applicable) or significant laboratory abnormality: 1) occurring during the DLT
assessment period of 21 days from the start of the first RO7121661 administration; 2) 
considered to be related to study treatment RO7121661 by the Investigator and; 3) is not 
attributed to disease progression or another clearly identifiable cause.
Investigators are encouraged to perform additional tests to determine the underlying 
etiology and most appropriate attribution.
For the purpose of this study the following AEs are considered DLTs:

Hematological toxicities:
–
Grade 4 neutropenia (ANC0.5109/L) lasting 5 days. 
–
Grade3 febrile neutropenia associated with single body temperature38.3°C 
or sustained body temperature38°C for1 hour, and/or with infection.
–
Grade 4 thrombocytopenia lasting48 hours.
–
Grade 3 thrombocytopenia associated with bleeding episodes requiring a 
platelet transfusion.
–
Grade 4 anemia
–
Grade3 anemia with hemolysis

Any non-hematological toxicity of Grade 3 including:
–
Any Grade 3 immune-mediated AE.
–
Grade 3 hyperbilirubinemia lasting for48 hours or Grade 4 hyperbilirubinemia.


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–
Grade3 AST or ALT elevations with hyperbilirubinemia of Grade2.
–
Grade 4 AST or ALT elevations.
–
Grade3 nausea, vomiting, or diarrhea despite maximal supportive treatment.
–
Grade3 non-hematological laboratory abnormality requiring medical 
treatment/intervention or hospitalization.

The following Grade3 non-hematological toxicity are exceptions for 
consideration as DLTs: 
–
Alopecia (any grade).
–
Grade 3 nausea or vomiting that resolves to Grade1 with or without 
supportive therapy within one week. 
–
Grade 3 hypophosphatemia resolved within one week. 
–
Grade ≥3 fatigue/asthenia that resolves to Grade2 within one week. 
–
Grade 3 anorexia or constipation.
–
IRRs are not considered to be DLTs because, on the basis of experience with 
mAbs, IRRs are not dose-related events. Hence, IRRs that require removal of 
participants from the study will be considered as treatment limiting toxicities 
and not DLTs. Precautions, including pre-medication, will be taken if IRRs of 
Grade2 occur. If described precautions are not sufficient, other options will 
be discussed between the Sponsor and the Investigator (see Section 8.3.8.1). 
However, re-occurrence of an IRR event in a participant that precluded the 
administration of the full dose or the administration of the next scheduled dose 
of study drug will be considered a DLT. If clinical judgment suggests that an 
IRR is related to dose (e.g., driven by on-target mediated release of cytokines
by immune cells), a Grade 3 or Grade 4 IRR may be considered a DLT. 
–
Grade 3 fever (in the absence of any clinically significant source of fever) that 
resolves to Grade2 within 7 days with supportive care. 
–
Fever40°C (i.e., Grade 3) that occurs within 48 hours of RO7121661 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 is asymptomatic and 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 tumor flare defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 


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–
Grade 3 neuropathy if the participant began therapy with a Grade 2 
neuropathy at baseline. 
–
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 RO7121661-related toxicity that results in a dose-delay of 
the next scheduled administration of more than 14 days is defined as a DLT.
4.1.4
Stopping Rules Criteria
4.1.4.1
Part A Dose Escalation
The algorithm of the mCRM with EWOC will propose to stop the dose escalation under 
the following circumstances: 

The maximum sample size of 
 evaluable participants has been reached OR 

Enough information on MTD has been achieved (i.e., at least a minimum of 
participants enrolled and at least 
participants have been accrued near the 
MTD dose - where near is defined as differing from the MTD by at most 15% - and
the probability that the MTD dose lies within the target toxicity interval is above 
50%)
OR 

The maximum dose has been tested and is considered safe (i.e., at least a 
minimum of 
participants have been accrued at the maximum dose or near -
differing from the maximum dose by at most 5% - and it is at least 50% likely that 
the probability of a DLT for that maximum dose is below 20%). 
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 
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
For Part A: Upon completion of all screening evaluations and confirmation that a 
participant has met all inclusion and exclusion criteria, investigator sites will contact the 
Sponsor to confirm the dose, participant number and cohort assignment via a 
Confirmation of Enrollment form (ESF). This will guarantee that the Sponsor is notified 


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prior to the administration of RO7121661 to any participant. Then sites will need to 
contact the interactive response technology system (IRT) vendor who will generate 
confirmation of participant number, dose and cohort assignment. The IRT participant 
number should be generated prior to first dose.
For Part B: An Interactive Response Technology (IRT) system will be utilized to manage 
(pre-) screening and enrollment. All pre-screening evaluations must be recorded in the 
IRT system with a proposed cohort. Roche will review and approve the pre-screened 
participants for the proposed cohort. After signing informed consent, the screening 
transaction should be performed in the IRT system and once it is confirmed that 
participants meet all eligibility criteria the participants should be enrolled in the 
respective cohort using the IRT system.
A participant Enrollment List must be maintained by the Investigator.
In Part A: After each participant receives RO7121661 the Investigator(s) must confirm to 
the Sponsor that the participant has been dosed and provide a brief summary of the 
status of the participant in terms of safety and tolerability to RO7121661. The 
Investigators and the Sponsor will communicate regularly and on an ad-hoc basis to 
discuss the occurrence of any safety events including DLTs. 
In the event of a DLT, the Investigator will contact the Sponsor immediately (within 
1 business day via DLT notification form) to discuss participant status and action 
taken/to be taken. 
In addition, as outlined above, during dose-escalation, after each participant cohort has 
been completed (i.e., at least  participants are DLT evaluable), the Sponsor will 
organize a teleconference with the Investigators to discuss the safety and tolerability of 
RO7121661 and to discuss the proposed dose(s) for the next cohort. The 
dose-escalation decision criteria are outlined in Section 4.1.2. 
During these teleconferences, NCI CTCAE Version 5.0 toxicities will be discussed along 
with the results of any available PK/PD data, in addition to safety laboratory results and 
any other available data that may assist the dose-escalation decision process. The 
decision will be based on all relevant available data and not based solely on DLT 
information, as well as being guided by the mCRM-EWOC recommendation.
Study Investigators and the Sponsor should reach a consensus on the next dose-level 
which may include dose escalation, de-escalation, or recruitment into the current or 
particular previously cleared cohorts. Dose-escalation may proceed to the next dose 
level if the Investigators and the Sponsor are satisfied with the safety profile of the 
previous participant cohort and agree to move to the next escalated dose level or 
whether to de-escalate and/or extend recruitment into particular cohorts.  The dose 
discussion will be documented in writing, including the final dose decision whether it is 


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the mCRM recommended dose, or an intermediate dose, and both the Sponsor and 
Investigators will approve the Minutes of these meetings to confirm agreement. 
In addition to these communications, the Sponsor and Investigators will be in regular 
contact throughout the study by email/telephone/fax per normal interactions during the 
conduct of a clinical study and the Sponsor will arrange regular teleconferences and 
meetings to discuss the study status. The Sponsor will be available 24 hours a day to 
discuss any medical or study-related issues that may arise during the conduct of this 
study.
4.2
JOINT MONITORING COMMITTEE
In Part B of the study, the Sponsor will in addition form a Joint Monitoring Committee 
(JMC), with the aim to monitor participants’ safety throughout. The JMC will consist of 
designated Sponsor personnel, including a JMC Chair, clinical scientist, drug safety 
officer, biostatistician, and independent clinical expert(s) (i.e., expert[s] independent from 
the Sponsor).
The JMC will conduct regular assessments on an ongoing basis of the incidence and 
nature of AEs, serious adverse events (SAEs), adverse events of special interest (AESI), 
frequency of death from all causes, and clinically significant laboratory abnormalities. 
The JMC will review all safety study data at regular intervals, as defined in the JMC 
charter.
At the time of each review, the JMC will make one of the following recommendations: the 
study may continue unchanged, the study is to be stopped, additional analyses are to be 
performed, enrollment is to be held pending further safety evaluations, or a protocol 
amendment is recommended. The JMC will report recommendations to the Sponsor.
4.3
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
For Part A, RO7121661 dose escalation will be carried out according to a mCRM with 
EWOC design and will be based on the occurrence of DLTs. 
The mCRM EWOC design has many favorable characteristics:

It adaptively fits a dose DLT response curve by incorporating toxicity data from 
eligible participants among different cohorts, and preclinical or clinical information 
from compounds with similar modes of action via the prior.

The design also locates the MTD efficiently without pre-specifying exact dose 
levels for each cohort. Dose selections are made based on the DLT dose response 
curve measured by a 2 parameter logistic model over the dose range, subject to 
clinical judgment and mandated safety constraints that limit the size of dose 
increments. Moreover, the EWOC algorithm highly reduces risks of exposing 


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participants to overly toxic doses.  Of note, the model provides only the upper limit 
for recommended dose.  A dose less than the model recommended dose may be 
selected based on clinical judgment. 
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 parameters of the design as implemented for this study 
(Appendix 10).
For Part B, RO7121661 will be administered at the determined MTD/RDE to specific 
participant populations in expansion cohorts. From the data available from Part A, a 
dosing regimen of 2.1 g Q2W was selected as the dose for Part B expansion cohorts.
Please refer to Section 4.4 for further rationale.
4.3.1
Rationale for Study Population
Part A dose-escalation of this study will enroll participants with advanced and/or 
metastatic solid tumors who have progressed on a cancer therapy or for whom no 
effective standard therapy exists. In the event that additional data is required to confirm 
PK, PD, safety, etc., additional participants, potentially enriched in certain tumor types
and/or characteristics, may be enrolled.
Part B of this study will enroll melanoma patients who have progressed on prior CPI (B1) 
or NSCLC patients who are CPI and platinum chemotherapy experienced (B2) and CPI 
naïve SCLC (B4) and ESCC patients (B5). If exploration is supported by CPI 
experienced patients in Parts B1 and/or B2, then Part B of this study will also enroll 
NSCLC patients who are CIT and chemotherapy naïve (B3). SCLC and ESCC patients 
who are CPI naïve may enroll without data from B1 or B2.
Data from PD-1/PD-L1 inhibitors which are approved or in development as described in 
Section 2.2, have demonstrated clinical benefit in the NSCLC and melanoma 
populations. Therefore, CPI experienced populations allow for an assessment of the 
combination of PD-1 and TIM-3 targeting with the potential of providing participants an 
opportunity for therapeutic benefit if continued PD-1 targeting in combination with 
targeting TIM-3 can help re-initiate or improve on the anti-PD-1/PD-L1 CPI response. 
Recent data from PD-1/PD-L1 inhibitors demonstrate benefit in both the previously 
treated and untreated SCLC population (see Section 2.2.2). In addition, there is early but 
limited data suggesting potential activity of a monospecific TIM-3 antibody in SCLC, thus 
suggesting a potential role of TIM-3 (Harding et al 2019). 
Additionally, CPI naïve ESCC patients who are refractory or intolerant to combination 
therapy with fluoropyrimidine and platinum-based drugs (B3) will be enrolled. Recent 


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data from PD-1 inhibitors demonstrate benefit in the ESCC population (see
Section 2.2.4). Compared to esophageal adenocarcinoma PD-L1 expression is enriched 
in ESCC, which might increase tumor susceptibility in these patients to elimination 
following immune checkpoint inhibition. The reported prevalence of PD-L1 expression in 
ESCC ranges from 15% to 83% in tumor cells, and from 13% to 31% in tumor-infiltrated 
immune cells (Jiang et al 2017, Lam et al 2017,.Guo et al 2018, Qu et al 2016). TIM-3 
has also been shown to be expressed on TILs in patients with ESCC (Zhao et al. 2020). 
RO7247669 may therefore have the potential to be a therapeutic option for patients with 
ESCC.
For CIT naïve previously untreated NSCLC patients, focus will be on those participants 
with at least50% PD-L1 expression as based on pembrolizumab study KEYNOTE-024 
(Reck et al 2016), as these are participants felt to have the highest opportunity for 
response to PD-1 therapy and therefore may gain additive activity from the TIM-3 
mechanism of the BsAb.
Other indications may be explored in the tumor-specific expansion cohorts in Part B 
based on emerging clinical data from the Part A dose-escalation and/or based on 
emerging scientific rationale. These additional indications may be proposed and added 
to this study for Part B via an amendment.
4.3.2
Rationale for Biomarker Assessments
Biomarker exploration will focus on PD effects associated with anti-PD-1/TIM-3 therapy. 
A driving hypothesis is that PD-1/TIM-3 dual blockade will increase T-cell infiltration and 
proliferation in the tumor microenvironment provided sufficient RO (or drug coverage) is 
obtained.
Fresh tumor biopsies will be collected according to the SoA (see Section 1.3), to 
measure changes in the degree and extent of T-cell infiltration (such as CD8/Ki67) and 
select inflammatory gene expression profiles/signatures.
In peripheral blood, serial blood sampling will be done to assess kinetic changes in drug 
RO, immune cellular profiles and selected cytokines. The analysis of cytokines during 
study treatment has demonstrated increases of interleukin (IL)-6, IL-8, and IFNin 
previous CPI trials and might serve as markers of the mode-of-action. These cytokines 
may also be important in the context of drug safety and might therefore be analyzed in 
the case of (severe) AEs. Furthermore, soluble CD25, which has been described as a 
circulating marker of IL-2 mediated immune cell activation (Ribas et al 2009) may be 
measured at baseline and selected time points after initial treatment. Additionally, 
peripheral blood will be collected to assess kinetic changes, such as TMB and potentially 
circulating tumor DNA (ctDNA).
Whether predictive markers of response to therapy exist for RO7121661 and for which 
cancer type or clinical settings will also be explored. The hypothesis that PD-1/TIM-3 


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dual blockade might be most effective in settings where there is a composite profile 
consisting of but not limited to T-cell infiltration/activation, PD-L1 status, PD-1 and TIM-3
target expression, and TMB, will be explored in baseline tumor biopsies. 
Archival tumor tissue biopsies will be collected from all participants if available. Archival 
samples will be tested for similar predictive markers that the fresh screening biopsies will 
be tested for. 
Additional biomarkers may be measured if initial data lead to a strong scientific rationale 
for these measurements.
4.4
DOSE JUSTIFICATION
Part A
The starting dose regimen of RO7121661 will be 70 mg administered Q2W by IV 
administration in this first study in humans with RO7121661. The RO7121661 starting 
dose and schedule have been selected on the basis of the integration of several factors 
including non-clinical toxicology, PK and in-vitro/ex-vivo functional assays.
RO7121661 was well tolerated in both the dose range finding and GLP monkey 
toxicology studies up to the highest dose evaluated (150 mg/kg).  Toxicology findings 
were consistent with reported findings in cynomolgus monkey studies with marketed 
CPIs. 
The safety profile of the proposed Q2W dosing regimen for RO7121661 administration in 
human has been supported by a more frequent dosing (QW schedule) in non-clinical 
toxicology studies conducted in cynomolgous monkeys. The entry-into-human starting 
dose of 70 mg Q2W (corresponding to a 1 mg/kg Q2W in an average 70-kgweight 
participant) for the dose-escalation portion of this study was derived from a translational 
PK/PD approach, which was informed by in vitro and ex vivo staphylococcal enterotoxin 
B superantigen-induced (SEB) cytokine release assays as well as clinical safety 
experience with pembrolizumab, nivolumab (antiPD-1), other PD-1/PD-L1 inhibitors, 
and TSR-022, a mAb directed against the TIM-3 receptor.  Since there are extensive 
clinical (safety) data available from PD-1 inhibitors, a non-MABEL (minimum anticipated 
biological effect level) approach using PK/PD was considered appropriate to estimate a 
safe starting dose.  The PK/PD approach is expected to reduce the number of 
participants exposed to sub-pharmacological doses of RO7121661 while ensuring that 
the starting dose is in a safe range.  The projected area under the curve (AUC)0-336 and 
maximum concentration (Cmax) in humans at the flat dose of 70 mg after single dose 
(Q2W) are 3900 μg h/mL and 25.2 μg/mL, respectively.  These values are 
approximately 180- and 116-fold lower, respectively, than the exposure observed in 
cynomolgus monkeys at the 150 mg/kg NOAEL in the 4-week GLP toxicology study 
(differences in potency and dosing schedule were accounted for). For further information 


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on exposure ratios from non-clinical safety findings to human exposures for single 
administration and steady state, see Appendix 11.
Human PK simulation via allometric scaling of the linear clearance data from 
cynomolgus monkey is consistent with an IgG-like PK, with a projected human half-life of 
~19 days at target-mediated drug disposition (TMDD)-saturated doses. At lower doses,
RO7121661 is predicted to show a more rapid clearance due to TMDD. 
The safe starting dose is predicted to show a maximal response in an ex vivo SEB
cytokine release assay up to 70% (with unknown TIM-3 contribution) which should result 
in pharmacological activity in participants. To support comparison of these functional 
assays, pembrolizumab, another PD-1 inhibitor currently on the market where tolerable 
doses (no DLT observed) up to 10 mg/kg Q2W were investigated, was included for 
benchmarking. The starting dose selected for pembrolizumab was 1 mg/kg and showed 
full saturation in target engagement in these assays (Patnaik et al 2015).
Compared to a classical MABEL approach, the approach used here reduces the number 
of participants exposed to sub-therapeutic doses of RO7121661 while ensuring that the 
starting-dose is in a safe range.
The initially proposed Q2W dosing interval is supported by the predicted clearance and 
elimination half-life (t1/2) of RO7121661 with a projected human elimination t1/2 of 
approximately 19 days.
A maximum feasible dose of 2.1 g of RO7121661 has been defined based on predicted 
IC95 for PD-1/TIM-3 of approximately 320 g/mL and confidence in ex vivo and in vitro 
SEB data and benchmarking results to pembrolizumab. Based on product specifications, 
the dosing is currently limited to 2.1 g and must not be exceeded under any 
circumstances. In case dose escalation is planned to progress beyond 2.1 g, the 
corresponding chemistry, manufacturing, control (CMC) documents and protocol will be 
amended as appropriate.
Flat dosing was selected for this protocol because no strong influence of body surface 
area (BSA) or body weight on overall exposure is expected. On the basis of the PK data 
emerging from this clinical study, any potential covariates on exposure to RO7121661, 
such as BSA, body weight, age, ethnicity and gender will be explored in order to confirm 
this dosing approach.
In conclusion, a 70 mg flat dose is proposed as the starting dose of RO7121661 for 
Part A, on the basis of both data from nonclinical studies with RO7121661 and previous 
clinical experiences with PD-1/PD-L1 and TIM-3 inhibitors.


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Part B
From the data available from Part A of this study, a dosing regimen of 2.1 g Q2W was 
selected as the dose for Part B expansion cohorts. This was based on RO7121661 
being well tolerated in the patients dosed in Part A where no specific safety concern 
associated with RO7121661 was identified. One DLT (Grade 3 Troponin T increased) 
was observed at the 1200 mg dose group, however no MTD was identified.
A two compartmental PK linear model predicts the exposure data well, particularly at the 
higher dose range and supports a dose of 2.1 g at Q2W for further investigation. A dose 
regimen of 2.1 mg QW is predicted to result in a trough concentration of >320 µg/mL, the 
predicted EC95 from an ex vivo SEB cytokine assay, in 62% of patients. The dose and 
regimen may be optimized based on ongoing exposure-response analysis.
The supporting data for the RDE from Part A can be found in the current RO7121661 
Investigator’s Brochure.
4.5
END OF STUDY DEFINITION
The end of the study is defined as the last participant’s last visit (LPLV) per protocol 
(includes the safety follow-up visit 60 days (Part A) or 90 days (Part B) after last dose of 
study drug) or the date at which the last data point from the last participant required for 
statistical analysis is received (last participant, last observation), whichever is the latest 
date. Because of the exploratory nature of this clinical study, any part of 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 4.3.1.
The study population consists of male and female participants with advanced and/or 
metastatic solid tumors.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Participants enrolled in the study but who do not maintain eligibility or withdraw consent 
prior to the first dose will not be included in the database.
5.1
INCLUSION CRITERIA
General Inclusion Criteria for Parts A and B
Participants are eligible to be included in the study only if all of the following criteria 
apply prior to dosing on Cycle 1, Day 1.


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Informed Consent
1.
Signed written informed consent and ability to comply with the study protocol 
according to International Council for Harmonization 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 A only: Patients with advanced and/or metastatic solid tumors who have 
progressed on a cancer therapy, for whom no effective standard therapy exists, or 
who decline treatment with approved therapies.
4.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and a life 
expectancy of 12 weeks.
5.
Adequate cardiovascular function:

New York Heart Association (NYHA) Heart Failure Stage2.

Baseline-corrected QT (QTcF) interval470 ms.

Resting systolic blood pressure150 mmHg and diastolic blood pressure 100 
mmHg (average of3 readings on 2 sessions with short break between 
sessions) (no clinically significant hypertension).

Resting heart rate (HR) between 45-100 bpm (no clinically significant 
tachycardia).
6.
Adverse events from any prior radiotherapy, chemotherapy, or surgical procedure 
must have resolved to Grade 1, except alopecia (any grade), vitiligo, 
endocrinopathy managed with replacement therapy and Grade 2 peripheral 
neuropathy.
7.
Adequate hematological function: neutrophil count of1.5109 cells/L (1500/l), 
platelet count of100109/L (100,000/L), hemoglobin9 g/dL (90 g/L), lymphocyte 
count of0.5109 cells/L (500/L).

Hemoglobin must be stable for at least a week without need for packed red 
blood cell transfusion.
8.
Adequate liver function: total bilirubin1.5ULN; aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), and alkaline phosphatase2.5ULN; with the 
following exceptions:

Participants with known Gilbert disease or hepatocellular carcinoma: serum 
bilirubin level3ULN.

Participants with documented liver metastases: AST and ALT5ULN.

Participants with documented liver or bone metastases: ALP5ULN.


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9.
Adequate renal function: serum creatinine1.5ULN or creatinine clearance by 
Cockcroft-Gault formula50 mL/min for participants in whom, in the Investigator‘s 
judgment, serum creatinine levels do not adequately reflect renal function. Cockcroft-
Gault glomerular filtration rate estimation:
(140age)(weight in kilograms)(0.85 if female)
72(serum creatinine in mg/dL)
10. Additional adequate laboratory parameters: 

Serum albumin25 g/L (2.5 g/dL).

For participants not receiving therapeutic anticoagulation: Prothrombin time 
(PT) and activated partial thromboplastin time (aPTT)1.5ULN or 2ULN 
for participants with HCC.

For participants receiving therapeutic anticoagulation: stable anticoagulant 
regimen.
11. Negative HIV test at screening.
12. Negative hepatitis B surface antigen (HBsAg) test at screening.
13. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening.

The HBV DNA test will be performed only for participants who have a positive 
total HBcAb test.
14. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody 
test followed by a negative HCV RNA test at screening.

The HCV RNA test will be performed only for participants who have a positive 
HCV antibody test.
15. Diagnosis of locally advanced and/or metastatic solid tumors with radiologically 
measurable disease according to RECIST v1.1.

Previously irradiated lesions should not be counted as target lesions unless 
clearly progressed after the radiotherapy.

Participants must have at least one measurable lesion (target lesion [TL]) not 
intended to be biopsied.

Lesions that are intended to be biopsied should not be counted as target 
lesions.
Contraception
16. Male and/or 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 


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abstinence (e.g., calendar, ovulation, symptom-thermal, 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:

Not a woman of childbearing potential (WOCBP, as defined in Section 1 of 
Appendix 5).

WOCBP, who:
–
Agree to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive methods that result in a failure rate of 1% per year during 
the treatment period and for at least 4 months after the final dose of 
RO7121661.
–
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal occlusion, male sterilization, established proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices and copper intrauterine devices (see Appendix 5).
–
Have a negative pregnancy test (blood) within the 7 days prior to the first 
study RO7121661 administration.
b)
Male Participants
During the treatment period and for at least 4 months after the final dose of 
RO7121661, agreement to:

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that 
together result in a failure rate of 1% per year, with partners who are women 
of childbearing potential (WOCBP, as defined in Section 1 of Appendix 5).
With pregnant female partners, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid
exposing the embryo.

Refrain from donating sperm during this period.
Specific Inclusion Criteria for Biopsies
17. Participants who are enrolled on the parts of the study where fresh biopsies are 
requested (i.e. biomarker cohort(s) and expansion cohorts B1, B2, B3, B4 and B5)
must have at least one non-target tumor lesion accessible to biopsy per clinical 
judgment of the treating physician and consent to undergo mandatory fresh baseline 
and on-treatment biopsy. Participants in Part B, presenting with only one target 
lesion and no non-target lesions that can be biopsied may omit mandatory biopsies. 
In such cases, the Medical Monitor is available to the Investigator to advise and 
answer any questions in this regard. A lesion with evidence of progression by 
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accurately. Bone lesion biopsies, bronchoscopy/trans-bronchial biopsies, and 
cytology fine needle aspirates are not acceptable.
Specific Inclusion Criteria for Part B Expansion in CPI Experienced Patients
CPI experienced patients are defined in this study as those who have had prior 
treatment with an anti-PD-1 or anti-PD-L1 agent. Participants must meet the following 
additional criteria to be eligible for inclusion in Part B of the study if they are CPI 
experienced.
18. Participants with advanced and/or metastatic malignancies who have progressed on 
an anti-PD-L1/ anti-PD-1 agent.
19. Participants who are considered to be deriving benefit from treatment post 
progression, as per clinical judgment, are not considered eligible. Screening tumor 
assessment should confirm progression.
20. Prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may have 
been administered as indicated for the respective indications, with the exception of 
adjuvant therapy.
Melanoma Cohort (CPI-Experienced; Part B1)
21. Participants with histologically confirmed advanced metastatic melanoma previously
treated with approved anti-PD-L1/anti-PD-1 agents with or without approved 
anti-CTLA-4 therapy and up to one additional treatment regimen

Eligibility of participants receiving previous treatment with non-approved anti 
PD-1 or anti-PD-L1 inhibitors or combination treatment with other non-approved 
agent(s) may be discussed with the Medical Monitor prior to enrollment. The 
decision to enroll the patient in the study is the responsibility of the 
Investigator.
22. Participants whose tumors have a known BRAFV600 mutation must also have 
experienced disease progression (during or after treatment) or intolerance with
BRAF inhibitor(s) and/or MEK inhibitor(s) if treatment is available. Participants with 
BRAFV600 mutation but refusing such inhibitor(s), or not available to them, will be 
eligible.
23. Enrollment will be managed so that:

No more than approximately 10% of participants in this cohort will be 
participants with ocular (uveal) melanoma.

Up to 10 patients with primary resistance to CPI will initially be enrolled. This 
may be expanded if efficacy and or biomarker assessments for proof of 
mechanism warrant further exploration.
–
Primary resistance is defined as Investigator assessed best overall 
response of progressive disease within the first 10 weeks of anti-PD-
L1/anti-PD-1 treatment.

If a scan within the first 10 weeks exists and shows progressive 
disease the patient is considered primary resistant (i.e. the scan 


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result cannot be overruled by investigator assessment of clinical 
benefit). 

Should a subsequent scan for the same line of treatment show 
clinical benefit after initial radiographic progression (i.e. 
pseudoprogression) the patient is not considered primary 
resistant.
NSCLC Cohort (CPI-Experienced; Part B2)
24. Participants with histologically confirmed advanced NSCLC previously treated with 
approved PD-L1/PD-1 inhibitors and platinum based chemotherapy, either 
sequentially or concurrently.

Eligibility of participants receiving previous treatment with non-approved anti 
PD-1 or anti-PD-L1 inhibitors or combination treatment with other non-
approved agent(s) may be discussed with the Medical Monitor prior to 
enrollment. The decision to enroll the patient in the study is the responsibility 
of the Investigator.
25. Patients must be PD-L1 ( ) defined as 1% PD-L1 expression based on 
immunohistochemistry using antibody clone 22c3, sp263 or 28-8. Expression will be 
determined in a fresh tumor biopsy collected during study screening or a possibly 
available archival sample, provided that the latter is not older than 12 months and 
has been obtained after failure of last CPI treatment line and prior to receiving study 
treatment.
26. Participants must have experienced Investigator assessed initial clinical benefit 
(stable disease or better) from most recent CPI therapy for at least 4 months. 

If a scan within the first 4 months exists and shows progressive disease the 
patient is not eligible, (i.e. the scan result cannot be overruled by Investigator 
assessment of clinical benefit). 

Should a subsequent scan for the same line of treatment show clinical benefit 
after initial radiographic progression (i.e. pseudoprogression) the patient is 
eligible.
27. Patients should have had only one CPI and one platinum based regimen, whether 
sequentially or concurrently. The acceptable sequences are:

Platinum-based chemotherapy (1L) CPI treatment (1L); i.e., study treatment 
is second line therapy

Platinum-based chemotherapy (1L) CPI treatment (2L); i.e., study treatment 
is third line therapy

CPI treatment (1L) Platinum-based chemotherapy (2L); i.e., study treatment 
is third line therapy
–
Adjuvant chemo-radiation treatment with anti-PD-1/PD-L1 inhibitors or 
consolidation treatment with anti-PD-1/PD-L1 inhibitors after definitive 
chemo-radiation therapy is allowed but participants do require an additional 
line of anti-PD-1/PD-L1 treatment in the metastatic setting. 


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Specific Inclusion Criteria for Part B3 Expansion in PD L1 High, CPI Naïve, First 
Line NSCLC Cohort
28. Participants with histologically confirmed advanced NSCLC with PD-L1 high defined 
as 50% PD-L1 expression based on immunohistochemistry using antibody clone 
22c3, sp263, or 28-8. Expression will be determined in a fresh tumor biopsy collected 
during study screening or a possibly available archival sample, provided that the 
latter is not older than 12 months and has been obtained after failure of last CPI 
treatment line and prior to receiving study treatment.
Specific Inclusion Criteria for Part B4 Expansion in CPI-Naïve SCLC Cohort
29. Participants must have histologically confirmed SCLC.
30. Participants may have had prior chemotherapy, radiation therapy or declined 
approved therapies for SCLC.
Additional Specific Inclusion Criteria for Part B5: CPI Naïve Esophageal 
Squamous Cell Carcinoma
31. Participants whose major lesion was histologically confirmed squamous cell 
carcinoma or adenosquamous cell carcinoma of the esophagus.
32. Patients who have previously received not more than 1 prior lines of treatment for 
metastatic disease prior to enrolling to the study. The prior line must be a 
fluoropyrimidine and platinum-based regimen and patients must have experienced 
progressive disease.
33. Patients who underwent a radical resection (R0 resection confirmed) in conjunction 
with chemotherapy with fluoropyrimidine and platinum-based drugs including neo-
adjuvant/adjuvant therapy and chemo-radiation (including patients who underwent 
chemo-radiation followed by salvage surgery) are allowed. 
o
If recurrence was confirmed by imaging within 24 weeks after the last dose of 
the treatment, the therapy should be counted as equivalent to metastatic 
treatment. Such patients are eligible and do not require an additional line of 
therapy in the metastatic setting. 
o
If recurrence occurred later than 24 weeks after the completion of the initial neo-
adjuvant/adjuvant therapy the patients need to be exposed to an additional line 
of fluoropyrimidine and platinum-based drugs in the metastatic setting to be 
eligible for the study - unless the investigator considers the patient not eligible 
for the re-exposure with fluoropyrimidine and platinum-based drugs.
5.2
EXCLUSION CRITERIA
General Exclusion Criteria for Parts A and B
Participants are excluded from the study if any of the following criteria apply prior to 
dosing on Cycle 1, Day 1:
1.
Pregnancy, lactation, or breastfeeding.


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2.
Known hypersensitivity to any of the components of RO7121661, including but not 
limited to hypersensitivity to Chinese hamster ovary cell products or other 
recombinant human or humanized antibodies.
Medical Conditions
3.
Known symptomatic central nervous system (CNS) metastases.

Participants with previously treated brain metastases may participate provided 
they:

Are stable (without evidence of progression by CT or MRI for at least 4 weeks 
prior to Cycle 1/Day 1).

Have no evidence of new or enlarging brain metastases within at least 4 weeks 
from Cycle 1/Day 1.

Are off systemic steroids for at least 28 days prior to Cycle 1/Day 1
4.
Spinal cord compression not definitively treated with surgery and/or radiation or 
without evidence that disease has been clinically stable for 2 weeks before 
Cycle 1/ Day 1.
5.
Active or history of carcinomatous meningitis/leptomeningeal disease. Known 
asymptomatic CNS primary tumors or metastases if they have requirement for 
steroids or enzyme-inducing anticonvulsants in the last 28 days prior to Cycle 1/
Day 1.
6.
Participants with an active second malignancy. Concurrent malignancy exceptions 
include: curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer and any previously 
treated early stage non-hematological malignancy that has been in remission for at 
least two years.
7.
Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including diabetes mellitus, 
history of relevant pulmonary disorders, and known autoimmune diseases or 
immune deficiency, or other disease with ongoing fibrosis (such as scleroderma, 
pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis, 
etc.).
8.
Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed 
consent.
9.
Severe dyspnea or requiring supplemental oxygen therapy at rest.
10. Significant cardiovascular/cerebrovascular vascular disease within 6 months prior to 
Day 1 of study drug administration, including any of the following: 

hypertensive crisis/encephalopathy

unstable angina

transient ischemic attack/stroke

congestive heart failure (for NYHA classification, refer to inclusion criteria)


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
serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, 
paroxysmal supraventricular tachycardia)

history of thromboembolic events (such as myocardial infarction, stroke or 
pulmonary embolism)
11. Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not 
limited to tuberculosis [TB] and typical mycobacterial disease), parasitic, or other 
infection (excluding fungal infections of nail beds) or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of 
the course of antibiotics, except if for tumor fever) within 4 weeks prior to the start of 
drug administration.
12. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease.
13. Major surgical procedure or significant traumatic injury (excluding biopsies) within 
28 days prior to Cycle 1, Day 1 (i.e., first RO7121661 infusion), or anticipation of the 
need for major surgery during the course of the study.
14. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the participant at high risk from treatment 
complications.
15. Dementia or altered mental status that would prohibit informed consent.
16. Uncontrolled pleural effusion (with the exception of participants with indwelling 
catheters, e.g. PleurX), pericardial effusion, or ascites requiring recurrent drainage 
procedures (expected to occur once monthly or more frequently). 
17. Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis, with the following exceptions:

Participants with a history of autoimmune-mediated hypothyroidism or 
endocrinopathy who are on thyroid-replacement hormone or appropriate 
replacement therapy are eligible for the study.

Participants with controlled Type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study.

Participants with eczema, psoriasis, lichen simplex chronicus or vitiligo with 
dermatologic manifestations only (e.g., participants with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
–
Rash must cover 10% of body surface area
–
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids


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–
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months
Prior/Concomitant Therapy
18. Vaccination with live vaccines within 28 days prior to the start of treatment.
19. For Part A, Part B1 (CPI experienced melanoma patients) and Part B2 (CPI and 
platinum experienced NSCLC patients), prior treatment with CPIs, 
immunomodulatory mAbs, and/or mAb derived therapies is allowed, with the 
following exceptions:

4 weeks have elapsed between the last dose of prior anti-PD-1 and the 
proposed Cycle 1, Day 1

5 half-lives or 28 days (whichever is shorter) have elapsed from prior 
treatment with specific immunomodulators, TLR agonists, inhibitors of 
IDO/TDO, or agonists (e.g., OX40)

Prior treatment with adoptive cell therapies, such as CAR-T therapies is not 
permitted
20. Prior treatment with a TIM-3 inhibitor is prohibited.
21. Concurrent therapy with any other investigational drug (defined as treatment for 
which there is currently no regulatory authority-approved indication) 28 days or 
5 half-lives of the drug, whichever is shorter, prior to the first RO7121661 
administration on Cycle 1, Day 1 is prohibited.
22. Immuno-modulating agents:

Last dose with any of the following agents, for example, etanercept, infliximab, 
tacrolimus, cyclosporine, mycophenolic acid, alefacept, or efalizumab (or similar 
agents)28 days prior to Cycle 1, Day 1 is prohibited.

Regular immunosuppressive therapy (i.e., for organ transplantation, chronic 
rheumatologic disease) is prohibited.
23. Chronic use of steroids (excluding topical and inhaled) and concurrent high doses of 
systemic corticosteroids will not be allowed. Participants receiving baseline 
corticosteroid therapy (10 mg prednisone/day or equivalent) within 1 week prior to 
the first dose of study drug are excluded.
24. Radiotherapy within the last 4 weeks before start of study drug treatment is not 
allowed, with the exception of limited palliative radiotherapy.
25. Enrollment of participants who require blood transfusion (before and after the start 
of the study) is at the discretion of the Investigator. The Medical Monitor/Sponsor 
is available to the Investigator to advise and answer any question as needed.


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Specific Exclusion Criteria for Part B1 and Part B2 Expansion cohorts (CPI 
experienced patients)
26. Any history of an immune-mediated Grade 4 adverse event attributed to prior cancer 
immunotherapy (other than endocrinopathy managed with replacement therapy or 
asymptomatic elevation of serum amylase or lipase)
27. Any history of an immune-mediated adverse event attributed to prior CIT (other than 
endocrinopathy managed with replacement therapy or asymptomatic elevation of 
serum amylase or lipase) that resulted in permanent discontinuation of the prior 
immunotherapeutic agent.
28. All immune-mediated adverse events related to prior immunomodulatory therapy 
(other than endocrinopathy managed with replacement therapy or stable vitiligo) 
must have resolved completely to baseline. Participants treated with corticosteroids 
for immune-mediated adverse events except for corticosteroids replacement therapy 
for adrenal insufficiency (provided that the patient receives 10 mg prednisone/day 
or equivalent), must demonstrate absence of related symptoms or signs for 4 
weeks following discontinuation of corticosteroids.
Specific Exclusion Criteria for Part B3 Expansion (1st line CIT naïve patients)
29. Prior therapy for metastatic disease is not permitted i.e., treatment with any immune 
CPIs (such as anti-PD-L1/PD-1, CTLA-4), immunomodulatory mAbs, other 
immunomodulator therapies, chemotherapy or TKIs.
30. Adjuvant anti-PD-1 or anti-PD-L1 therapy is not allowed. Adjuvant chemotherapy is 
permitted as long as treatment was administered 6 months prior to Cycle 1, Day 1.
Specific Exclusion Criteria for NSCLC patients (Part B2)
31. NSCLC patients with the following mutations, rearrangements, translocations are 
not eligible for Part B2: EGFR; ALK; ROS1, BRAFV600E, NTRK
Specific Exclusion Criteria for Part B4 Expansion (CPI-naïve SCLC patients)
32. Prior therapy with any immune CPIs (such as anti-PD-L1/PD-1, anti-CTLA-4), is not 
permitted.
Specific Exclusion Criteria for Part B5: CPI Naïve Esophageal Squamous Cell 
Carcinoma
33. Prior therapy with any immunomodulatory agents including CPIs (such as anti-PD-
L1/PD-1, anti-CTLA-4), is not permitted.
5.3
LIFESTYLE CONSIDERATIONS
Participants will be expected to follow protocol requirements for contraception (see) and 
study center rules during visits, but there are no other lifestyle restrictions during the 
study. 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.
All screening evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before entering 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, after advice from the 
Sponsor. In case of uncertain or questionable results, any of the tests performed during 
Screening may be repeated before study drug administration to confirm eligibility (or 
clinical significance).
Biopsy samples will only be entered in the eCRF and analyzed for enrolled participants.
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.


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5.5
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, Institutional Review Board (IRB)/Ethics Committee (EC) approved newspaper/radio
advertisements, and mailings 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.
All investigational medicinal products (IMPs) required for completion of this study 
(RO7121661) will be provided by the Sponsor. All study drug administration will be at the 
study center under supervision of site staff.
6.1
TREATMENTS ADMINISTERED
Table 5 summarizes the treatments administered.
Table 5
Summary of Treatments Administered
Ro 712-1661/F01-01 (Active)
Ro 712-1661/F02-01 (Diluent)
Administration
Intravenous a
Dosage form
Concentrate for solution for i.v. 
infusion
Solution for infusion. For i.v. 
infusion
Concentration of RO7121661
50 mg/mL
0 mg/mL
Primary packaging
6-mL colorless glass vial
20-mL colorless glass vial
Extractable volume
6.0 mL
20.0 mL
a 0.2-m inline filter to be used for drug administration.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the Investigator’s Brochure and Pharmacy Manuals for more details.
6.1.1
RO7121661
Ro 712-1661/F01-01 drug product can be administered IV, either undiluted or diluted, as 
directed in the study protocol and the Pharmacy Manual. If diluted, Ro 712-1661/F01-01 
drug product must be diluted either in 0.9% (w/v) sodium chloride solution or in the 
Sponsor’s diluent, Ro 712-1661/F02-01, as directed in the Pharmacy Manual. A 0.2 µm 
inline filter must be mandatorily used with the infusion set during administration.
In Part A, the initial dose and subsequent infusions of RO7121661 will be delivered over 
120 10 minutes (although the infusion may be slowed or interrupted for participants 


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who experience infusion-associated symptoms; see Section 8.3.8.1), followed by a 
90-minute observation period. If no IRR has been reported, the catheter may be 
removed at the end of the observation period.
In Part B, the initial dose of RO7121661 will be delivered over 120 10 minutes 
(although the infusion may be slowed or interrupted for participants who experience 
infusion-associated symptoms; see Section 8.3.8.1), followed by a 90-minute 
observation period. If the 120-minute infusion is tolerated without infusion-associated 
AEs, the second infusion may be delivered over 60 10 minutes, followed by a 60 
minute observation period. If the 60-minute infusion is well-tolerated, all subsequent 
infusions may be delivered over 30 10 minutes, followed by a 30-minute observation 
period. If no IRR has been reported, the catheter may be removed at the end of the 
observation period.
During infusion, vital signs (including, if possible, supine diastolic and systolic blood 
pressure, pulse rate, and temperature) must be monitored as described in the SoA 
(Section 1.3). Vital signs during the infusion are not required to be captured in the eCRF, 
unless abnormalities are observed.
If feasible, the line for drawing blood for PK samples (opposite extremity to the one with 
the infusion line) will remain in place until the 24-hour sample is taken.
Dose, date, and time of the infusion start, date and time of end of infusion, total dose 
administered, interruption or adjustment of infusion rate, and reason will be recorded for 
each participant. If the infusion is interrupted, the date and time of stopping and 
resuming will be recorded.
6.1.2
Pre-medication
No pre-medication is foreseen prior to the first administration of RO7121661.
However, if administered, all pre-medications should be captured as concomitant 
medications in the participant’s electronic Case Report Form (eCRF).
If Grade2 IRRs or tumor inflammatory events occur in the majority of participants 
during dose escalation, the utility of prophylactic pre-medications including paracetamol 
and antihistamine may be considered for newly enrolled participants and premedication 
regimen and schedule should be discussed between Sponsor and Investigator(s).  
Participants who experienced a Grade 2 or higher IRR on a previous infusion should be 
pre-medicated for subsequent infusions. 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 


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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 RO7121661 administrations. The 
event will be reported as a single AE (e.g., fever). Pre-medication with corticosteroids for 
those participants at subsequent infusions needs approval from the Sponsor and the
treatment and management at the time of a single and isolated event is at the discretion 
of the Investigator.
All pre-medications should be captured as concomitant medications in the participant’s 
electronic Case Report Form (eCRF).
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Roche 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 Roche 
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 utilizing the Pharmacy Manual.
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 


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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).
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
Study NP40435 is a non-randomized open-label study. The specific treatment to be 
administered to the participant will be assigned using an IRT. An IRT User Guide will be
provided to each site.
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the cohort assignment. This individual will write the date 
dispensed and participant number on the study treatment vial label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study.
6.5
CONCOMITANT THERAPY
For the purpose of the study, RO7121661 is considered investigational medicinal 
product (IMP). All other medications given during the study are considered non-IMPs. 
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 can advise if there are any questions 
regarding concomitant or prior therapy.


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All concomitant medications or vaccines should be reported to the Investigator and 
recorded on the Concomitant Medications electronic Case Report Form (eCRF). All 
therapy and/or medication administered to manage adverse events should be recorded 
on the Adverse Event eCRF.
Radiotherapy 
Participants should not receive study treatment during radiation treatment.
The use of limited field palliative radiotherapy is allowed at any time during the study, 
except for: 

Days where RO7121661 is administered. 

During the DLT evaluation window. 
–
If radiotherapy is administered during the DLT evaluation window, the 
participant will not be evaluable. 
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 and therapy for pre-existing 
conditions, unless the rationale for exception is discussed and clearly documented.
Use of the following therapies is prohibited during the study and for at least 28 days or 
5 half-lives of the drug, whichever is shorter, prior to initiation of study treatment, unless 
otherwise specified below:

Investigational or unlicensed/unapproved agents 

Immunotherapy/radio-immunotherapy 

Chemotherapy / targeted therapy

Radiotherapy (with the exception of limited field palliative radiotherapy). 

Biologic agents (e.g., bevacizumab, cetuximab). 

Chronic use of steroids (inhaled and topical steroids are permitted) at baseline 
of 10 mg of prednisone/day or equivalent. Concurrent high doses of systemic 
corticosteroids will not be allowed. 

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.


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6.6
DOSAGE MODIFICATION
Instructions for RO7121661 administration, change of infusion rate, and interruption of 
infusion are provided in Section 6.1 and Section 7.
Participants who experience toxicities fulfilling the definition of a DLT in the first cycle, or 
DLT-equivalent toxicities in subsequent cycles should be discontinued from study 
treatment. Nevertheless, the Investigators, after discussion with the Sponsor, will have 
the option to reduce the dose of RO7121661 to the previous tolerated dose level, if 
participant is deemed to be deriving clinical benefit.
A delay of RO7121661 administration for up to two cycles, will be acceptable to allow for 
resolution of toxicity to NCI CTCAE Grade 2 for hematological toxicities or Grade 1 
for non-hematological toxicities (with the exception of a toxicity considered as non-
RO7121661 related).
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 RO7121661 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 discussed 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.
For participants with documented liver metastasis and elevated liver function test (LFT) 
results at baseline, further elevations of LFT results may not require dose interruptions if 
there are no progressive changes in the ALT and/or AST (less than a doubling) and if 
there are no progressive elevations in total bilirubin or international normalized ratio 
(INR).
Investigators are encouraged to contact the Sponsor for further guidance if needed. After 
Cycle 1 is completed, dose modifications should be discussed with the Sponsor. In these 
instances, a confirmation with the Sponsor is requested and documentation in the eCRF 
is requested. Treatment delays of up to 3 days due to logistical considerations (e.g., 
center closure for holiday) are generally acceptable and do not need to be discussed 
with the Sponsor. In no instance are cycles shorter than 14 days of duration (i.e. Q2W) 
allowed in this study.
For participants on treatment for at least 4 cycles, minor elective surgery will be 
permitted with resumption of treatment as soon as possible post-procedure, assuming 
normal recovery (see Section 7.1.1 for temporary interruption or dose delay). This can 


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be done to allow participants who could potentially benefit from RO7121661 to remain 
on the study treatment.
6.7
TREATMENT AFTER THE END OF THE STUDY
Currently, the Sponsor does not have any plans to provide RO7121661 or any other 
study treatments or interventions to the participants after the end of the study or when 
participants discontinue or have been withdrawn from the study. The Sponsor will 
evaluate whether to continue providing RO7121661 to participants after the main study 
is over, in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
7.
DISCONTINUATION OF STUDY 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 Study Governance 
Considerations Study.
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.
Participants must permanently discontinue study treatment if they experience any of the 
following (also see Appendix 6):

Intolerable toxicity related to study treatment, including development of an immune 
mediated adverse event determined by the Investigator to be unacceptable given 
the individual participant's potential response to therapy and severity of the event

Pregnancy.

Grade 4 IRR.

IgE-mediated hypersensitivity reactions, including anaphylaxis.

Any toxicity which is not manageable with dose delays (as allowed per protocol), 
dose decrease, and appropriate treatment.

Unacceptable toxicity as determined by Investigator.  


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
For cardiac changes: 
o
If a clinically significant finding is identified (including, but not limited to 
QTcF500 ms and/or an increase of60 ms in QTcF from screening), 
the Investigator or qualified designee will determine if the participant can 
continue in the study and if any change in clinical management is needed. 
This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an 
AE. 

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study. 

Investigator or Sponsor determines it is in the best interest of the participant. 

Participant non-compliance, specifically defined as disregarding protocol. 

Symptomatic disease progression when there is a consensus that the participant 
will not benefit from study treatment.
As with other immunotherapies, treatment beyond RECIST Version 1.1 progression may 
be considered following discussion between the Investigator and the Sponsor. When 
considering treatment beyond progression, locally approved and available treatment 
options need to be taken into account.
The criteria below are needed for continuing treatment beyond initial apparent 
progressive disease per RECIST Version 1.1 (e.g., radiological progression secondary 
to tumor inflammation): 

Absence of clinically important symptoms and signs (including worsening of 
laboratory values) indicative of disease progression

Investigator-assessed potential clinical benefit for the participant 

The participant is tolerating study drugs. 

No decline in ECOG performance status.

Absence of rapid progression of disease or of progressive tumor at critical
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.
Participants who discontinue study treatment 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 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 and will not be entered into the database.


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
Participants who fail to complete their DLT assessment period because of non-drug-
related reasons.

In the case of a major protocol violation participants will be excluded from the 
MTD/DLT analysis but might continue the treatment if deemed beneficial, and if there 
is no safety concern associated with the protocol violation criteria and according to 
clinical judgment. 
Participants will be treated until disease progression, loss of clinical benefit, 
unacceptable toxicities, or withdrawal from treatment for other reasons, or death.
7.1.1
Temporary Interruption
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator or Sponsor), an interruption should be considered. 
Participants, who have temporarily interrupted study treatment, should be considered to 
re start as soon as medically justified in the opinion of the Investigator.
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed. The acceptable length of interruption will depend on the discussion between the 
Investigator and the Medical Monitor.
In case of toxicity requiring RO7121661 treatment to be put on hold, the study treatment 
should only re-start once the toxicities have resolved to NCI CTCAE Grade 2 for 
hematological toxicities or Grade 1 for non-hematological toxicities. Participants who 
do not recover from drug-related toxicities after omission of up to 2 doses (delay of 4
weeks in the Q2W schedule) of RO7121661 and who in the opinion of the Investigator 
are not receiving clinical benefit from RO7121661 treatment, should be permanently 
discontinued from the study. 
If in the judgment of the Investigator, the participant is likely to derive clinical benefit from 
RO7121661 after a hold of more than 2 doses, study drug may be re-started.
If an IRR develops, the infusion of RO7121161 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). 
Study treatment should be re-started as soon as medically justified in the opinion of the 
Investigator.
7.1.2
Resumption of Study Treatment
If a participant has a complete response (CR) or achieves maximum clinical benefit as 
determined by the Investigator and the Sponsor after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status, the study treatment 


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may be paused at the discretion of the treating physician after discussion with the
Medical Monitor. The participant may remain on study and be followed according to the 
SoA (Section 1.3). If the disease relapses or progresses, the study treatment may be 
resumed after consultation with the Medical Monitor.
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. Reasons for withdrawal from the 
study may include, but are not limited to, the following:

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he/she continues in the study.

Investigator or Sponsor determines it is in the best interest of the participant.

Participant non-compliance.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will 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 will be replaced (see 
Section 7.1).
See 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.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant repeatedly fails to
return for scheduled visits and is unable to be contacted by the study site.


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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 
have withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the Schedules of Activities 
(SoA; Section 1.3). Protocol waivers or exemptions are not allowed.
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.
Certain samples for exploratory tests will be sent to one or several central laboratories or 
to the Sponsor for analysis. Instruction manuals and supply kits will be provided for all 
central laboratory assessments.
Based on continuous analysis of the data in this study, any sample type or time-point 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 response will be evaluated according to RECIST Version 1.1 (see Appendix 7)
and modified criteria for immunotherapies (see Appendix 8 for iRECIST). Response will 
be assessed by the Investigator on the basis of physical examinations and CT scans (or 
magnetic resonance imaging [MRI]) of chest, abdomen, and pelvis as defined in the SoA
(Section 1.3). CT scans of the neck should be included, if clinically indicated. Ultrasound 
and X rays are not acceptable for monitoring target lesions. All measurable disease must 


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be documented at Screening and re assessed at each subsequent tumor evaluation. 
Consistency of consecutive CT scans (or MRIs) should be ensured during all 
assessments for each participant; the same method of assessment (preferable also by 
same evaluator) and the same technique must be used to evaluate lesions throughout 
the entire study. Use of CT (or MRI) is required for baseline lesions 20 mm and must 
be documented in medical records and used consistently throughout the study. The 
same radiographic procedure used to define measurable disease sites at Screening 
must be used throughout the study (e.g., the same contrast protocol for CT scans). 
Tumor measurements should be made by the same Investigator/Radiologist for each 
participant during the study to the extent that this is feasible. At the Investigator’s 
discretion, CT scans may be repeated at any time if progressive disease is suspected. 
In case of clinically measurable superficial (such as skin) lesions, repeated photographs 
should be used to document tumor response (Section 8.1.2).
The data collected for RECIST v1.1 will be used by the Sponsor to calculate 
programmatically timepoint responses for iRECIST, a recently published guideline 
developed by the RECIST working group in an effort to harmonize immune-based 
response criteria across the academic and industrial cancer immunotherapy field
(Appendix 8).
In the absence of clinical deterioration, any initial assessment of radiological progressive 
disease or mixed response should be confirmed by a repeat evaluation at the next time 
point for tumor assessment. As with other immunotherapies, treatment beyond RECIST 
progression could be considered after approval of the Sponsor. The criteria needed for 
continuing treatment beyond initial apparent progressive disease (e.g., radiological 
progression secondary to tumor inflammation) are described in Section 7.1.2.
Tumor assessment will be performed at the time points described in the SoA 
(Section 1.3). All tumor assessments after baseline may be done within 7 days of the 
scheduled visit. Confirmation of objective responses (partial and complete responses) 
will be done at the next scheduled visit after at least 28 days from the initial response. If 
disease progression is determined solely by symptomatic deterioration, a RECIST 
Tumor Assessment eForms must be completed at that time indicating disease 
progression. At the Investigator’s discretion, CT scans may be repeated at any time if 
progressive disease is suspected.
8.1.2
Photography of Cutaneous Lesions
Cutaneous lesions not evaluable by CT or MRI will be documented by color digital 
photography, including a ruler to estimate lesion size. Cutaneous lesions may be 
considered target lesions if they meet RECIST 1.1 criteria (see Appendix 7), otherwise 
they may be considered non-target lesions.


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Photographs of cutaneous lesions will be taken at screening and on the same day as
tumor assessment visit or at the first clinic visit following each tumor assessment.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3). On 
dosing days, the safety assessments are to be performed prior to the study treatment 
administration. If the assessments have been performed within maximum 72 hours prior 
to dosing, they do not need to be repeated on the scheduled dosing day.
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological, 
musculoskeletal in addition to head, eyes, ears, nose, throat, neck and lymph nodes 
systems. Height and weight will also be measured and recorded. Further examination of 
other body systems may be performed in case of evocative symptoms at the 
Investigator’s discretion.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen)

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
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 adverse events on the Adverse 
Event eCRF.
8.2.2
Royal Marsden Hospital Risk Score
The Royal Marsden hospital risk score will be derived at screening for each participant
(Arkenau et al 2008).  This risk based score is derived from: (LDH normal0 vs 
LDHUNL1, albumin 35 g/L0 vs 35 g/L1, site of metastasis 20 vs 21).
8.2.3
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status will be assessed as specified in the SoA (Section 1.3). It 
is recommended, where possible, that a participant’s Performance Status will be 
assessed by the same person throughout the study.
8.2.4
Vital Signs
Routine vital signs including supine diastolic and systolic blood pressure, pulse rate, 
respiratory rate, and body temperature will be assessed as specified in the SoA (see 
Section 1.3), including during infusions of RO7121661.  Vital signs during the infusion 
are not required to be captured in the eCRF, unless abnormalities are observed.


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Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated 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).
Participants experiencing Grade3 vital sign abnormalities on the day of any 
administration of study treatment or at a previous cycle should stay at site for the next 
study treatment administration for at least 24 hours post infusion. In case of drop in 
blood pressure associated with hemodynamic instability and/or abnormal HR, 
particularly arrhythmia, RO7121661 administration should be interrupted and the 
participant should be fully monitored until normal cardiac function is regained.
8.2.5
Electrocardiograms
Triplicate 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. Refer to 
Section 7.1 for QTc withdrawal criteria and additional QTc readings that may be 
necessary.
At each time-point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 
approximately 2 minutes apart. The average of the 3 readings will be used to determine 
ECG intervals (e.g., PR, QRS, and QT). Additional unscheduled ECG assessments 
should be performed in case of abnormalities and if clinical symptoms occur. ECGs for 
each participant should be obtained from the same machine whenever possible.
To minimize variability, it is important that participants be in a resting position for at 
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 Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcB (Bazett’s correction, see Appendix 9), QTcF 
(Fridericia’s correction, see Appendix 9) and RR will be calculated by the Sponsor and 


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recorded on the eCRF. Changes in T‑wave and U‑wave morphology and overall ECG 
interpretation will be documented on the eCRF. T-wave information will be captured as 
normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
8.2.6
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 CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.

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.
If laboratory values from non-protocol specified laboratory assessments performed 
at the local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or 
dose-modification) then, the results must be recorded in the AE CRF.
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 lab results is considered uncertain, screening 
lab tests may be repeated before randomization to confirm eligibility.
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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8.2.7
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse} and all medications (e.g., prescription drugs, OTC 
drugs, herbal or homeopathic remedies, nutritional supplements) used by the participant 
within 30 days prior to the screening visit. 
Demographic data will include age, sex, and self‑reported race/ethnicity. Data on race 
and ethnicity will be used to explore associations between base-line demographic data 
and risk of adverse events.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 2.
The non-serious adverse events of special interest 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.
The Investigator and any qualified designees are responsible for ensuring that all 
adverse events (including assessment of seriousness, severity and causality; see
Appendix 2) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Appendix 2.
Procedures used for recording adverse events 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 adverse events at each participant’s contact. All 
adverse events, whether reported by the participant or noted by study personnel, will be 
recorded in the participant’s medical record and on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only serious adverse events caused by a protocol-mandated intervention should be 
reported (e.g., serious adverse events related to invasive procedures such as biopsies).
Any other adverse event should not be reported.
After initiation of study treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until the last follow-up visit 60 days (Part A) and 
90 days (Part B) after last dose. DLTs will be reported during the DLT assessment 
window.


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Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period – that is, after the last follow-up visit. 
However, if the Investigator learns of any SAE (including a death) or other adverse 
events 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 
adverse event information at all participant evaluation time-points.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the 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 serious adverse events 
considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant’s medical record to facilitate source 
data verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.


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8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a 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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a 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.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB and EC, 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 4 months after the final 
dose of RO7121661. 
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
4 months after the final dose of RO7121661.
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).


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8.3.6
Non-Serious Adverse Events of Special Interest
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Appendix 2 for reporting instructions).
Non-serious adverse events 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. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product. This term applies only
when a contamination of the study treatment is suspected.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
No disease-related events have been identified for this study.
8.3.8
Management of RO7121661 Specific Adverse Events
Based on the MoA, PD-1/TIM-3 is expected to show a safety profile that is similar to 
other CPIs. Toxicities from CPIs can be divided into infusion reactions and immune-
mediated adverse events (imAEs). Toxicities associated or possibly associated with 
RO7121661 treatment should be managed according to standard medical practice. 
Additional tests, such as autoimmune serology or biopsies, should be used to determine 
a possible immunogenic etiology.
Measures will be taken to ensure the safety of participants participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
participants during the study. Administration of RO7121661 will be performed in a 
monitored setting in which there is immediate access to trained personnel and adequate 
equipment and medicine to manage potentially serious reactions. 
For events in which management guidelines are not covered in this protocol, participants 
should be managed as deemed appropriate by the Investigator according to best 
medical judgment and local medical guidelines. Clinical judgment may be applied and 
risk/benefit consideration may suggest deviating from these guidelines. In this specific 
case, decisions on study treatments will be taken by the Investigator upon consultation 
with the Medical Monitor.


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8.3.8.1
Infusion-Related Reactions
Administration of therapeutic antibodies may cause IRRs characterized by symptoms 
such as fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, 
sweating, flushing, skin rash, tachycardia, tachypnea, headache, tumor pain, nausea, 
and/or vomiting. Respiratory and cardiac symptoms such as, bronchospasm, larynx, and 
throat irritation, wheezing, laryngeal edema and atrial fibrillation may also occur. Such 
reactions typically occur during or shortly after an infusion or within 24 hours after study 
treatment infusion, predominantly at the first infusion. The incidence and severity 
typically decrease with subsequent infusions.
Participants may also develop immunoglobulin (Ig)E mediated hypersensitivity reactions. 
IRRs may be indistinguishable from an anaphylactic reaction; however, in case of IgE 
mediated hypersensitivity, symptoms typically occur after previous exposure and very 
rarely with the first infusion. In case of confirmed IgE mediated hypersensitivity reaction, 
treatment should be permanently discontinued.
No premedication is indicated for the administration of Cycle 1 of RO7121661.  
However, patients who experience a grade 2 or higher infusion-related reaction (IRR) 
with RO7121661 should receive premedication for subsequent infusions (see Section 
6.1.2). In case of Grade 4 IRR related to RO7121661, the participant should be 
permanently discontinued from the study treatment. If an IRR occurs during the infusion 
of RO7121661, please refer to Table 6.


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Table 6
Recommendations for RO7121661 Infusion-Related Reaction 
Prevention and Management
aInfusion-Related Reactions
Guidance
Grade 1−2
Slow infusion to 50% or interrupt infusion
Give supportive treatmentb
Upon symptom resolution may resume infusion (if 
interrupted) at 50% starting rate.  The infusion must 
remain at the lower rate resulting in symptom resolution 
for the remainder of the infusion.
For grade 2 IRRs, subsequent cycles of RO7121661 
should be administered with pre-medication including 
acetaminophen/paracetamol and an antihistamine, such 
as diphenhydramine.
Notes:
1. For Grade 2 wheezing or urticaria, patient must also 
be pre-medicated prior to subsequent doses (as 
described above).
2. If symptoms recur with the same or greater severity 
following the slower or interrupted infusion, the infusion 
must be stopped immediately.  No further RO7121661 
will be administered for the cycle.
Grade 3
Discontinue infusion.  No further RO7121661 will be 
administered for the cycle.
Give supportive treatmentb
Subsequent cycles of RO7121661 should be 
administered with pre-medication including paracetamol, 
antihistamine and corticosteroids. c
Notes:
1. If symptoms recur despite pre-medications with the 
same or greater severity at subsequent cycles, the 
infusion must be stopped immediately and patient 
permanently discontinued from study treatment.
2. Patients who experience Grade 3 wheezing, 
bronchospasm or generalized urticaria at first occurrence 
must be discontinued from study treatment.
Grade 4
Discontinue infusion immediately
Give supportive treatment
Permanently discontinue study treatment


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a Refer to the NCI-CTCAE, v5.0 scale for the grading of symptoms.
b Supportive treatment: Patients should be treated with acetaminophen/paracetamol and an antihistamine, 
such as diphenhydramine, if they have not been administered in the last 4 hours.  Intravenous fluids (e.g., 
normal saline) may be administered as clinically indicated.  For bronchospasm, urticaria, or dyspnea, 
antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or 
bronchodilators may be administered per institutional practice.
c Subsequent infusions may be started at the original rate in consultation with the Medical Monitor.
8.3.8.2
Immune-mediated adverse events
Most immune-mediated adverse events (imAEs) observed with immunomodulatory 
agents have been mild and self-limiting, however such events should be recognized 
early and treated promptly to avoid potential major complications. Any organ or tissue 
can be involved, although some imAEs occur much more commonly than others. The 
most frequently occurring imAEs affect skin, colon, endocrine organs, liver, and lungs. 
Others are very infrequent, but may be very serious, even lethal, such as neurological 
disorders and myocarditis.
Discontinuation of RO7121661 may not have an immediate therapeutic effect, and in 
severe cases, immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNF-α inhibitors. 
RO7121661 therapy may be suspended for most Grade 2 toxicities, with consideration 
of resuming when symptoms revert to Grade 1 or less. Corticosteroids may be 
administered. Grade 3 toxicities generally warrant suspension of RO7121661 and the
initiation of high-dose corticosteroids (prednisone, 1-2 mg/kg/day, or 
methylprednisolone, 1-2 mg/kg/day). Corticosteroids should be tapered over the course 
of at least 4-6 weeks. Some refractory cases may require infliximab or other 
immunosuppressive therapy. In general, permanent discontinuation of RO7121661 is 
recommended with grade 4 toxicities, with the exception of endocrinopathies that have 
been controlled by hormone replacement. The management guidelines for imAEs 
associated with RO7121661 are provided in Appendix 6.
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 adverse event 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/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:

Contact the Sponsor’s Medical Monitor immediately.


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
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.

Obtain a blood sample for PK analysis within 14 days from the date of the last dose 
of study treatment, if advised by the Medical Monitor (determined on a case-by-
case basis).

Document the quantity of the excess dose, as well as the duration of the overdose, 
in the CRF.
For this study, any dose of RO7121661 greater than 150% of the recommended dose 
level will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose. 
8.5
PHARMACOKINETICS
Mandatory blood samples to evaluate concentrations of study treatment will be collected 
from an IV line from the arm opposite to that used for study treatment administration. 
The date and time of each sample collection will be recorded in the eCRF. RO7121661 
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 
RO7121661 can be adequately characterized (but without increasing overall blood 
collection volume for PK). This will be documented in a Note to File and a new SOA will 
be provided. Additional PK samples will be taken at the time of treatment 
discontinuation, if the participant experiences an infusion-related AE (such as an IRR), 
or if the participant experiences an AE leading to dose-reduction or delay of RO7121661 
administration (see Section 6.6).
Remaining volumes of PK samples may also be used for additional PK/ADA analysis or 
assay development or validation, for RO7121661-related exploratory analyses, or to help 
develop further blood tests for exploratory analysis (e.g., further characterization of 
immune responses), after they are used for the mentioned intended use and as deemed 
appropriate. 
The PK samples will be destroyed within 2 years after the date of final Clinical Study 
Report (CSR). Details on sampling procedures, sample storage, and shipment are given 
in the Study Flow Chart and Laboratory Manual.
8.5.1
Immunogenicity Assessments
Although RO7121661 is a human antibody, there is a risk that anti-drug antibody (ADA) 
against RO7121661 could develop, potentially reducing its efficacy and/or potentially 
resulting in symptomatic hypersensitivity reaction, in particular immune-complex 
reactions.


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Antibodies to RO7121661 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2 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 RO7121661 concentration.
Validated screening, confirmatory, and titer assays will be employed to detect ADAs 
against RO7121661.The date and time of each sample will be recorded in the eCRF. If 
required, ADA positive samples will be further characterized in an exploratory assay.
If required, remaining ADA samples may also be used for additional exploratory 
analyses (e.g., further characterization of immune responses) and/or PK/ADA assay 
development/validation experiments after the mentioned intended uses, as deemed 
appropriate.
The blood samples will be destroyed within 2 years after the date of final CSR. 
Details on sampling procedures, sample storage and shipment are documented in the 
Sample Handling Manual.
8.6
PHARMACODYNAMICS/EXPLORATORY BIOMARKERS
Blood and tissue samples will be collected as specified in the SoA (Section 1.3). The 
date and time of each sample collection should be recorded in the eCRF. Details on 
processes for collection and shipment of these samples can be found in the Laboratory 
Flow Chart.
These samples will be tested for protein, nucleic acid, or other tissue or blood derived 
biomarkers relating to the proposed mechanism of action of RO7121661. These include, 
but are not limited to, drug RO, cellular profile and activation status of immune cells in 
blood and tumor, cytokines and other soluble markers of inflammation.  Analysis 
techniques may include, but are not limited to, flow cytometry, immunohistochemistry, 
gene expression, and gene sequencing. DNA and/or RNA will be extracted for
exploratory research on genetic biomarkers (including, but not limited to, cancer-related 
genes and biomarkers associated with common molecular pathways, or immune-
mediated markers, microsatellite instability (MSI) and tumor mutational burden), and to 
enable genomic analysis for exploratory research on genetic biomarkers.
The specimens will also be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to RO7121661 treatment, identifying biomarkers 
useful for predicting and monitoring RO7121661 safety, assessing PD effects of 
RO7121661 treatment, and investigating mechanism of therapy resistance. This may 
include retrospective and longitudinal testing of bacterial or viral infection (including but 


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not limited to SARS-CoV-2) by serological methods. These analyses may inform any 
association of bacterial or viral infection and response to treatment.
Additional markers may be measured in case a strong scientific rationale for these
analyses develops. Any remaining samples after the specified analyses may also be 
used for additional (assay) validation experiments. Samples may be used for research to 
develop methods, assays, prognostics and/or companion diagnostics related to
RO7121661, disease process, pathways associated with disease state, and/or 
mechanism of action of the study treatment. Note that as science and research is 
evolving, the list of biomarkers that will be evaluated cannot be fully defined.
Based on continuous analysis of data any sample type, time point, and/ or analysis not 
considered to be critical for safety may be stopped at any time if the data does not 
support a strong scientific justification to continue. During the course of the study, 
sampling time-points may be modified on the basis of emerging data to ensure the PD of 
RO7121661 can be adequately characterized (but without increasing overall blood 
collection volume). This will be documented in a Note to File and a new SOA will be 
provided. 
Archival tumor blocks will be returned, unless notified by the site that they do not want it 
back. Blood, tissue and other residual material (slides, extracts, on-study blocks, etc.) 
will be destroyed within 2 years after the final closure of the clinical database unless the
participant gives specific consent for the remainder of the material to be stored for 
optional exploratory research (RBR).
When a participant withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the participant specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
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.
8.6.1
Blood Samples
The following samples for PD and biomarker research are required and will be collected 
from all participants in this study:

Blood samples will be collected for measurement of RO during dose escalation.

Blood samples will be collected for measurement of cytokines/chemokines (e.g., 
IL-2, IL-6, IL-8, and IFN) and immune activation markers such as sCD25

Blood samples will be collected for measurement of soluble target (PD-1, TIM-3)

Blood samples will be collected for the measurement of IgE/Tryptase


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
Blood for whole genome sequencing (see Section 8.7.1). If this sample is missing 
on Cycle 1 Day 1, it should be collected at the next scheduled visit, where possible 
The following additional samples for PD and biomarker research are required and will be 
collected from Part B participants only

Blood samples will be collected for flow cytometry. The samples will be analyzed 
for changes in the numbers and activation status of lymphocyte subsets including 
but not limited to CD4+, CD8+, and/ or NK cells

Blood for RNA extraction will be collected for gene expression analysis

Blood for bTMB

Blood for ctDNA
8.6.2
Tissue Samples
8.6.2.1
Archival Tumor Samples
FFPE archival tumor tissue is to be obtained from all participants, if available. The 
primary and the most recent metastasis (if both are available) should be submitted for 
analysis. Ideally these samples should include the invasive margin.  Tumor blocks are 
preferred but slides will be accepted. Samples will be collected for IHC and 
immunofluoresence analyses (such as, but not limited to, CD8/Ki67, PD-1, TIM-3, PD-
L1). Samples may also be used for TMB or gene expression.
Archival tumor blocks will be returned to the sites when requested by the investigator or 
at the end of the study, unless notified by the site that they do not want it back.
8.6.2.2
Fresh Tumor Biopsies
Screening and on treatment fresh tumor biopsies may be required for additional 
participants (i.e., if dose cohort extended to confirm safety, PK and/or RO and/or the
biomarker profile) in Part A1 and A2, unless otherwise specified by the Sponsor. In Part 
B, screening and on treatment biopsies are mandatory in all cohorts. In order to mitigate 
the potential risk associated with tumor biopsies, all participants required to have a 
biopsy must have tumor lesions from which biopsies can be safely obtained, as per 
clinical judgment of the treating physician.
The screening sample should be collected after eligibility is confirmed unless the fresh 
biopsy sample is needed to confirm patient eligibility (e.g. to confirm PD-L1 expression 
levels for Cohorts B2 and B3). Post dose samples can be collected 2/ 1 day from 
scheduled time-point. If the participant progresses and discontinues treatment prior to on 
treatment biopsy day, the tumor biopsy should be taken at the time of treatment 
discontinuation. An additional biopsy at the time of partial response, stable disease, 
progression or at any other time-point of interest based on participants’ course of 
disease may be taken after discussion between the Investigator and the Sponsor.


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Use of available existing biopsies at the sites prior to the participant’s entry in the study 
should be discussed with the Sponsor (i.e., biopsy should have recently been obtained 
as part of diagnosis biopsy and participants should have not received any tumor 
treatment after this collection).
Collection of tumor biopsies should be guided by ultrasound, CT scan, or other methods 
according to the location of the selected lesion using a 16-gauge needle (preferred) to 
provide cores, ideally, of at least 20 mm in length or equivalent size.  Ideally 4 (minimum 
2) core biopsies will be obtained at each time-point (at the physician’s discretion).  Fine-
needle aspiration is not acceptable. The biopsies will be taken from accessible tumor 
locations, including, but not limited to, skin, lymph node, rectum, liver etc. Bone biopsies 
and trans-bronchial biopsies are not acceptable. 
If feasible, on-treatment biopsies may be repeated if the initial biopsy did not contain 
sufficient tumor material for analysis. The location of each biopsy will be documented in 
relation to each tumor lesion as determined by imaging. The baseline and on-treatment 
biopsies should be preferably taken from the same tumor lesion (metastasis) to ensure 
comparability. If the sample cannot be collected from the same lesion (e.g., lesion 
disappears after treatment) then preferably the biopsy should be collected from the 
same organ, if possible. 
Additional participants may be enrolled in Part B in the event that paired fresh baseline 
and on-treatment biopsies are not evaluable for the key biomarker analyses to ensure 
that at least 60% of paired fresh biopsy samples are evaluable to conclude the PD
analysis. 
In the event that a fresh biopsy is taken during the screening period and the participant 
is not enrolled into the study, the fixed and embedded biopsy (FFPE block) can be 
returned to the site upon site request. The site must confirm that a written consent is 
obtained from the participant before return request submission to Roche. If the 
participant does enroll in the study, fresh biopsies will not be returned to the site. 
Biopsies will be used for IHC (e.g., CD8/Ki67, PD-1, TIM-3, PD-L1), TMB and gene 
expression. 
8.7
GENETICS
8.7.1
Whole Genome/Exome/Targeted DNA Analysis
At participating sites, blood samples will be collected for DNA extraction to enable whole 
genome sequencing (WGS) to identify mutations that are predictive of response to study 
drug, are associated with progression to a more severe disease state, are associated 
with acquired resistance to study drug, are associated with susceptibility to developing 
adverse events, can lead to improved adverse event monitoring or investigation, or can 
increase the knowledge and understanding of disease biology and drug safety.  The 
DNA may also be used to determine if alleles at genes associated with immunity, such 


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as KIR and HLA alleles, affect the PK/PD/efficacy/safety of the treatment. Research may 
distinguish germline mutations from somatic mutations.  The samples may be sent to 
one or more laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research by each site's Institutional Review Board or Ethics 
Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for WGS sampling, this section of the protocol will not be 
applicable at that site.
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 or new methods for monitoring efficacy and safety or predicting which 
participants are more likely to respond to a drug or develop adverse events.  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 and 
characterization of important biomarkers and pathways to support future drug 
development.
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
Participant medical information associated with WGS samples is confidential and may 
be disclosed to third parties only as permitted by the Informed Consent Form (or 
separate authorization for use and disclosure of personal health information) signed by 
the participant, unless permitted or required by law.
Given the complexity and exploratory nature of the WGS analyses, data derived from 
these analyses will generally not be provided to study investigators or participants unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
8.8
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY
8.8.1
Overview of the Research Biosample Repository
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The 
collection, storage and analysis of these specimens will facilitate the 
development/assessment of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for participants in the 
future.


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Specimens will be collected from participants who give specific consent to participate in 
this optional Research Biosample Repository. Collected specimens will be used to 
achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, 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.
8.8.2
Sample Collection
The following samples will be collected for identification of genetic (inherited) 
biomarkers: 

Saliva for DNA extraction 
Saliva will be collected to assess comparability of DNA extraction from saliva and whole 
blood. This collection will serve as a pilot for an overall strategy to decrease participant
burden and blood volume collection for DNA extraction in exploratory research.
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7121661 or diseases:

Leftover blood samples

Leftover tissue samples
The samples collected for DNA extraction 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.
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 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. Participant will not be identified by 


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name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, WGS 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 Research Biosample Repository storage period will be in accordance 
with the IRB/EC‑approved Informed Consent Form 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
HEALTH ECONOMICS
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. Informed Consent Forms 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (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) unless 
indicated in the SoA (see Section 1.3).


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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 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 schedule of 
assessments. 
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study or discontinue from the study early will be asked to 
return to the clinic 28 days (7 days) after the last dose of study drug for a follow‑up 
visit (see Section 1.3). The visit at which response assessment shows progressive 
disease may be used as the study completion/early termination visit.
8.10.4
Follow-Up Assessments
Participants will be treated with study treatment, until disease progression, unacceptable 
toxicity, or withdrawal of consent. Participants may continue study treatment for 
24 months or longer if the participant is still benefitting from treatment at the time of 
last visit at the end of the two-year period.
As with other immunotherapies, treatment beyond RECIST progression could be 
considered after approval by the Sponsor. The criteria needed for continuing treatment 
beyond initial apparent progressive disease per RECIST Version 1.1 (e.g., radiological 
progression secondary to tumor inflammation, TLS) are outlined in Section 7.1.
After the study completion/early termination visit, adverse events should be followed as 
outlined in Sections 8.3.1 and 8.3.3.
8.10.4.1
Post-Study Safety Follow-up
The sites will provide to the Sponsor an update on safety status 60 days (±7 days) after 
last treatment for Part A and 90 days (±7 days) after last treatment for Part B.
8.10.4.2
Post-study Survival Follow-up
The sites will provide to the Sponsor an update on survival status 90 days (±7 days) 
after last treatment and then every 3 months thereafter up until 24 months (48 months 
for the extended treatment period) post initial treatment for each participant enrolled in 
the study. Contact can be either in person or via a phone call to document; the sites will 
use a designated section of the eCRF for this purpose.
8.10.5
Assessments at Unscheduled Visits
Please see Section 1.3 for activities that are required to be performed in case of an 
unscheduled visit. For an unscheduled visit in the event of an IRR or hypersensitivity 


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eventGrade 2 or AE leading to dose reduction or delay, please see Section 8.3.8.1 and 
Appendix 6.
9.
STATISTICAL CONSIDERATIONS
The data will be analyzed by the Sponsor and/or designated contract research
organization. Any data analysis carried out independently by the Investigator should be
submitted to the Sponsor before publication or presentation. 
When appropriate, data will be summarized by dose cohort and regimen within each 
part. 
9.1
STATISTICAL HYPOTHESES
Not applicable
9.2
SAMPLE SIZE DETERMINATION
This study is intended to obtain preliminary safety, PK, PD, and activity information in the 
treated populations, and the sample sizes do not reflect explicit power and Type I error 
considerations.
The maximum planned enrollment for this study is approximately 270-280 participants 
for both Parts A and B.
For the dose escalation stage in Part A, up to 
 DLT evaluable participants are planned 
for the Q2W schedule with an additional 
 participants if confirmation of safety, PK, 
RO and/or biomarkers are needed prior to opening Part B cohorts. The exact sample 
size cannot be pre-determined and depends on the number of cohorts needed to reach 
the MTD/RDE with the maximum planned dose set at 2.1 g.
Up to approximately 
participants may be enrolled in the expansion stages across 
the indication-specific cohorts in Part B.


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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 7.
Table 7
Analysis Populations
Population
Description
Dose Limiting Toxicity 
The DLT-evaluable population is defined as all participants 
who received at least two doses of study medication and
either:
experienced a DLT within the DLT period OR
cleared the DLT period without a DLT
The DLT period is 21 (Q2W) from Day 1/Cycle 1 to Day 
7/Cycle 2. If there is a delay in Cycle 2 treatment the DLT 
period should be adjusted to cover Day 7/Cycle 2 up to a 
maximum of 35 (Q2W) days, since the maximum dose delay 
allowed is 14 days.
Efficacy
All participants in the safety population who received at least 
one dose of study drug and who have at least one baseline 
and one on-study tumor assessment. Participants who 
received at least one dose of study drug and discontinued the 
study because of progression before the first on-study tumor 
assessment will be considered as response-evaluable.
Safety
All participants who received at least one dose of the study 
treatment, whether prematurely withdrawn from the study or 
not, will be included in the safety analysis. Unless otherwise 
specified, the safety population will be the default analysis set 
used for all analyses.
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.
9.4
STATISTICAL ANALYSES
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 
dose cohort and regimen within each part.


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9.4.2
Efficacy Analyses
The primary and secondary efficacy analyses listed in Table 8 will include all participants 
in the efficacy population with participants grouped according to dose cohort within each 
study part. 
Table 8
Efficacy Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
According to RECIST Version 1.1 criteria and 
iRECIST:

Objective response rate (ORR) 

Disease control rate (DCR)

Duration of response (DoR)

Progression-free survival (PFS) 
No formal statistical model and no formal 
hypothesis testing are planned in this study. 
Tumor response data will be reported using 
descriptive statistics. Response data will be listed. 
ORR and DCR will be summarized by using 
relative frequencies and 90% confidence interval 
(CI). If data are sufficient, duration of response 
and PFS will be summarized by using 
time-to-event analyses and Kaplan-Meier curves. 
The above analyses will be carried out for 
RECIST Version 1.1 (primary analysis) and 
iRECIST (exploratory analysis).
Overall Survival (OS)
OS data may be tabulated and summarized using 
time-to-event analyses and Kaplan-Meier curves if 
data is collected and mature.
Eventually, summaries will be carried out by 
cohort separately for each part. 
Objective response rate (ORR) and disease control rate (DCR) are determined as the 
rate of participants with an objective tumor response of CR or partial response (PR) 
(ORR) or CR, PR or stable disease [SD] (DCR). For this protocol, confirmation of 
response is required at least 4 weeks after a first response occurred. To classify a 
response as SD, measurements will have to be classified as stable (according to 
RECIST Version 1.1) at least once at a minimum of 4 weeks after study entry. 
In the primary analysis ORR and DCR will be derived for RECIST Version 1.1 and will be 
based on Investigators’ assessment. Participants with missing or no response 
assessments will be classified as not evaluable unless there is documented clinical 
deterioration, in which case participant will be classified as non-responders. 
DoR will be calculated for participants who have a best (confirmed) overall response of 
CR or PR and will be defined as the time from first occurrence of a documented 
response until the time of documented disease progression or death (death within 30 
days from last study treatment) from any cause, whichever occurs first. Censoring 
methods will be the same as the one applied for progression-free survival (PFS).
PFS will be defined as the time from study treatment initiation (Cycle 1 Day 1) to the first 
occurrence of documented disease progression (based on RECIST Version 1.1 
Investigator’s assessment) or death from any cause, whichever occurs first. For 


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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.
Sensitivity analyses of response endpoints (ORR, DRC, DoR, and PFS) may include the 
evaluation of response according to iRECIST. 
OS is defined as the time from the first dose of study treatment to the time of death from 
any cause. Participants who are still alive at the time of analysis will be censored at the 
time of their last study assessment (for active participants) or at the last date known alive 
(for participants in follow-up).
9.4.3
Safety Analyses
Unless otherwise specified all safety analyses listed in Table 9 will be based on the 
safety population. All safety parameters will be analyzed using descriptive statistics, 
summarized and presented in tables. Data will be summarized by dose and regimen (if 
applicable) within each part. 
Safety will be assessed through summaries of DLTs (for Part A), adverse events, 
changes in laboratory test results, changes in vital signs and ECGs, and exposure to 
study treatment.


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Table 9
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
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, using the most up-to-date 
version of the MedDRA terminology for AEs and diseases. AEs will be 
graded according to NCI CTCAE grades v5.0.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level. Toxicity grade, seriousness, and relationship to study 
treatment will be presented, as well as summaries of deaths, AEs leading to 
death and premature withdrawal from study treatment. Glossary of AEs, 
medication, and procedures will be provided.
Nature and 
frequency of DLTs
DLT events will be presented by individual listings. The MTD will be 
estimated with a 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 (Standard International) 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, as appropriate.
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 dose level.
AE = adverse event; DLT = dose-limiting toxicity; ECG = electrocardiogram; eCRF = electronic 
cases report form; EWOC = Escalation with overdose control; mCRM = modified Continuous 
Reassessment Method; MedDRA = Medical Dictionary for Regulatory Activities; 
MTD = maximum tolerated dose; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events.


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9.4.4
Pharmacokinetic Analyses
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 dose levels 
and/or dosing regimen.
Individual and mean serum RO7121661 concentration versus time data will be tabulated 
and plotted by dose levels and/or dosing regimen. Graphical displays of PK data may 
also be provided. The serum PK of RO7121661 will be summarized by estimating total 
exposure (AUC), maximum concentration, total clearance, volume of distribution at 
steady‑state, and terminal half-life (when applicable). Estimates for these parameters 
will be tabulated and summarized. Inter‑participant variability and drug accumulation will 
be evaluated. 
9.4.5
Immunogenicity Analyses
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any treatment 
(Shankar et al 2014).
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence during both the treatment and follow-up periods) will be summarized.

Participants are considered to be ADA positive if they are ADA negative at baseline 
but develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and the 
titer of one or more post-baseline samples is greater than the titer of the baseline 
sample by a scientifically reasonable margin such as at least 4-fold 
(treatment-enhanced ADA response).

Participants are considered to be ADA negative if they are ADA negative at baseline 
and all post-baseline samples are negative, or if they are ADA positive at baseline 
but do not have any post-baseline samples with a titer that is greater than the titer of 
the baseline sample by a scientifically reasonable margin such as at least 4-fold 
(treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses.
9.4.6
Pharmacodynamic Analyses
The PD analysis will be based on the availability of evaluable blood or tumor samples.  
PD parameters will be listed by participant. Parameters may be tabulated by dose-
level/regimen and time-point. Depending on findings, descriptive statistics may be used
in summarizing relevant peripheral blood and tumor PD markers. Absolute change from 
baseline may be calculated for the PD markers. Graphical techniques may be employed 
to better understand the relationship of the PD markers with dose and time. Correlations 


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between PD markers, PK of RO7121661, and clinical response may be assessed 
through data tabulations and graphical techniques. The potential prognostic value of the 
PD markers may also be investigated.
9.5
INTERIM ANALYSES
It is anticipated that at least one interim analysis will be conducted in Part B of the study, 
with the earliest interim analysis taking place when at least 
participants have been 
enrolled per expansion, and participants have been followed for a minimum of 18 weeks.
If no complete or partial responses are observed, enrollment will be stopped.
In general, predictive probabilities might be used to guide eventual additional interim 
analyses of clinical activity compared with expected activity from the SoC.
These futility analyses are not binding and may be overruled if other endpoints (such as 
DCR rate, DoR, PFS, or OS) show significant improvement over the expected benefit in 
the population.
Recruitment will not be interrupted while waiting for data maturity.
At any time during the study, parts, cohorts, and arms may be closed based on 
emerging data external to the study or operational reasons.
9.6
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed.
10.
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vaccination and cancer iImmunotherapy [press release on the Internet].: 23
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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 of recording), 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/EC by the Principal Investigator and reviewed and approved by the IRB/EC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix).
The Investigator should follow the requirements for reporting all 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/EC, 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/EC submission. The 
final IRB/EC‑approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative.
The 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/EC-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/EC 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.
Participants who are re-screened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. A separate signature will be required to 
document a participant's agreement to allow any remaining specimens to be used for 
exploratory research.
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 


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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/EC) and, if applicable, an appropriate 
regulatory body. If a site has not been granted approval for RBR sampling, this section 
of the protocol will not be applicable at that site
Withdrawal from the Research Biosample Repository
Participants who give consent to provide 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 NP40435 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 NP40435. Data 
already generated before time of withdrawal of consent to RBR will still be used.
1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 


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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.
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 


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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/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the samples.
1.5.
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 


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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/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
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.
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.


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2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients 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.
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/ECs to inspect facilities and records relevant to this study.


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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 (see Appendix 3, Section 4).

Exacerbation of a chronic or intermittent pre-existing condition, including either an
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even
though it may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including
those that occur prior to assignment of study treatment (e.g., screening invasive
procedures such as biopsies).
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by
the Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)
present or detected at the start of the study that do not worsen.


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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 
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.


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
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), which can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 6 of this Appendix for reporting instructions), per the definition of 
serious adverse event in Section 2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for 
reporting instructions), per the definition of serious adverse event in Section 2. Grade 4 
laboratory abnormalities would only be reported as SAEs if these meet one or more of the 
conditions outlined in Section 2 (Definition of Serious Adverse Events) of Appendix 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.

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 AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology, if available.
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)

DLTs during the DLT assessment window (defined in Section 4.1.3; see 
Appendix 2; Section 5.1 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.


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
Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS, NON-SERIOUS ADVERSE EVENTS OF SPECIAL
INTEREST AND DOSE-LIMITING TOXICITIES
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC)
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
After the end of the adverse event reporting period (see Section 8.3.1) all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival Follow-
Up eCRF. 
In addition, if the Investigator becomes aware of a SAE that is believed to be related to 
prior study treatment, the event should be reported directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the SAE Reporting Form using 
the fax number or email address provided to investigators.


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5.2.
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error: accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Appendix 2, Section 5.1).  
For RO7121661, 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.
In addition, all special situations associated with RO7121661, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

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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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:

RO7121661 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
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 
(e.g., "infusion-related reaction") on the Adverse Event eCRF. If possible, avoid 
ambiguous terms such as “systemic reaction”. Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF. If a participant 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS
For adverse events other than IRRs (see Section 1.1), a diagnosis (if known) should be 
recorded on the Adverse Event eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF. If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER
EVENTS
In general, 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.
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.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (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. 


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Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN 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
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5 of Appendix 2) that are
attributed by the Investigator solely to tumor progression should be recorded only on the 
Death Attributed to Progressive Disease eCRF. All other on-study deaths, regardless of 
relationship to study treatment, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5 of Appendix 2).
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).


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9.
LACK OF EFFICACY OR WORSENING OF TUMOR
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. These data will be 
captured as efficacy assessment data only. In most cases, the expected pattern of 
progression will be based on RECIST Version 1.1. In rare cases, the determination of 
clinical progression will be based on symptomatic deterioration. However, every effort 
should be made to document progression 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.
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 AE 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.
All study-required safety laboratory assessments will be performed by local laboratories, 
with the exception of the following: 

Analysis of IgE and tryptase samples will be performed centrally and locally.


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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 or 
BUN, creatinine, protein, albumin, phosphate, calcium, total 
and direct bilirubin, alkaline phosphatase, ALT, AST, urate, 
LDH, CRCL (determined by Cockcroft Gault formula)a, 
GGT, Magnesium, CRP, ferritin.
Coagulation
Including PT (optional), INR, and aPTT; additional
coagulation parameters (i.e., anti thrombin III [antigenic or 
chromogenic], fibrinogen, PT, fibrin degradation products, D 
dimer) maybe be assessed according to clinical judgment.
Viral Serology
HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis B surface antigen (HBsAg), total 
hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) 
antibody.
Lipids
Cholesterol, LDL cholesterol, HDL cholesterol, triglycerides.
Thyroid Hormones
Free T4, free T3, TSH
Infusion related reactions 
IgE and tryptase and cytokine samples will be collected for 
central and local analysis if a participant experiences a 
Grade2 IRR for the first time with the second or 
subsequent study drug infusion or with clinical signs of 
hypersensitivity reaction at any time of the conduct of the 
study. A second sample for central IgE/tryptase analysis will 
be collected approximately 48 hours after onset of the 
reaction.
Quantitative Immunoglobulins
IgA, IgG, IgM, IgE
Urinalysis
Specific gravity
Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, 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.


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Laboratory Assessments
Parameters
Pregnancy Test
All women of childbearing potential (including those who 
have had a tubal ligation) will have a blood pregnancy test 
at Screening within 7 days before first dose of study 
treatment on Cycle 1 Day 1, blood or urine tests during the 
treatment period (according to the SoA – see Section 1.3), 
at the discontinuation visit, and at the 60 day (Part A)/90 
day (Part B) safety follow up visit. Further blood or 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. 
Auto-antibody panel
The auto-antibody panel will be assessed in participants 
who develop signs and/or symptoms suggestive of auto-
immune disease while on-treatment, the auto-antibody 
panel (anti-nuclear antibody, anti−double-stranded 
deoxyribonucleic acid (DNA), circulating anti-neutrophil 
cytoplasmic antibody [cANCA], and perinuclear anti 
neutrophil cytoplasmic antibody [pANCA]) should be 
repeated. Patients with confirmed positive serology of at 
least one of the auto-antibody panel during the course of 
the study should be discussed between Sponsor and 
Investigators, and if judged clinically relevant, could be 
referred to a specialist to exclude an underlying auto-
immune disease.
Urinalysis
Specific gravity
Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, 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
sCD25
a CRCL={[(140age)weight]/(72SCR)}0.85 (if female); 
CRCL (creatinine clearance) mL/minute; ageyears; weightkg; 
SCr (serum creatinine) mg/dL
The results of each test must be entered into the CRF.
Investigators must document their review of each laboratory safety report.


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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. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
– Documented hysterectomy.
– Documented bilateral salpingectomy.
– Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an
alternative medical cause other than menopause. A high follicle-stimulating
hormone (FSH) level in the post-menopausal range may be used to confirm a
post-menopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT). However, in the absence of 12 months
of amenorrhea, a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to
use one of the non-hormonal highly effective contraception methods if they
wish to continue their HRT during the study. Otherwise, they must discontinue
HRT to allow confirmation of post-menopausal status before study enrollment.


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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.
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly as described in Table 1 below.
Table 1
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependenta
(Failure rate of 1% per year when used consistently and correctly)
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation:
Oral
Intravaginal
Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation:
Oral
Injectable
Highly Effective Methods That Are User-Independent
(Failure rate of 1% per year)

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
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.
Acceptable Birth Control Methods Which May Not Be Considered as Highly Effective
(Failure rate of 1% per year when used consistently and correctly)


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
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action

Male or female condom with or without spermicide b

Cap, diaphragm or sponge with spermicide b
a)
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.
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.
b)
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not highly
effective, birth control methods. i.e., when the risk of teratogenicity and genotoxicity 
is unlikely.
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.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice.
4.
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). This applies only to male participants who receive 
RO7121661.
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 


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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. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.
5
ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2).


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Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male patient exposed to study treatment should be classified as a serious 
adverse event, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 8.3).


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Appendix 6
Risks Associated with RO7121661 and Guidelines for 
Management of Adverse Events Associated with RO7121661 
Toxicities associated or possibly associated with RO7121661 treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications.  Discontinuation of RO7121661 
may not have an immediate therapeutic effect, and in severe cases, immune- mediated
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, or other immunosuppressive agents. 
The Investigator should consider the benefitrisk balance a given patient may be 
experiencing prior to further administration of RO7121661.  In patients who have met the 
criteria for permanent discontinuation, resumption of RO7121661 may be considered if 
the patient is deriving benefit and has fully recovered from the immune- mediated event.  
The decision to rechallenge patients with RO7121661 should be based on Investigator’s 
assessment of benefit-risk and documented by the investigator (or an appropriate 
delegate). Medical Monitor is available to advise as needed.
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates may be
associated with the administration of RO7121661.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have computed 
tomography (CT) scans of the chest performed at every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 1.


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Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue RO7121661 and monitor closely.

Re-evaluate on serial imaging.

Consider patient referral to pulmonary specialist.
Pulmonary 
event, Grade 2 

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor. c

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue RO7121661 and contact Medical Monitor.

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over1 month.
BALbronchoscopic alveolar lavage.
a RO7121661 may be withheld for a longer period of time (i.e.,12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to advise 
and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before RO7121661 can be resumed.
HEPATIC EVENTS
Immune-mediated hepatitis may be associated with the administration of RO7121661.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.


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Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, 
Grade 1

Continue RO7121661.

Monitor LFTs until values resolve to within normal limits. 
Hepatic event, 
Grade 2
All events:

Monitor LFTs more frequently until return to baseline values. 
Events of 5 days’ duration:

Withhold RO7121661 for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
LFTliver function tests.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before RO7121661 can be resumed.


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Table 2
Management Guidelines for Hepatic Events (cont.)
Event
Management
Hepatic event, 
Grade 3 or 4

Permanently discontinue RO7121661 and contact Medical 
Monitor.

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
LFTliver function tests.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before RO7121661 can be resumed.
GASTROINTESTINAL EVENTS
Immune-mediated colitis may be associated with the administration of RO7121661. 
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein,
platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 


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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue RO7121661.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold RO7121661 for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Patient referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment 
with 12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor. c
Diarrhea or 
colitis, Grade 3

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or equivalent
upon improvement.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
GIgastrointestinal.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to advise 
and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before RO7121661 can be resumed.


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Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.)
Event
Management
Diarrhea or 
colitis, Grade 4

Permanently discontinue RO7121661 and contact Medical Monitor.

Refer patient to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to advise 
and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before RO7121661 can be resumed.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders may 
be associated with the administration of RO7121661.  Management guidelines for 
endocrine events are provided in Table 4.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free triiodothyronine and thyroxine levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests (e.g., 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, 
prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may 
help to differentiate primary pituitary insufficiency from primary adrenal insufficiency.


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Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue RO7121661.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold RO7121661.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume RO7121661 when symptoms are controlled and 
thyroid function is improving.
Asymptomatic 
hyperthyroidism
TSH0.1 mU/L and 0.5 mU/L:

Continue RO7121661.

Monitor TSH every 4 weeks.
TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism

Withhold RO7121661.

Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume RO7121661 when symptoms are controlled and 
thyroid function is improving.

Permanently discontinue RO7121661 and contact Medical 
Monitor for life-threatening immune-mediated
hyperthyroidism.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before RO7121661 can be resumed.


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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume RO7121661. b

If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
RO7121661, permanently discontinue RO7121661 and 
contact Medical Monitor.
Hyperglycemia, 
Grade 1 or 2 

Continue RO7121661.

Investigate for diabetes. If patient has Type 1 diabetes, treat 
as a Grade 3 event. If patient does not have Type 1 
diabetes, treat as per institutional guidelines

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold RO7121661.

Initiate treatment with insulin.

Monitor for glucose control.

Resume RO7121661 when symptoms resolve and glucose 
levels are stable.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before RO7121661 can be resumed.


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Table 4
Management Guidelines for Endocrine Events (cont.)
Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while 
withholding RO7121661, permanently discontinue 
RO7121661 and contact Medical Monitor.

For recurrent hypophysitis, treat as a Grade 4 event.
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue RO7121661 and contact Medical 
Monitor. c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
MRImagnetic resonance imaging; TSHthyroid-stimulating hormone.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 
mg/day oral prednisone or equivalent before RO7121661 can be resumed.
OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5.


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Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue RO7121661.

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold RO7121661 for up to 12 weeks after event onset. a

Patient referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
Ocular event, 
Grade 3 or 4

Permanently discontinue RO7121661 and contact Medical Monitor c

Refer patient to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.  

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to advise 
and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before RO7121661 can be resumed.


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IMMUNE-MEDIATED MYOCARDITIS
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-
type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope.  Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a patient who reports a recent history of gastrointestinal illness), 
ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.  
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An 
endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated.
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6.
Table 6
Management Guidelines for Immune-Mediated Myocarditis
Event
Management
Immune-mediated
myocarditis, Grade 2-4

Permanently discontinue RO7121661 and contact Medical Monitor.

Refer patient to cardiologist.

Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. a,b

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
ECMOextracorporeal membrane oxygenation; VADventricular assist device.
a RO7121661 may be withheld for a longer period of time (i.e.,12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent.
The Investigator determines an acceptable length of the extended period of time. The Medical 
Monitor is available to the Investigator to advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before RO7121661 can be resumed.


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PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, may be associated with the administration of RO7121661.  
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate work-up should include an evaluation for ductal obstruction, as well as 
serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 7.
Table 7
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
Amylase and/or lipase 
elevation, Grade 2
Amylase and/or lipase 1.52.0 ULN:

Continue RO7121661.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g.,3 weeks), consider treatment 
with 10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:
Treat as a Grade 3 event.
Amylase and/or lipase 
elevation, Grade 3 or 4

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day 
oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while
withholding RO7121661, permanently discontinue 
RO7121661 and contact Medical Monitor.

For recurrent events, permanently discontinue RO7121661 
and contact Medical Monitor.
GIgastrointestinal.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent. The Investigator determines an acceptable length of the extended period of 
time. The Medical Monitor is available to the Investigator to advise and answer questions 
in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before RO7121661 can be resumed.


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Table 7
Management Guidelines for Pancreatic Events, Including 
Pancreatitis (cont.)
Event
Management
Immune-mediated
pancreatitis, Grade 2 or 3

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while 
withholding RO7121661, permanently discontinue 
RO7121661 and contact Medical Monitor.

For recurrent events, permanently discontinue RO7121661 
and contact Medical Monitor.
Immune-mediated
pancreatitis, Grade 4

Permanently discontinue RO7121661 and contact Medical 
Monitor.

Refer patient to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
GIgastrointestinal.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or 
equivalent. The Investigator determines an acceptable length of the extended period of 
time. The Medical Monitor is available to the Investigator to advise and answer questions 
in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day 
oral prednisone or equivalent before RO7121661 can be resumed.
DERMATOLOGIC EVENTS
Treatment-emergent rash may be associated with RO7121661. A dermatologist should 
evaluate persistent and/or severe rash or pruritus.  A biopsy should be considered 
unless contraindicated.  Management guidelines for dermatologic events are provided in
Table 8.


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Table 8
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue RO7121661.

Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue RO7121661.

Consider patient referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if 
event does not improve.
Dermatologic 
event, Grade 3 

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve 
within 4872 hours.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
Dermatologic 
event, Grade 4

Permanently discontinue RO7121661 and contact Medical 
Monitor.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before RO7121661 can be resumed.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome may be observed with RO7121661. 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic work-up is essential for an accurate characterization to differentiate between 
alternative etiologies. Management guidelines for neurologic disorders are provided in
Table 9.


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Table 9
Management Guidelines for Neurologic Disorders
Event
Management
Immune-
mediated
neuropathy, 
Grade 1

Continue RO7121661.

Investigate etiology.
Immune-
mediated
neuropathy, 
Grade 2 

Withhold RO7121661 for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
Immune-
mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue RO7121661 and contact Medical 
Monitor.

Initiate treatment as per institutional guidelines.
Myasthenia 
gravis and 
Guillain-Barré
syndrome (any 
grade)

Permanently discontinue RO7121661 and contact Medical 
Monitor.

Refer patient to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to 10 mg/day oral 
prednisone or equivalent. The Investigator determines an acceptable length of the 
extended period of time. The Medical Monitor is available to the Investigator to 
advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month 
to 10 mg/day oral prednisone or equivalent before RO7121661 can be resumed.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis may be associated with the administration of 
RO7121661. Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, 
but not limited to, headache, neck pain, confusion, seizure, motor or sensory 
dysfunction, and altered or depressed level of consciousness. Encephalopathy from 
metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of 
malignancy, or secondary to a paraneoplastic process.  


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All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 10.
Table 10 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephalitis, 
all grades

Permanently discontinue RO7121661 and contact Medical Monitor.

Refer patient to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
RENAL EVENTS
Immune-mediated nephritis may be associated with the administration of RO7121661. 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment. Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as 
non-steroidal anti-inflammatory drugs). Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 11.
Table 11 Management Guidelines for Renal Events 
Event
Management
Renal event, 
Grade 1

Continue RO7121661.

Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 


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Renal event, 
Grade 2

Withhold RO7121661 for up to 12 weeks after event onset. a

Refer patient to renal specialist.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
Renal event, 
Grade 3 or 4

Permanently discontinue RO7121661 and contact Medical 
Monitor. 

Refer patient to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day oral prednisone.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The Investigator determines an acceptable length of 
the extended period of time. The Medical Monitor is available to the Investigator 
to advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before RO7121661 can be resumed.


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IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis may be associated with the administration of RO7121661.  
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-
mediated
myositis, Grade 1

Continue RO7121661.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-
mediated
myositis, Grade 2

Withhold RO7121661 for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The Investigator determines an acceptable length of 
the extended period of time. The Medical Monitor is available to the Investigator 
to advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before RO7121661 can be resumed.


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Table 12 Management Guidelines for Immune-Mediated Myositis (cont.)
Immune-
mediated
myositis, Grade 3

Withhold RO7121661 for up to 12 weeks after event onset a
and contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume RO7121661. b

If event does not resolve to Grade 1 or better while withholding 
RO7121661, permanently discontinue RO7121661 and contact 
Medical Monitor.

For recurrent events, treat as a Grade 4 event.
Immune-
mediated
myositis, Grade 4

Permanently discontinue RO7121661 and contact Medical 
Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
a RO7121661 may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
10 mg/day oral prednisone. The Investigator determines an acceptable length of 
the extended period of time. The Medical Monitor is available to the Investigator 
to advise and answer questions in this regard.
b If corticosteroids have been initiated, they must be tapered over 1 month to the 
equivalent of 10 mg/day oral prednisone before RO7121661 can be resumed.


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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
Participants with suspected HLH should be diagnosed according to published criteria 
by McClain and Eckstein (2014). A participant should be classified as having HLH if 
five of the following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL)
–
Platelet count 100 109/L (100 000/L)
–
ANC 1.0 109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Participants with suspected MAS should be diagnosed according to published criteria 
for systemic juvenile idiopathic arthritis by Ravelli et al. 2016. A febrile participant
should be classified as having MAS if the following criteria are met: 

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/µL)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Participants with suspected HLH or MAS should be treated according to the guidelines 
in Table 13.


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Table 13 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH
or MAS

Permanently discontinue study drug and contact Medical 
Monitor. 

Consider participant referral to hematologist.

Initiate supportive care, including intensive care monitoring 
if indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an 
immunosuppressive agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, 
contact Medical Monitor and initiate treatment as 
appropriate according to published guidelines (La Rosée 
2015; Schram and Berliner 2015; La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
HLH Hemophagocytic lymphohistiocytosis; IV Intravenous; MASMacrophage activation 
syndrome.
REFERENCES
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram. 2015:190–6.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465–77.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 
October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage 
activation syndrome complicating systemic juvenile idiopathic arthritis: a 
European League Against Rheumatism/American College of 
Rheumatology/Paediatric Rheumatology International Trials Organisation 
Collaborative Initiative. Ann Rheum Dis 2016;75:481–9.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:2908–14.


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Appendix 7 New Response Evaluation Criteria in Solid Tumours 
– 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 CT or 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 below on ‘Baseline 
documentation of target and non-target lesions’ for information on lymph node 
measurement. 
1.1.2 Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter 10 mm or 
pathological lymph nodes with 10 to 15 mm short axis) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inﬂammatory breast disease, 
lymphangitic involvement of skin or lung, peritoneal spread, abdominal 
masses/abdominal organomegaly identiﬁed by physical exam that is not measurable by 
reproducible imaging techniques. 
1.1.3 Special Considerations regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment. 


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Bone lesions:
Bone scan, PET scan or plain ﬁlms are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to conﬁrm the 
presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identiﬁable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the 
deﬁnition of measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions:
Lesions that meet the criteria for radiographically deﬁned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by deﬁnition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the deﬁnition of measurability described above.  However, if 
noncystic lesions are present in the same patient, these are preferred for selection 
as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 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 identiﬁed 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 
superﬁcial and 10 mm diameter as assessed using calipers (e.g., skin nodules). For 


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the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly deﬁned and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has deﬁned measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the subject at baseline and 
during study, should be guided by the tumor type under investigation and the anatomic 
location of the disease. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed, should also be based on the tumor type, 
anatomic location of the disease and should be optimized to allow for comparison to the 
prior studies if possible. Each case should be discussed with the radiologist to determine 
if substitution of these other approaches is possible and, if not, the patient should be 
considered not evaluable from that point forward.
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 deﬁned by the presence of at least one 
measurable lesion (as detailed above in Section 1.1.1). 


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2.2.
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline.
This means in instances where patients have only one or two organ sites involved, a 
maximum of two (one site) and four lesions (two sites), respectively, will be recorded. 
Other lesions (albeit measurable) in that organ will be recorded as non-measurable 
lesions (even if size is greater than 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 since 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 deﬁned as measurable and may be identiﬁed as target 
lesions must meet the criterion of a short axis of 15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. 
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node which is reported as being 20 mm 30 mm has a 
short axis of 20 mm and qualiﬁes as a malignant, measurable node. In this example, 
20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis 10 mm but 15 mm) should be considered non-target lesions. 
Nodes that have a short axis 10 mm are considered non-pathological and should not 
be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 


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All other lesions (or sites of disease) including pathological lymph nodes should 
be identiﬁed as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (see also Section 2.3.4).
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
2.3.
RESPONSE CRITERIA 
This section provides the deﬁnitions of the criteria used to determine objective tumor 
response for target lesions. 
2.3.1. Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): 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 PD. 
2.3.2. Special notes on the assessment of target lesions
Lymph nodes: Lymph nodes identiﬁed as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is deﬁned as 
having a short axis of10 mm. 


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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 likely disappeared, the 
measurement should be recorded as 0 mm.
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a deﬁnable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and BML should also be ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked (BML is equivalent to a less than sign ).
Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
2.3.3. Evaluation of non-target lesions 
This section provides the deﬁnitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points speciﬁed in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions (and, if applicable, 
normalization of tumor marker level). All lymph nodes must be non-pathological in size 
(10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.


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Progressive Disease (PD): 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 patient 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 patient 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 
quantiﬁed (by deﬁnition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e. 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 patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore the increase must be 
substantial. 
2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change 
in imaging modality or ﬁndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or ﬂare of pre-existing 


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lesions). This is particularly important when the patient’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 identiﬁed during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans conﬁrm 
there is deﬁnitely a new lesion, then progression should be declared using the date of 
the initial scan. 
2.4
EVALUATION OF RESPONSE 
2.4.1 Time Point Response (Overall response )
It is assumed that at each protocol specified time point, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.
Table 1 Time Point Response – Target (w/wo non- target) Lesions


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Table 2 Time Point Response – Non-Target Lesions only
2.4.2
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient 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 PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
during study only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing lesion. 
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” since the patient is not 
evaluable. Similarly, if one or more non-target lesions are indicated as ‘not assessed’, 
the response for non-target lesions should be “Unable to Assess” (except where there is 
clear progression).  Overall response would be “Unable to Assess” if either the target 
response or the non-target response is “Unable to Assess” (except where this is clear 
evidence of progression) as this equates with the case being not evaluable at that time 
point.


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Best response determination in trials where conﬁrmation of complete or partial response 
IS NOT required: 
Best response is deﬁned as the best response across all time points (for example, a 
patient who has SD at ﬁrst assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol speciﬁed minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments. For example, a 
patient who has SD at ﬁrst assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD. The same patient lost to follow-up after 
the ﬁrst SD assessment would be considered not evaluable. 
Best response determination in trials where conﬁrmation of complete or partial response 
is required: 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as speciﬁed in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
Table 3 Best Overall Response when Confirmation is required
2.4.1 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 patients with CR may not have a total sum of ‘zero’ on the case 
report form (CRF). 


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Patients 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 patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3. 
For equivocal ﬁndings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is conﬁrmed, the date of 
progression should be the earlier date when progression was suspected. 
In studies where patients with advanced disease are eligible (i.e., 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.
2.5 FREQUENCY OF TUMOR RE-EVALUATION 
Frequency of tumor re-evaluation while on treatment should be protocol speciﬁc and 
adapted to the type and schedule of treatment. However, in the context of Phase II 
studies where the beneﬁcial effect of therapy is not known, follow-up every 6–8 weeks 
(timed to coincide with the end of a cycle) is reasonable. Smaller or greater time 
intervals than these could be justiﬁed in speciﬁc regimens or circumstances. The 
protocol should specify which organ sites are to be evaluated at baseline (usually those 
most likely to be involved with metastatic disease for the tumor type under study) and 
how often evaluations are repeated. Normally, all target and non-target sites are 
evaluated at each assessment. In selected circumstances certain non-target organs may 
be evaluated less frequently. For example, bone scans may need to be repeated only 
when complete response is identiﬁed in target disease or when progression in bone is 
suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on
whether the trial has as a goal the response rate or the time to an event 
(progression/death). If ‘time to an event’ (e.g., time to progression, disease-free survival, 
progression-free survival) is the main endpoint of the study, then routine scheduled re-
evaluation of protocol speciﬁed sites of disease is warranted. In randomized comparative 
trials in particular, the scheduled assessments should be performed as identiﬁed on a 
calendar schedule (for example: every 6–8 weeks on treatment or every 3–4 months
after treatment) and should not be affected by delays in therapy, drug holidays or any 


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other events that might lead to imbalance in a treatment arm in the timing of disease 
assessment. 
2.6 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
2.6.1
Conﬁrmation 
In non-randomized trials where response is the primary endpoint, conﬁrmation of PR and 
CR is required to ensure responses identiﬁed are not the result of measurement error. 
This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required conﬁrmation in such trials [2]. However, in all 
other circumstances, i.e. in randomized trials (phase II or III) or studies where stable 
disease or progression are the primary endpoints, conﬁrmation of response is not 
required since it will not add value to the interpretation of trial results. However, 
elimination of the requirement for response conﬁrmation may increase the importance of 
central review to protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks) that is deﬁned in the 
study protocol. 
2.6.2
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
ﬁrst met for CR/PR (whichever is ﬁrst recorded) until the ﬁrst date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement 
criteria are ﬁrst met for CR until the ﬁrst date that recurrent disease is objectively 
documented.
2.6.3
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from 
date of randomization) until the criteria for progression are met, taking as reference the 
smallest sum on study (if the baseline sum is the smallest, this is the reference for 
calculation of PD).


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3.
REFERENCES
1.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer
2009;45:228-47.
2.
Bogaerts J, Ford R, Sargent D, et al, Individual patient data analysis to assess 
modifications to the RECIST criteria Eur J Cancer 2009;45:248-60.


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Appendix 8 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 (see Appendix 7) also apply to 
iRECIST.  After disease progression per RECIST v1.1, the same target and non-target 
lesions selected at baseline will continue to be followed, along with any new lesions that 
develop, to support iRECIST response evaluations, as described below and summarized 
in Table 1. Once a lesion has been categorized as a target, non-target, or new lesion, it 
will remain classified as such.


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TARGET LESIONS
The target lesions selected at baseline should continue to be measured at all tumor 
assessment timepoints after disease progression per RECIST v1.1, according to 
RECIST v1.1 conventions.
NON-TARGET LESIONS
Non-target lesions selected at baseline should continue to be followed at all tumor 
assessment timepoints after disease progression per RECIST v1.1. At each timepoint, 
non-target lesions should continue to be categorized as "absent" (complete response 
[CR]), "unequivocal progression" relative to baseline (progressive disease [PD]), or 
"present without unequivocal progression" (non-CR/non-PD), as defined by 
RECIST v1.1. In addition, any non-target lesions that were categorized as PD at the 
previous timepoint should be evaluated to determine whether there has been any further 
increase in size.  
NEW LESIONS
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST v1.1
(e.g., nonlymph node lesions must be 10 mm on the longest diameter; new lymph 
nodes must be 15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment timepoints.
Up to a maximum of five measurable new lesions total (with a maximum of two lesions 
per organ) should be selected and measured at each timepoint. New lesions that are not 
measurable at first appearance but meet measurability criteria at a subsequent timepoint
should be measured from that point on, if the maximum number of measurable new 
lesions has not been reached. However, for calculation of the sum of diameters for new 
lesions, iRECIST excludes measurements from new lesions that were not measurable at 
first appearance.
All non-measurable new lesions (including those that subsequently become measurable) 
and additional measurable new lesions (in excess of five total or two per organ) should 
be assessed to determine whether there is any increase in size relative to the previous 
assessment timepoint.
Note regarding new lymph node lesions: If at first appearance the short axis of a lymph 
node lesion is 15 mm, it will be considered a measurable new lesion. If at first 
appearance the short axis of a lymph node lesion is 10 mm and 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 


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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).
Table 1
Guidelines for Evaluation of Lesions to Support iRECIST 
Response Assessment after Disease Progression per 
RECIST v1.1
Lesion Type
Evaluation of Lesions to Support iRECIST Response Assessment 
after Disease Progression per RECIST v1.1
Target lesions

Measurements should be continued according to RECIST v1.1 
conventions.
Non-target lesions

Non-target lesions should continue to be categorized as absent 
(CR), unequivocal progression (PD), or present without 
unequivocal progression (non-CR/non-PD), as defined by 
RECIST v1.1.  In addition, any non-target lesions that were 
categorized as PD at the previous timepoint should be 
evaluated to determine whether there has been any further 
increase in size.
New lesions

New lesions should be evaluated for measurability per 
RECIST v1.1.

All new lesions (measurable or non-measurable) must be 
assessed and recorded at the time of identification and at all
subsequent tumor assessment timepoints.

Up to a maximum of five measurable new lesions total (with a 
maximum of two lesions per organ) should be selected and 
measured at each timepoint.

All non-measurable new lesions (including those that 
subsequently become measurable) and additional measurable 
new lesions (in excess of five total or two per organ) should be 
assessed to determine whether there is any increase in size 
relative to the previous assessment timepoint.
CRcomplete response; PDprogressive disease; RECIST v1.1Response Evaluation 
Criteria in Solid Tumors, Version 1.
SUMMARY OF CRITERIA FOR OVERALL RESPONSE AT A SINGLE 
TIMEPOINT
Timepoint response per iRECIST will be calculated programmatically by the Sponsor.  A 
complete description of the iRECIST criteria can be found in 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47.  
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20.
Seymour L, Bogaerts J, Perrone A, et al., on behalf of the RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 2017;18:e14352.


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Appendix 9 Correction Formulas for QTc Intervals
Fridericia’s correction for QTc Measurement - QTcF
QTcF (ms)
QT (ms)
3
1000
/)
ms
(
RR
Example:
QTcF of a subject with a QT of 386 ms and a RR of 848 ms
QT (ms)386
RR (ms)848
QT (ms)
408 ms
3
1000
/)
ms
(
RR
Bazett’s correction for QTc Measurement - QTcB
QTcB (ms)
QT (ms)
1000
/)
ms
(
RR
Example:
QTcB of a subject with a QT of 386 ms and a RR of 848 ms
QT (ms)386
RR (ms)848
QT (ms)

419 ms
1000
/)
ms
(
RR


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Appendix 10 Modified Continuous Reassessment Method with 
Escalation with Overdose Control Design
This appendix provides details of the design that will guide the monotherapy dose-
escalation stage of this study and examines its operating characteristics through 
simulations. All analyses were performed using the R statistical software R version 3.4.2.
RATIONALE FOR MODEL BASED DESIGN
The modified Continuous Reassessment Method (mCRM) design uses a statistical 
model that actively seeks a dose level close to the maximum tolerated dose (MTD) by 
using toxicity data from all enrolled evaluable patients to compute a precise dose-toxicity 
curve. It locates the MTD efficiently and minimizes the number of patients 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, 
while keeping the probability of overdose 
. 
STATISTICAL MODEL
A two-parameter logistic model will be used to fit the dose-toxicity relationship.
The probability of DLT at dose dj, p(dj) is defined as (1) 
where
and d* is the reference dose (in this case d*70 mg). 
The model (1) thus can be rewritten as (2):


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where and are the parameters to be estimated and assumed to follow a bivariate 
normal distribution.
Model Prior
A minimally informative bivariate normal prior for the parameters of the DLT-dose 
response curve (, ) is constructed in order to have a weak impact to the final MTD 
determination (Neuenschwander et al. 2008). 
The parameters of the minimal informative prior are listed below (3):  
where and are the parameters of the bivariate normal distribution.
The prior distribution used to determine the dose-escalation decision for this study is 
shown in Figure 1.
Figure 1. Minimally informative prior


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Maximum Dose-Increments
The following rules for selecting the maximum allowed dose increment will be applied.

Maximum Dose-Increments Relative to Dose Levels 
In absence of DLT, the maximum allowable dose-increment will be 200% (i.e. next dose 
could be as high as 3 fold as previous one) for dose-levels 700 mg and 100% (i.e. 2 
fold) for dose-levels 700 mg 

Maximum Dose-Increments Relative to DLT 
In case of one event of DLT in a dose-level, the maximum allowable dose increment 
becomes 100% (i.e. 2 fold), while in presence of 2 DLTs an increment of 50% is allowed 
(i.e. 1.5 fold).
After the two rules have been applied the maximum allowed dose increment will be 
defined as the lower increment of the two resulting increments.
Stopping Rules
The algorithm will recommend stopping the trail if any of the following applies: 

Maximum number of patients: stop if the maximum sample size of 60 pts have 
been reached OR 

Enough information on MTD: at least a minimum of 12 pts enrolled and at least 6 
patients have been accrued near the MTD dose (where near means differing from 
the MTD by at most 15%) and the probability that the MTD dose lies within the 
target toxicity interval is above 50% OR 

Maximum dose is safe: at least a minimum of 6 pts have been accrued at the 
maximum dose or near (differing from the maximum dose by at most 5%) and it is 
at least 50% likely that the probability of a DLT for that maximum dose is below 
20%.
Dose Grid
The following dose grid has been used for the simulations: 

from 30 mg to 100 mg by 2.5 

from 105 mg to 1000 mg by 5

from 1010 mg to 2100 mg by 10.


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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 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, STOP indicates that the model would stop escalating and the trial would be 
halted.
Table 1. Dose Escalation Mock Runs
Model recommendation (and % increment) in 
case of
Cohort 
number
Dose (mg)
0 DLT
1 DLT
2 DLTs
3 DLTs
1
70
210 
(+200%)
80    
(+14%)
35          
(-50%)
STOP
2
210
615
(+193%)
220
(+5%)
82.5         
(-61%)
45       
(-79%)
3
615
1840 
(+199%)
615 
(+2%)
225         
(-63%)
115         
(-81%)
4
1840
2100
(+14%)
2050 
(+11%)
550         
(-70%)
255         
(-86%)
As can be seen from the Table above, in general in presence of no DLTs the model will 
suggest to escalate as the max increments indicate, while in presence of one DLT the 
increments are really limited. Then, with 2 or 3 DLTs the model always recommends to 
de-escalate or STOP. Therefore, the results show that the design will adequately adapt 
the dose in the presence of observed DLTs.
SIMULATION STUDY
A simulation study is conducted to evaluate the operating characteristics for the chosen 
design parameters (priors, reference dose, stopping rules) under various dose-toxicity 
scenarios. 
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. 
As shown in Figure 2, we explore 8 scenarios. The first 7 represent decreasing levels of 
toxicity, while the last one considers the toxicity depicted in the prior as true toxicity. 


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Some scenarios are really extreme, but still they will be informative on how the model 
would eventually perform, despite the likelihood of the scenario remains extremely low.
Figure 2. True Dose-Toxicity Scenarios: [Scenario number]: dose range 
corresponding to target toxicity. 


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Simulation Results
For each of the scenarios, 1000 trials were simulated and in all cases the starting dose 
of 70 mg was assumed.  
The design is evaluated using the following criteria: the MTD chosen, the number of 
subjects treated at doses higher than the MTD and the total number of subjects treated. 
For each criterion, we report in Table 2 the median (and 10th 90th percentiles) from the 
1000 simulations. 
Table 2. Median (and 10th 90th percentiles) from the 1000 simulations
Scenario
Target Dose 
Interval in True 
Scenario
Overall N of 
Patients
N Patients 
Treated above 
Target Toxicity 
Interval
Proportions of 
DLTs in the 
trials
Doses 
selected as 
MTD
1
10-30
6 (3,15)
6 (3,15)
66.7%
(41.7%, 100%)
0
(0,0)
2
300-350
21 (15,27)
6 (3,9)
23.8%
(19%, 27.8%)
280
(220,360)
3
500-750
24 (18,33)
3 (0,12)
20.8%
(18.5%, 25%)
512.5
(365,765)
4
500-1500
27 (24,36)
6 (3,9)
19%
(12.3%, 25%)
572.5
(230,1310)
5
1000-1200
27 (24,36)
6 (3,9)
18.5%
(16.7%, 22.2%)
935
(735,1170)
6
1800-2000
36 (27,42)
6 (6,12)
12.1%
(5.1%, 18.5%)
2000
(1350,2100)
7
3500-7000
39 (30,51)
0 (0,0)
4.2%
(0%, 11.1%)
2100
(2100,2100)
8
204-2142
21 (6,39)
0 (0,0)
23.8%
(16.7%, 50%)
215
(0,711)
From these simulations, we see that the design is able to provide a reliable estimate of 
the MTD: usually, the median of the doses selected as MTD is within the target toxicity 
dose range. Only in case the toxicity curve is very steep (e.g. Scenario 5) the median 
might lie just below the target toxicity, which means that we are conservative. 
At last, in case of very low toxicity (dose range of target toxicity between 3500 and 7000 
mg), the maximum dose is selected as MTD. 
In addition, we see that we the number of patients treated over the dose toxicity interval 
is quite limited, with the exception of the first scenario where –by definition since all 
doses were too toxic- all pts were treated above the target toxicity. 
The good performances of the algorithm are also confirmed by the median number of 
DLTs observed in the simulations, which is always <25% (again, Scenario 1 is an 
exception). 


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Finally, also the sample size required seems to be reasonable: the median number of 
patients required to give an MTD recommendation is maximum 39 patients across all 
scenarios. In case of too high toxicity, the required number of treated patients is even 
lower. 
REFERENCES
Neuenschwander, B.; Branson, M. & Gsponer, T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Statistics in Medicine, John Wiley & Sons, Ltd., 2008, 
27, 2420-2439
Schöffski 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. Annals of Oncology 2004;15: 1816–1824.
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. 
J Natl Cancer Inst 2009;101:708-20.


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Appendix 11 Exposure Ratios from Nonclinical Safety Findings 
to Human Exposures
Prediction of human PK followed an allometric scaling approach.  Based on first-week 
DRF and GLP data in cynomolgus monkey, a two-compartment model was developed 
with additional Michaelis Menten approximation to describe the nonlinear clearance. It is 
expected that at therapeutically relevant doses, the nonlinear clearance in human is fully 
saturated. Therefore, the predicted exposures in humans were calculated using the 
linear PK model only.
The projected AUC0-336 and Cmax in humans after a single flat dose of 70 mg 
(corresponding to 1 mg/kg) are 3900 g⋅h/mL and 25.2 g/mL, respectively. These 
values are approximately 180- and 116-fold lower, respectively, than the exposure 
observed in cynomolgus monkeys at the 150 mg/kg NOAEL in the 4-week GLP 
toxicology study (differences in potency i.e., 2-fold more potent in humans than in 
monkeys and dosing schedule were accounted for).
Prediction of human exposure (Cmax and AUC0-336) and associated margins as compared 
to the NOAEL dose level of 150 mg/kg identified in the cynomolgus monkey at steady 
state (i.e., following eight administrations) are provided in Table 1 (including non-clinical 
safety findings).


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Table 1
Predicted Human Exposures and Associated Margins at Steady State as Compared with the NOAEL 
Based on NHP GLP Study
Mean Values from 4-week GLP 
Toxicology and Toxicokinetic 
Monkey Study after Repeated 
Weekly Administration
Simulated Exposure in Human at Steady Statea
Non Clinical Findings at 
NOAEL in Cynomolgus 
Monkey
70 mg
2100 mg
Marginal, increased incidence 
and/or severity of 
inflammatory cell 
foci/infiltrates in several 
tissues and organs, no 
evidence of progression or 
worsening after recovery, 
slight increase in IL-10
NOAEL 
(mg/kg)
Cmax
(g/mL)
AUC0-168 
(g·h/mL)
Cmax
(g/m
L)
AUC0336 
(µg·h/mL)
Cmax
(g/mL)
AUC0336 
(µg·h/mL)
150
5835
697500
45.2
9200
1355
275000
Estimated Human Exposure Margins 
at Steady Statea
65x
76x
2.2x
2.5x
AUC0-168/336 area under the concentration–time curve from time 0 to 168/336 hours; Cmax maximum concentration 
observed; NOAEL no-observed-adverse-effect level; Q2W every 2 weeks; QW weekly.
Notes:
Cynomolgus monkey: the mean AUC0-168 values are for the recovery animals only after last dosing interval.
AUC multiples include additional factor of 2 due to different dosing schedule in monkey (QW) and human (Q2W). AUC and 
Cmax multiples include additional factor of 2 due to higher expected potency in human compared to monkey.
a Exposure marginsratios of exposure in monkey/human.