Clinical trial NCT02460224
Conditions: Advanced Solid Tumors
Keywords: Non-small cell lung cancer Melanoma Renal cancer Mesothelioma Triple Negative Breast TNBC Renal
Sponsor: Novartis Pharmaceuticals
Start date: 2015-06-17; Completion date: 2020-12-31
Enrollment: 490 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of LAG525 as a single agent and in combination with PDR001 to adult patients with solid tumors. The study consists of a dose escalation (phase 1) to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) for LAG525 as a single agent and in combination with PDR001, and a dose expansion (phase 2) which characterized treatment of LAG525 in combination with PDR001 at the MTD or RP2D.

Detailed description:
This was a Phase 1/2, multi-center, open-label study comprising a Phase 1 dose escalation part followed by a Phase 2 dose expansion part.

During the Phase 1 dose escalation part patients with any advanced solid tumor received the study treatment until the MTD was reached or a lower RP2D was established. The study had the following 3 dose escalation parts: 1) Single-agent LAG525; 2) Single-agent LAG525 in Japanese patients; 3) Combination of LAG525 with PDR001.

Once the RP2D or MTD had been determined in the escalation parts, additional patients were to be enrolled in the Phase 2 expansion parts in order to assess the preliminary anti-tumor activity. Phase 2 expansion cohorts testing single-agent LAG525 were not opened for enrollment based on emerging data including but not limited to preliminary anti-tumor activity. Phase 2 expansion cohorts for the combination of LAG525 with PDR001 were opened and 5 tumor types were assessed: 1) Non-small cell lung cancer (NSCLC); 2) Melanoma; 3) Renal cell cancer (RCC); 4) Mesothelioma; 5) Triple negative breast cancer (TNBC). The efficacy and safety of the combination of LAG525 with PDR001 in these tumor types was assessed in both the PD-1/PD-L1 pre-treated and naïve settings.

Arms: arm 1: Single-agent LAG525 1 mg/kg Q2W arm 2: Single-agent LAG525 3 mg/kg Q2W arm 3: Single-agent LAG525 5 mg/kg Q2W arm 4: Single-agent LAG525 10 mg/kg Q2W arm 5: Single-agent LAG525 15 mg/kg Q2W arm 6: Single-agent LAG525 240 mg Q2W arm 7: Single-agent LAG525 400 mg Q2W arm 8: Single-agent LAG525 3 mg/kg Q4W arm 9: Single-agent LAG525 5 mg/kg Q4W arm 10: Single-agent LAG525 10 mg/kg Q4W arm 11: Single-agent LAG525 400 mg Q4W arm 12: Combination LAG525 0.3 mg/kg + PDR001 1 mg/kg (Q2W/Q2W) arm 13: Combination LAG525 1 mg/kg + PDR001 1 mg/kg (Q2W/Q2W) arm 14: Combination LAG525 80 mg + PDR001 80 mg (Q2W/Q2W) arm 15: Combination LAG525 80 mg + PDR001 240 mg (Q2W/Q2W) arm 16: Combination LAG525 240 mg + PDR001 240 mg (Q2W/Q2W) arm 17: Combination LAG525 240 mg + PDR001 300 mg (Q3W/Q3W) arm 18: Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) arm 19: Combination LAG525 600 mg + PDR001 300 mg (Q3W/Q3W) arm 20: Combination LAG525 80 mg + PDR001 240 mg (Q4W/Q4W) arm 21: Combination LAG525 400 mg + PDR001 400 mg (Q4W/Q4W) arm 22: Combination LAG525 800 mg + PDR001 400 mg (Q4W/Q4W) arm 23: Combination LAG525 1000 mg + PDR001 400 mg (Q4W/Q4W) arm 24: Combination LAG525 80 mg + PDR001 400 mg (Q2W/Q4W) arm 25: Combination LAG525 240 mg + PDR001 400 mg (Q2W/Q4W) arm 26: Combination LAG525 300 mg + PDR001 400 mg (Q2W/Q4W) arm 27: Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients naïve to anti-PD-1/PD-L1 arm 28: Combination LAG525 600 mg + PDR001 400 mg (Q4W/Q4W) in patients naïve to anti-PD-1/PD-L1 arm 29: Combination LAG525 400 mg + PDR001 300 mg (Q3W/Q3W) in patients pre-treated with anti-PD-1/PD-L1
Interventions: intervention 1: LAG525 intervention 2: PDR001
Intervention descriptions: intervention 1: LAG525 was administered via intravenous (i.v.) infusion intervention 2: PDR001 was administered via i.v. infusion

Protocol documents:
Prot_000.pdf: 
Clinical Development
LAG525
Protocol CLAG525X2101C / NCT02460224
A Phase I/II, open label, multicenter study of the safety and 
efficacy of LAG525 single agent and in combination with 
PDR001 administered to patients with advanced 
malignancies
Document type
Amended Protocol Version
EUDRACT number
2015-000449-21
Version number
10 (Clean)
Development phase
I/II
Document status
Final
Release date
27 Jun 2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 02-Dec-2013


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................8
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................10
Glossary of terms...............................................................................................................12
Protocol summary:.............................................................................................................14
Amendment 10 (27-Jun-2019) ..........................................................................................19
Amendment 09 (16-Aug-2018).........................................................................................21
Amendment 08 (21-Jun-2017) ..........................................................................................24
Amendment 07 (09-Dec-2016)..........................................................................................27
Amendment 06 (05-Jul-2016) ...........................................................................................31
Amendment 05 (12-Apr-2016)..........................................................................................33
Amendment 04 (12-Feb-2016)..........................................................................................34
Amendment 03 (04-Dec-2016)..........................................................................................38
Amendment 02 (14-Sep-2015)..........................................................................................40
Amendment 01 (27-Apr-2015)..........................................................................................44
1
Background........................................................................................................................45
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............45
1.2
Introduction to investigational treatment(s) and other study treatment(s).............46
1.2.1
Overview of LAG525 ...........................................................................46
1.2.2
Overview of PDR001............................................................................47
1.2.3
Overview of the combination of LAG525 and PDR001.......................48
2
Rationale............................................................................................................................49
2.1
Study rationale and purpose...................................................................................49
2.2
Rationale for the study design ...............................................................................51
2.2.1
Phase I...................................................................................................51
2.2.2
Japanese single-agent dose escalation (Arm C)....................................52
2.2.3
Phase II..................................................................................................52
2.3
Rationale for dose and regimen selection..............................................................52
2.4
Rationale for choice of combination drugs............................................................53
3
Objectives and end points..................................................................................................54
4
Study design ......................................................................................................................57
4.1
Description of study design ...................................................................................57
4.1.1
Phase I dose escalation..........................................................................59
4.1.2
Phase II expansion.................................................................................60


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4.1.3
Study Periods ........................................................................................60
4.2
Timing of interim analyses and design adaptations...............................................61
4.3
Definition of end of the study................................................................................61
4.4
Early study termination..........................................................................................61
5
Population..........................................................................................................................62
5.1
Patient population..................................................................................................62
5.2
Inclusion criteria ....................................................................................................62
5.3
Exclusion criteria...................................................................................................63
6
Treatment...........................................................................................................................66
6.1
Study treatment......................................................................................................66
6.1.1
Dosing regimen.....................................................................................66
6.1.2
Ancillary treatments..............................................................................67
6.1.3
Treatment duration................................................................................68
6.2
Dose escalation guidelines.....................................................................................68
6.2.1
Starting dose rationale...........................................................................68
6.2.2
Provisional dose levels..........................................................................69
6.2.3
Guidelines for dose escalation and determination of MTD/ RP2D ......70
6.2.4
Definitions of dose-limiting toxicities (DLTs) .....................................75
6.3
Dose modifications ................................................................................................77
6.3.1
Dose modification and dose delay ........................................................77
6.3.2
Follow-up for toxicities.........................................................................83
6.3.3
Permitted concomitant therapy .............................................................83
6.3.4
Permitted concomitant therapy requiring caution and/or action...........84
6.3.5
Prohibited concomitant therapy ............................................................84
6.4
Patient numbering, treatment assignment or randomization .................................85
6.4.1
Patient numbering .................................................................................85
6.4.2
Treatment assignment or randomization...............................................85
6.5
Study drug preparation and dispensation...............................................................85
6.5.1
Study drug packaging and labeling.......................................................86
6.5.2
Drug supply and storage........................................................................86
6.5.3
Study drug compliance and accountability ...........................................86
6.5.4
Disposal and destruction .......................................................................86
7
Visit schedule and assessments .........................................................................................86
7.1
Study flow and visit schedule................................................................................86
7.1.1
Screening...............................................................................................91
7.1.2
Treatment period...................................................................................91


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7.1.3
Discontinuation of study treatment .......................................................92
7.1.4
Withdrawal of Consent .........................................................................93
7.1.5
Follow up period ...................................................................................94
7.1.6
Lost to follow up...................................................................................95
7.2
Assessment types...................................................................................................95
7.2.1
Efficacy assessments.............................................................................95
7.2.2
Safety and tolerability assessments.......................................................97
7.2.3
Pharmacokinetics and immunogenicity assessments..........................100
103
8
Safety monitoring and reporting......................................................................................107
8.1
Adverse events.....................................................................................................107
8.1.1
Definitions and reporting ....................................................................107
8.1.2
Laboratory test abnormalities..............................................................108
8.2
Serious adverse events.........................................................................................109
8.2.1
Definitions...........................................................................................109
8.2.2
Reporting.............................................................................................110
8.3
Pregnancies..........................................................................................................111
8.4
Warnings and precautions....................................................................................111
8.5
Data Monitoring Committee................................................................................111
9
Data collection and management.....................................................................................112
9.1
Data confidentiality .............................................................................................112
9.2
Site monitoring ....................................................................................................112
9.3
Data collection.....................................................................................................113
9.4
Database management and quality control..........................................................113
10 Statistical methods and data analysis ..............................................................................114
10.1
Analysis Sets........................................................................................................115
10.1.1
Full Analysis Set .................................................................................115
10.1.2
Safety Set ............................................................................................115
10.1.3
Per-Protocol Set ..................................................................................116
10.1.4
Dose- Determining Analysis Set.........................................................116
10.1.5
Pharmacokinetic analysis set...............................................................117
10.2
Patient demographics / other baseline characteristics .........................................117
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................117
10.4
Primary Objective................................................................................................118
10.4.1
Variable...............................................................................................118
10.4.2
Statistical hypothesis, model, and method of analysis........................118


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10.4.3
Handling of missing values/censoring/discontinuations.....................121
10.4.4
Supportive analyses.............................................................................121
10.5
Secondary Objectives ..........................................................................................123
10.5.1
Key secondary objective(s).................................................................123
10.5.2
Other secondary objectives .................................................................123
10.5.3
Safety Objectives ................................................................................124
127
127
128
10.7
Interim Analysis...................................................................................................128
10.8
Sample size calculation........................................................................................129
10.9
Power for analysis of key secondary variables....................................................131
11 Ethical considerations and administrative procedures ....................................................131
11.1
Regulatory and ethical compliance......................................................................131
11.2
Responsibilities of the investigator and IRB/EC/REB........................................131
11.3
Informed consent procedures...............................................................................132
11.4
Discontinuation of the study................................................................................132
11.5
Publication of study protocol and results.............................................................132
11.6
Study documentation, record keeping and retention of documents.....................133
11.7
Confidentiality of study documents and patient records .....................................134
11.8
Audits and inspections.........................................................................................134
11.9
Financial disclosures............................................................................................134
12 Protocol adherence ..........................................................................................................134
12.1
Amendments to the protocol................................................................................134
13 References (available upon request)................................................................................135
14 Appendices ......................................................................................................................137
14.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival 
 (based on RECIST 1.1) .137
14.1.1
Introduction.........................................................................................139
14.1.2
Efficacy assessments...........................................................................139
14.1.3
Definitions...........................................................................................139
14.1.4
Disease measurability..........................................................................139
14.1.5
Eligibility based on measurable disease..............................................140
14.1.6
Methods of tumor measurement - general guidelines.........................140
14.1.7
Baseline documentation of target and non-target lesions ...................142
14.1.8
Follow-up evaluation of target and non-target lesions........................143


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14.1.9
Follow-up and recording of lesions.....................................................143
14.1.10
Non-nodal lesions................................................................................143
14.1.11
Nodal lesions.......................................................................................144
14.1.12
Determination of target lesion response..............................................144
14.1.13
Determination of non-target lesion response ......................................146
14.1.14
New lesions .........................................................................................147
14.1.15
Evaluation of overall lesion response .................................................147
14.1.16
Efficacy definitions .............................................................................148
14.1.17
Best overall response...........................................................................148
14.1.18
Time to event variables .......................................................................150
14.1.19
Progression-free survival ....................................................................150
151
14.1.21
Time to progression.............................................................................151
14.1.22
Time to treatment failure.....................................................................151
14.1.23
Duration of response ...........................................................................151
14.1.24
Time to response .................................................................................152
14.1.25
Definition of start and end dates for time to event variables ..............153
14.1.26
Handling of patients with non-measurable disease only at baseline...154
14.1.27
Sensitivity analyses .............................................................................155
14.1.28
Data handling and programming rules................................................157
14.1.29
Study/project specific decisions..........................................................157
14.1.30
End of treatment phase completion.....................................................157
14.1.31
End of post-treatment follow-up (study phase completion)................158
14.1.32
Medical validation of programmed overall lesion response ...............158
14.1.33
Programming rules..............................................................................159
14.1.34
Calculation of ‘time to event’ variables..............................................159
14.1.35
Incomplete assessment dates...............................................................159
14.1.36
Incomplete dates for last known date patient alive or death ...............159
14.1.37
Non-target lesion response..................................................................159
14.1.38
Study/project specific programming...................................................159
14.1.39
Censoring reason.................................................................................159
14.1.40
References (available upon request) ...................................................160
14.2
Appendix 2: Guidelines for immune-related response criteria (IrRC) using 
one-dimensional measurements (simulating RECIST 1.1) .................................161
14.2.1
Introduction.........................................................................................161
14.2.2
New Lesions and non-target lesions ...................................................161


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14.2.3
Follow-up evaluation of target and non-target lesions........................161
14.2.4
Definitions of response categories and evaluation of overall lesion 
response...............................................................................................162
14.2.5
Only non-measurable disease at baseline............................................163
14.2.6
Reference (available upon request).....................................................163
14.3
Appendix 3: Statistical details of Phase I Bayesian logistic regression models 
(BLRM) and Phase II hierarchical models ..........................................................164
14.3.1
Phase I BLRM.....................................................................................164
14.3.2
Prior specifications for phase II hierarchical model ...........................177
14.4
Appendix 4: Statistical details of Phase I Bayesian logistic regression model 
(BLRM) in Japanese patients treated with single agent of LAG525...................180
14.4.1
Statistical model..................................................................................180
14.4.2
Prior specifications..............................................................................180
14.4.3
BLRM design properties for hypothetical data scenarios...................183


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List of figures
Figure 2-1
Blockade of PD-1/PD-L1 and LAG-3 by PDR001 and LAG525.........51
Figure 4-1
Study design..........................................................................................58
List of tables
Table 3-1
Objectives and related endpoints ..........................................................55
Table 6-1
Dose and treatment schedule.................................................................66
Table 6-2
Provisional dose levels (Ph I Arm A and Arm C: single-agent 
LAG525) ...............................................................................................69
Table 6-3
Provisional dose levels (Ph I Arm B: combinations of LAG525 and 
PDR001)................................................................................................70
Table 6-4
Criteria for defining dose-limiting toxicities.........................................76
Table 6-5
Recommended Dose Modifications for LAG525 and PDR001............78
Table 7-1
Visit evaluation schedule ......................................................................88
Table 7-2
Disease assessment collection plan.......................................................96
Table 7-3
ECOG performance status.....................................................................97
Table 7-4
Local clinical laboratory parameters collection plan ............................98
Table 7-5
12 Lead ECG collection plan..............................................................100
Table 7-6
Pharmacokinetic blood collection log for LAG525 alone, LAG525 
in combination with PDR001 and PDR001 in combination with 
LAG525 in all patientsb.......................................................................101
104
Table 10-1
Pharmacokinetic Parameters to be analyzed.......................................126
Table 10-2
Operating characteristics of the design (single agent LAG525).........130
Table 10-3
Operating characteristics of the design (LAG525+PDR001) .............131
Table 10-4
Operating characteristics of the design (LAG525 + PDR001) ...........131
Table 14-1
Response criteria for target lesions .....................................................144
Table 14-2
Response criteria for non-target lesions..............................................146
Table 14-3
Overall lesion response at each assessment ........................................147
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................154
Table 14-5
Options for event dates used in PFS, TTP, duration of response........155
Table 14-6
Overall response at each assessment...................................................162
Table 14-7
Prior distribution of model parameters – phase I single agent 
PDR001...............................................................................................165
Table 14-8
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the mixture prior in Table 14-7) ...................166


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Table 14-9
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the Component 1 prior in Table 14-7) ..........166
Table 14-10
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the Component 2 prior in Table 14-7) ..........166
Table 14-11
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent LAG525..............................................................167
Table 14-12
Prior distribution of model parameters – phase I LAG525 + 
PDR001...............................................................................................170
Table 14-13
Summary of prior distribution of DLT rates – phase I LAG525 + 
PDR001...............................................................................................170
Table 14-14
Hypothetical dose escalation scenarios for on-study decisions –
phase I LAG525 + PDR001................................................................171
Table 14-15
True underlying probabilities of DLT for Scenario 1 .........................174
Table 14-16
True underlying probabilities of DLT for Scenario 2 .........................175
Table 14-17
True underlying probabilities of DLT for Scenario 3 .........................175
Table 14-18
True underlying probabilities of DLT for Scenario 4 .........................175
Table 14-19
True underlying probabilities of DLT for Scenario 5 .........................176
Table 14-20
Results.................................................................................................177
Table 14-21
Prior distribution of hierarchical model parameters............................179
Table 14-22
Data from global patients in study CLAG525X2101C.......................181
Table 14-23
Prior distributions for the parameters of the MAP model used to 
derive the prior ....................................................................................182
Table 14-24
Prior distribution of model parameters ...............................................182
Table 14-25
Summary of prior distribution of DLT rates.......................................183
Table 14-26
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent LAG525..............................................................183
Table 14-27
dose-DLT scenarios ............................................................................185
Table 14-28
Operating characteristics of BLRM-based dose escalation design.....185


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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AMI
Acute Myocardial Infarction
APC
Antigen Presenting Cell
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BLRM
Bayesian Logistic Regression Model
CDP
Clinical Development Plan
CMO&PS
Chief Medical Office and Patient Safety
CRC
Colorectal cancer 
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR
CV
Cardiovascular
DCR
Disease Control Rate
DDP
Dose Determining Pharmacokinetic Set
DDS
Dose-Determining Safety Set
DLT
Dose Limiting Toxicity
DOR
Duration of Response
ECG
Electrocardiogram
ER
Estrogen Receptor
eSAE
Electronic Serious Adverse Event
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
FIH
First In Human
FU
Follow Up
GDPR
General Data Protection Regulation
GEJ
Gastro-Esophageal Junction
GLP
Good Laboratory Practice
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HED
human equivalent dose
HER2
Human Epidermal growth factor Receptor 2
HNSTD
highest non-severely toxic dose
i.v.
Intravenous(ly)
IEC
Independent Ethics Committee
IG
Immunogenicity
IL-6
Interleukin-6
IRB
Institutional Review Board
irAE
Immune Related Adverse Event
irRC
immune related Response Criteria


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ITIM
Immunoreceptor Tyrosine-based Inhibitory Motif
KO
Knockout
LAG-3
Lymphocyte activation gene-3
LLOQ
Lower Limit Of Quantitation
LMWH
Low Molecular Weight Heparin
mAb(s)
monoclonal Antibody(ies)
MHC
Major Histocompatibility Complex
MSI-H
Microsatellite instability high
MTD
Maximum Tolerated Dose
NOAEL
No Observed Adverse Effect Level
NPC
Nasopharyngeal cancer
NSCLC
Non-Small Cell Lung Carcinoma
NYHA
New York Heart Association
ORR
Overall Response Rate
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression Free Survival
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Progesterone Receptor
Q2W
Every 2 weeks dosing schedule
Q3W
Every 3 weeks dosing schedule
Q4W
Every 4 weeks dosing schedule
RAP
Report and Analysis Plan
RCC
Renal Cell Cancer
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SEC
Safety Event Categories
SJS
Stevens-Johnson syndrome 
TCR
T Cell Receptor
TEN
Lyell syndrome/toxic epidermal necrolysis 
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TNBC
Triple Negative Breast Cancer
TTR
Time To Response
US
United States
WT
Wild type


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Sample
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen 
(i.e. treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage
Patient Number (Patient No.)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Personal Data 
Patient information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes patient
identifier information, study information, and biological samples.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression 
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered 
to the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient 
withdrawal
Treatment group
A treatment group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. Cohorts are not expanded, new cohorts 
are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints


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Withdrawal of Study Consent
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data. 


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Protocol No. CLAG525X2101C
Protocol summary:
Protocol number
CLAG525X2101C
Title
A Phase I/II, open label, multicenter study of the safety and efficacy of LAG525 
single agent and in combination with PDR001 administered to patients with 
advanced malignancies.
Brief title
Phase I/II study of single agent LAG525 or combination of LAG525 and PDR001 
in patients with advanced malignancies.
Sponsor and
Clinical Phase
Novartis
Phase I/II
Investigation type
Monoclonal antibody
Study type
Interventional
Purpose and rationale
The purpose of this study is to characterize the safety, tolerability including 
determination of maximum tolerated dose (MTD) or recommended Phase 2 dose 
(RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity 
of LAG525 as a single agent and in combination with PDR001, an antibody 
directed against PD-1 under investigation in a separate study ([PDR001X2101]).
In addition, the safety, tolerability, pharmacokinetics and pharmacodynamics of 
single-agent LAG525 in Japanese patients will be evaluated and characterized.
LAG-3 binds its ligand MHC Class II, and regulates T cell signaling. Blockade of 
LAG-3 has been shown to increase T cell proliferation and cytokine secretion, 
most notably IFN-γ. LAG-3 expression is also correlated with increased 
suppressive function in both FoxP3-positive natural regulatory T cells and 
induced FoxP3-negative regulatory cells.
By blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, 
PDR001 inhibits the PD-1 immune checkpoint, resulting in activation of an 
antitumor immune response by activating effector T-cells and inhibiting 
regulatory T-cells.
Preclinical studies in the Sa1N fibrosarcoma and MC38 colon carcinoma models 
demonstrated tumor growth inhibition with anti-LAG-3 as a monotherapy with 
enhanced tumor growth inhibition observed with the combination of anti-LAG-3 
and anti-PD-1 immunotherapy. Expression analysis in human tumor infiltrating 
lymphocytes (TILs) from cancer patients supports this conclusion, with LAG-3 
and PD-1 co-expression identified on tolerized TILs in patients with ovarian 
cancer and microsatellite high colorectal carcinoma (MSI-H CRC).
Primary Objective(s)
Phase I part
●
To estimate the RP2D or MTD for single agent LAG525 in all patients 
(including for Japanese patients)
●
To estimate the RP2D or MTD for the combination of LAG525 and PDR001
Phase II part
●
To estimate the overall response rate per RECIST V1.1 for single agent 
LAG525 as well as for the combination of LAG525 and PDR001


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Secondary Objectives
●
To characterize the safety and tolerability of single agent LAG525 given 
alone and in combination with PDR001
●
To characterize the pharmacokinetic profile of single agent LAG525 given 
alone and in combination with PDR001
●
To assess emergence of anti-LAG525, and anti-PDR001 antibodies following 
one or more intravenous (i.v.) infusions of single-agent LAG525 given alone 
or in combination with PDR001
●
To evaluate the preliminary antitumor activity of single agent LAG525 given 
alone or in combination with PDR001
Study design
This study has been designed as a phase I/II, multi-center, open-label study 
starting with a phase I dose escalation part (including a separate Japanese 
single-agent dose escalation arm) followed by a phase II part.
Arm A: single agent LAG525
Arm B: combination of LAG525 and PDR001
Arm C: single agent LAG525 dose escalation in Japanese patients
Data from the dose-escalation arms will be analyzed separately and pooled as 
appropriate. If the recommended dose of single agent LAG525 is the same in 
Arms A and C, patients enrolled in Japan may be recruited into the Phase II 
single agent part of the study. In addition, if the recommended dose of PDR001 
for Japanese patients in the PDR001X1101 study is the same as that determined 
in study PDR001X2101, Japanese patients may also enter the combination parts 
of study LAG525X2101 at whichever dose is being tested at that time.
Both PDR001 and LAG525 will be administered i.v. once every two weeks until a 
patient experiences unacceptable toxicity, progressive disease as per irRC or 
treatment is discontinued at the discretion of the investigator or the patient. In the 
combination cohort, the two antibodies will be administered separately with a 
break of 30 minutes between administrations. Infusions of each antibody can be 
extended to up to 2 hours if clinically indicated and the break between LAG525 
and PDR001 antibody infusions can be up to 4 hours if clinically indicated. A 
cycle is defined as 28 days (21 days for patients on Q3W dosing schedule) for 
both monotherapy LAG525 and the combination of LAG525 and PDR001.
For the combination arm, the first dose for the first two patients treated at each 
untested dose level will be staggered by 24 hours.
Population
The phase I part of the study will be conducted in adult patients with advanced 
solid tumors.
The phase II part of the study, both single agent and combination arms, will be 
conducted in adult patients with melanoma, NSCLC and renal cancer with or 
without PD-1/PD-L1 treatment experience. The combination arm will also be 
conducted in patients with mesothelioma and TNBC with or without PD-1/PD-L1 
treatment experience.


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Inclusion criteria
1. Written informed consent must be obtained prior to any procedures. For ‘
Japan only: written consent is necessary both from the patient and his/her 
legal representative if he/she is under the age of 20 years.
2. Age ≥ 18 years
3. Phase I part: Patients with advanced/metastatic solid tumors, with 
measurable or non-measurable disease as determined by RECIST version 
1.1 (refer to Appendix 1), who have progressed despite standard therapy or 
are intolerant of standard therapy, or for whom no standard therapy exists.
4. Phase II part: Patients with advanced/metastatic solid tumors, with at least 
one measurable lesion as determined by RECIST version 1.1, who have 
had disease progression. Additionally, the following must apply:
a.
NSCLC:
i.
Disease recurrence or progression during or after no more than one 
prior platinum doublet-based chemotherapy regimen for advanced 
or metastatic disease. Prior maintenance therapy is allowed 
(considered pemetrexed, erlotinib, bevacizumab).
ii.
Patients must have been tested for mutations affecting EGFR 
and/or ALK. (Patients with a known mutation in one gene need not 
be tested for the other). Patients with ALK or EGFR-positive 
NSCLC must have had recurrent or progressive disease after 
treatment with the corresponding inhibitor and no more than one 
platinum doublet-based chemotherapy, in any sequence.
b.
Melanoma:
i.
Patients with BRAF V600 mutation positive disease must have 
objective evidence of progression of disease after treatment with a 
BRAF inhibitor alone or in combination with other agents.
ii.
Patients with BRAF wild-type disease must have objective evidence 
of progression of disease but are not required to have received 
prior therapy.
c.
Renal:
i.
Patients must have objective evidence of progression of disease 
during or following at least one regimen of treatment for advanced 
renal cancer.
d.
Mesothelioma:
i.
Patients must have objective evidence of progression of disease 
during or following at least one prior line of systemic chemotherapy 
for advanced disease.
e.
TNBC:
i.
Patients must have objective evidence of progression of disease 
during or following no more than 2 prior lines of systemic 
chemotherapy for advanced disease. Patients must have received 
a prior taxane-containing regimen.
5. ECOG Performance Status ≤ 1.
6. Phase I Part: Patients enrolled in the Phase I part of the study must provide a 
new tumor biopsy at baseline and during treatment if medically feasible.
Phase II part: Patients enrolled in the Phase II part of the study must provide a 
new tumor biopsy at baseline and during treatment, if medically feasible.
Exclusion criteria
(selected)
1. Presence of symptomatic central nervous system (CNS) metastases, or CNS 
metastases that require local CNS-directed therapy (such as radiotherapy or 
surgery), or increasing doses of corticosteroids within the prior 2 weeks. 
Patients with treated brain metastases should be neurologically stable for at 
least 4 weeks prior to study entry and off steroids for at least 2 weeks before 
administration of any study treatment.
2. History of severe hypersensitivity reactions to study treatment ingredients or 
other mAbs


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3. Patient with out-of-range laboratory values defined as:
●
Creatinine clearance (calculated using Cockcroft-Gault formula, or 
measured) < 40 mL/min
●
Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome 
who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x 
ULN
●
Alanine aminotransferase (ALT) > 3 x ULN
●
Aspartate aminotransferase (AST) > 3 x ULN
●
Absolute neutrophil count (ANC) < 1.0 x 109/L
●
Platelet count < 75 x 109/L
●
Hemoglobin (Hgb) < 9 g/dL
●
Potassium, magnesium, calcium or phosphate abnormality CTCAE > 
grade 2
4. Clinically significant cardiac disease or impaired cardiac function
5. Active, known or suspected autoimmune disease. Patients with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to an autoimmune condition 
only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or other conditions not expected to recur are permitted to enroll. 
Patients previously exposed to anti-PD-1 / PD-L1 treatment who are 
adequately treated for skin rash or who are receiving replacement therapy for 
endocrinopathies should not be excluded.
6.  Patients who required discontinuation of treatment due to treatment-related 
toxicities with prior therapy directed against the same target as the drug(s)
under study in this protocol.
7. History of drug-induced pneumonitis or current pneumonitis
8. Active infection requiring systemic antibiotic therapy. Patients requiring 
systemic antibiotics for infection must have completed therapy before 
screening is initiated.
9. HIV infection. Testing for HIV status is not necessary unless clinically 
indicated
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for 
HBV or HCV status is not necessary unless clinically indicated or the patient 
has a history of HBV or HCV infection.
11. Malignant disease, other than that being treated in this study
12. Any medical condition that would, in the investigator’s judgment, prevent the 
patient’s participation in the clinical study due to safety concerns, compliance 
with clinical study procedures or interpretation of study results.
13. a.
Systemic anti-cancer therapy within 2 weeks of the first dose of study
treatment.
b.
For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C, 
nitrosoureas or more recent immunotherapies, 4 weeks is indicated as 
washout period.
c.
For patients receiving anticancer immunotherapies such as CTLA-4 
antagonists, 8 weeks is indicated as the washout period.
14. Patients receiving chronic treatment with systemic steroid therapy (>10
mg/day prednisone or equivalent) within 7 days of the first dose of study 
treatment, other than replacement-dose steroids in the setting of adrenal 
insufficiency. Topical, inhaled, nasal and ophthalmic steroids are not 
prohibited.
15. Patients receiving systemic treatment with any immunosuppressive 
medication thought to interfere with the mechanism of action of the study 
drugs, other than replacement–dose corticosteroids in the setting of adrenal 
insufficiency.
16. Use of any live vaccines against infectious diseases within 4 weeks of 
initiation of study treatment.
17. Major surgery within 2 weeks of the first dose of study treatment.


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18. Radiotherapy within 2 weeks of the first dose of study drug, except for 
palliative radiotherapy to a limited field, such as for the treatment of bone 
pain or a focally painful tumor mass. To allow evaluation of response to 
treatment, patients enrolled in the Phase II part must have remaining 
measurable disease that has not been irradiated.
19. Participation in an interventional, investigational study within 2 weeks prior to 
the first dose of study treatment.
20. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral 
neuropathy and ototoxicity, which are excluded if ≥ CTCAE grade 3) due to 
prior cancer therapy.
21. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, 
GMCSF, M-CSF) ≤2 weeks prior to the first dose of study treatment
22. Pregnant or lactating women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test.
23. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 150 days after the last dose 
of LAG525 or PDR001.
24. Sexually active males unless they use a condom during intercourse while 
taking the drug and for 150 days after stopping study treatment and should 
not father a child in this period. A condom is required to be used also by 
vasectomized men as well as during intercourse with a male partner in order 
to prevent delivery of the drug via seminal fluid.
Investigational and 
reference therapy
LAG525 and PDR001
Efficacy assessments
Tumor assessment per RECIST v1.1 and per irRC
Safety assessments
Incidence and severity of AEs and SAEs, including changes in laboratory values, 
vital signs and ECGs
Other assessments
Serum PK parameters and immunogenicity.
Data analysis
The study data will be analyzed and reported based on all patients’ data of the 
Phase I and Phase II parts up to the time when all patients have completed at 
least six cycles of treatment or discontinued the treatment. Patient data from 
dose escalation will be analyzed by Arm and from Phase II by Group. Study data 
may be pooled where appropriate.
Key words
Phase I/II, LAG525, PDR001, Checkpoint inhibitor, PD-1, PD-L1, LAG-3.


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Amendment 10 (27-Jun-2019)
Amendment rationale 
The primary purpose of this amendment is to revise the definition of ‘end of study’ to include 
the option for patients still on study treatment and who, in the opinion of the investigator, are 
still deriving clinical benefit at the time of end of study, to transfer to another study or to an 
alternative treatment option to continue providing study treatment to these patients.
 
 
 
 
 
Changes to the protocol
 
 
 
 
Section 4.1.3 and Section 4.3 was updated to include the addition of language to account for 
patients who would transfer into another study or an alternative treatment option to continue 
provision of study treatment.
Section 7.1.3 was updated to include the addition of language to specify that patients who 
transfer to another study or an alternative treatment option to continue provision of study 
treatment will complete end of treatment procedures.
Section 7.1.5 was updated to include the addition of language to specify that patients who 
transfer into another study or an alternative treatment setting to continue provision of study 
treatment will not complete the safety, disease progression 
.
 
Study status
As of 26-Mar-2019, 450 patients have been enrolled in this trial. Of the 450 patients, 255 
patients have been treated in the dose escalation part, of which 134 received LAG525 single 
agent and 121 received LAG525 in combination with PDR001 and 235 patients that have been 
treated in the combination dose expansion part. As of 26-Mar-2019 there were 39 active patients. 
Ten of these patients were enrolled in the dose escalation part and 29 patients were enrolled in 
the dose expansion part.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 09 (16-Aug-2018)
Amendment rationale 
The primary purpose of this amendment is to incorporate health authority-requested language 
requiring study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS)/ 
toxic epidermal necrolysis (TEN). 
After the occurrence of a case of Stevens Johnson Syndrome (SJS) in a study with PDR001 in 
combination with another investigational agent, the dose modification guidelines for protocols 
using PDR001 were updated to mandate permanent discontinuation of study treatment for 
patients who experience SJS or Lyell syndrome/toxic epidermal necrolysis (TEN). This change 
has already been implemented as part of an urgent safety measure released on 15 June 2018. 
This protocol amendment is now formalizing these changes in the dose modification section 
and corresponding table describing the criteria for dose reduction/interruption and re-initiation 
of treatment for adverse drug reactions. Changes to other sections of the protocol have been 
made to align with the updated dose modification section.
In addition, the protocol has been revised to align with recently published guidelines on the 
clinical management of suspected immune-related toxicities.
Other modifications of the protocol are specified below:

Withdrawal of study consent language has been updated to reflect the European Economic
Area General Data Protocol Regulation (GDPR) requirements.
 
 

Clarify language regarding Progressive Disease in the End of Treatment disposition 
section. The criteria for progressive disease will include evaluation as per RECIST 1.1 and 
as determined clinically by the Investigator, in addition to per irRC. 

Language within the statistical analysis section of protocol was updated to add details and 
clarifications for reporting secondary safety and efficacy objectives. 
 
 
 

Language within guideline for irRC has been updated to clarify the selection of new 
measurable lesions, and calculation of follow-up evaluations. 
Study status:
The CLAG525X2101C study started enrollment on 17-June-2015. As of 21-Jun-2018, 255
patients have been treated in the Phase I study part and 212 patients have been treated in the 
Phase II study part which is currently ongoing. As anti-tumoral activity was not observed with 
LAG525 single agent but was seen at several dose levels of LAG525 in combination with 
PDR001, it was decided that only the combination portion Phase II expansion would be enrolled. 
This was not a consequence of any safety concern. 


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Glossary of terms was updated to include the definition for Personal Data and Withdrawal of 
study consent. 
Section 5.3 exclusion criteria was changed to align with updated recommended dose limiting 
toxicity table.
Section 6.2 and Table 6-4 was updated to align with recently published guidelines on the clinical 
management of suspected immune-related toxicities.
Section 6.3 and Table 6-5 was updated to align with recently published guidelines on the clinical 
management of suspected immune-related toxicities. 
Section 6.3.5 was updated to include allowed dose of systemic steroid used for the management 
of other concurrent medical conditions. 
Section 7.1.3 was updated to have progressive disease include per RECIST 1.1 or as determined 
clinically by the Investigator.
Section 7.1.4 was updated to differentiate sample use after a patient withdraws consent based 
on different regulations/laws around the world.
 
Table 7-6 footers were adjusted to clarify that the 1-hour post infusion sample should be taken 
at all dosing visits from Cycle 1 through Cycle 6 unless noted otherwise. 
Section 8.3 was updated to note that if the mother consents outcome data will be collected for 
up to 12 months after the birth of the child.
Section 10.5.2 was updated to clarify data reporting for secondary efficacy objectives.   
Section 10.5.3.1 was updated to clarify what analysis set will be used for safety analysis. 
Section 10.5.3.2 was updated to clarify which adverse event summaries will be produced.
Section 14.2 was updated to clarify the selection of new measurable lesions and calculation of 
follow-up evaluations. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 15 June 2018. These changes are required for patient 
safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH GCP 3.3.8). 
Therefore, they were required to have been implemented prior to IRB/IEC approval of this 
amendment.


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Protocol No. CLAG525X2101C
All other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 08 (21-Jun-2017)
Amendment rationale 
The purpose of this amendment is to incorporate the following modifications:

Addition of mesothelioma and triple negative breast cancer (TNBC) indications in the 
combination arm of the phase II part of the study, based on preliminary evidence of anti-
tumor activity seen in these indications during the dose-escalation portion of 
CLAG525X2101C (As of 20Mar2017, 2 partial responses in mesothelioma and 2 partial 
responses in TNBC per RECIST), as well as activity reported in recent publications (Alley 
2017; Nanda 2016) of other checkpoint inhibitors.

To allow single-agent LAG525 patients to continue study treatment with LAG525 in 
combination with PDR001 upon disease progression after at least 4 cycles of LAG525 
monotherapy treatment and to detail the required tests/samples to be collected. This 
modification to the protocol will: 1.) provide the opportunity for PDR001 treatment to a 
small number of patients who may not otherwise have access to a PD-1 inhibitor, and 2.) 
allow potentially more effective combination treatment with simultaneous LAG525 + 
PDR001 to patients who enrolled onto the LAG525 single-agent arm.

Reduced PK blood sampling timepoints in order to minimize the number of blood samples 
collected for the Phase II patients.  

Inclusion criteria 5: ECOG performance status to ≤ 1 (changed from ≤ 2) in order to ensure 
that patients enrolling into phase II indications have a better opportunity to receive and 
tolerate therapy.

Inclusion criteria 6: All phase II patients must provide a new tumor biopsy at baseline and 
during treatment, if medically feasible. The change from optional to mandatory biopsies is 
expected to increase the number of paired tumor specimens available for investigation of 
biomarkers relevant to anti-LAG-3 and anti-PD-1 therapy. 
 
 
   

Exclusion criteria 3: Modified potassium, magnesium, calcium or phosphate abnormality to 
CTCAE > grade 2 (changed from grade 1) as these lab values tend to fluctuate with frequent 
assessment and may not reflect the patient's overall clinical status. Low-grade changes can 
be managed with supplementation, and are not intended to be the basis for exclusion from 
the clinical trial if the patient otherwise meets inclusion/exclusion criteria.  Hemoglobin 
must not be < 9 g/dl (changed from < 8 g/dl) in order to potentially increase patients’ ability 
to tolerate therapy.

Exclusion criteria 14: provided washout and corticosteroid dose guidance, since this 
information was not provided previously.

LDH laboratory test has been added for TNBC patients. In the single-agent pembrolizumab 
trial (Nanda 2016) reported that LDH ≥ 2 times the upper limit of normal was a poor 
prognostic indicator, and was associated with disease progression. 


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
Best overall response per was changed from 30 to 150 days due to delayed patient response.  

Section 1.2.3.2 was updated with current clinical experience for LAG525 and PDR001.
Study status:
The CLAG525X2101C study started enrollment on 17-June-2015. As of 31-May-2017, 254 
patients have been treated, all in the Phase I dose escalation part. Dose escalation treatment is 
ongoing in all treatment arms. The single-agent Phase I dose escalation part enrolled 133 
patients (119 in Arm A and 14 in Arm C)
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Sections 2.1, 2.2.3, 4.1, 5.1, 5.2 and 10 have been updated as described in the above rationale 
section for the addition of mesothelioma and TNBC.
Sections 4.1.3, 7.1.1.2; and Table 7-1 have been updated to collect BRCA status if known for 
TNBC patients.
Sections 5.2 and 5.3 Inclusion/Exclusion criteria have been updated as described in the above 
rationale.
Table 7-4 has been updated for LDH to be collected for TNBC patients.
Table 7-6 has been updated related to PK blood samples as described in the above rationale 
section 
Section 7.2.4 has been updated per biopsy collection clarification Inclusion criteria 6.
Table 7-7 has been updated to note total volumes and remove tube types; also changed PBMCs 
to Whole Blood for RNA
Section 6.2.3.2.1, Table 7-1 and Section 7.2.3 has been updated as described in the above 
rationale section related to single-agent LAG525 patients being allowed to continue study 
treatment with LAG525 in combination with PDR001.
Section 14.1.17 best overall response has been updated as described in the above rationale.
Section 14.2 has been updated to provide additional details for new measurable lesions, 
unknown response and only non-measurable disease at baseline.
Study status:
The CLAG525X2101 study started enrollment on 17-June-2015. As of 31-May-2017, 254 
patients had been treated, all in Phase I the dose escalation study part. Dose escalation is 
ongoing in all treatment arms.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 07 (09-Dec-2016)
Amendment rationale 
The purpose of this amendment is to incorporate the following modifications requested by a 
regulatory authority:

Added guidance for patients with hyperglycemia or other signs and symptoms of diabetes 
and diabetic ketoacidosis.  In patients with severe hyperglycemia, the recommendation to 
omit the dose of LAG525 and PDR001 and manage as per Institutional guidelines until 
resolved to ≤ Gr 1 has been added. Additionally, patients without pre-existing diabetes or 
previously determined to be normoglycemic, but shown to have an abnormal random 
blood glucose at screening must have a fasting blood glucose test performed. Any 
subsequently diagnosed hyperglycemia should be managed appropriately as per 
Institutional guidelines.
 
 
 
 
 
 
 
 
 
 
 
 
 

In addition, the following eligibility criteria in sections 5.2 and 5.3 were updated in this 
amendment: Inclusion criteria 4: clarifications on prior therapy requirements for Phase II 
patients to account for current standard of care. In response to the rapidly changing 
approach to treatment of patients with melanoma, the eligibility criterion has been 
changed to no longer require patients with melanoma to have received systemic therapy 
prior to being eligible for study enrolment. All patients with BRAF V600 mutant 
melanoma must have received a BRAF inhibitor.

Inclusion criteria 6: Corrected formatting issue and clarified newly collected tumor biopsy 
is required at baseline for both Phase I and II if medically feasible. 

Exclusion criteria 1: Added additional guidance regarding patients with brain metastases 
to ensure suitability of patients to be enrolled.


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
Exclusion criteria 5: Clarified that patients with prior anti-PD-1/PD-L1 treatment who are 
adequately treated for skin rash or replacement therapy for endocrinopathies should not be 
excluded

Exclusion criteria 6: Added to exclude patients who discontinued prior checkpoint 
inhibitor therapy due to checkpoint inhibitor-related toxicity as these patients may be at 
higher risk of re-bound toxicity

Exclusion criteria 18: Clarified that patients enrolled in the Phase II part must have 
remaining measurable disease that has not been irradiated.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section 1.2.2.2 Clinical experience with PDR001: Updated based on CPDR001X2101 trial.
 
 
Section 5.2 and 5.3 Inclusion/Exclusion Criteria has been updated as described in the rationale 
section above.
Section 6.1 Dosing regimen: Clarified guidance regarding resuming study treatment after dose 
interruptions to accommodate all potential dosing schedules.
Section 6.1.2 Ancillary Treatments: Added that if a patient experiences a Grade ≥3 
anaphylactic/anaphylactoid reaction, the patient will be discontinued from the study.
Section 6.2.3 Guidelines for dose escalation: Clarified that the additional cohorts may be opened 
for additional pharmacodynamics data. 
Table 6-4 Criteria for defining DLTs:  Clarified DLT window for each Treatment Arm.
Section 6.3 Dose modifications: Adjusted guidance regarding resuming study treatment after 
dose interruptions.
Table 6-5 Recommended Dose Modifications: Added guidance for Type 1 Diabetes mellitus. 
Also clarified that decreasing the dose level or the dosing frequency is the recommendation for 
certain toxicities. 
Section 6.3.3 Permitted concomitant therapy: Added guidance for certain hormone therapies as 
well as bisphosphonates to allow patients who may benefit from study treatment to enroll but 
who are dependent upon the therapies described for symptomatic disease control. 
Section 6.3.4 Permitted concomitant therapy: Clarified concomitant therapy requirements apply 
to the DLT observation window (1 cycle for single agent, 2 cycles for combination treatment 
arms).
Table 7-1 Visit evaluation schedule: added and adjusted biomarker collections and removed 60 
and 120 day safety follow up visits.


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Section 4.1.3 and 7.1.5 Follow up period revised to align with the PDR001 program: removed 
60 and 120 day post-treatment safety follow up. Also clarified that the follow up can be done 
by telephone or patient visit.
Section 7.2.1 Efficacy assessments: Clarified the scope of vendor for independent review of 
imaging data for imaging data in Phase II.
Table 7-2 Disease assessment collection plan: Added guidance on bone scans.
Table 7-4 Local clinical laboratory parameters collection plan: Added note regarding fasting 
glucose. Also revised collection of LDH to encompass all melanoma patients regardless of when 
they enroll.
Section 7.2.2.5.2 Clinical Chemistry: Added guidance on when glucose testing should be 
fasting or non-fasting.
 
 
 
 
 
 
 
 
 
Section 8.1.1 Adverse Event definitions and reporting: Clarified that after initiation of new post-
treatment antineoplastic therapy, only AEs suspected to be related to study treatment will be 
collected in the safety follow up period. 
Section 8.2.2 Serious Adverse Event reporting: Clarified that if a patient starts a post treatment 
antineoplastic therapy, only SAEs suspected to be related to study treatment will be collected 
in the safety follow up period.
Section 8.5 Data Monitoring Committee: Clarified that events through the DLT observation 
window (through Cycle 1 for Arms A and C, through Cycle 2 for Arm B) will be discussed at 
dose escalation teleconferences.
Section 10.1.4 Dose-Determining Analysis Set: The dose-determining set definition has been 
clarified to account for possible different dosing schedules for LAG525 and PDR001.


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Section 11.5 Publication of study protocol and results: Added details regarding Novartis 
publication process
Study Status
The CLAG525X2101 study started enrollment on 17-June-2015. As of 25-Aug-2016, 117 
patients had been treated, all in Phase I the dose escalation study part. Dose escalation is 
ongoing in all treatment arms. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 06 (05-Jul-2016)
Amendment rationale
The purpose of this amendment is to incorporate changes related to the following: With the 
available PK data obtained from the single agent first-in-human study CPDR001X2101, an 
exploratory population PK (PopPK) analysis showed that the T1/2 of PDR001 in man is 20 [17, 
23] days (mean [90% CI]). Using five times the upper bound of the confidence interval of the 
half-life of 23 days and an added safety margin, the protocol is amended to increase the duration 
of contraception and safety follow-up periods post PDR001 treatment from 90 days to 150 days. 
These changes are related to an Urgent Safety Measure communicated on 08-June-2016 to all 
investigators. For logistical simplicity, these changes are applicable for all patients in both the 
single-agent LAG525 and combination LAG525 + PDR001 study arms.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Safety follow-up period increased from 90 to 150 days following end of treatment in the 
following sections:

4.1.3 Study Periods

4.3 Definition of end of the study

6.3.2 Follow-up for toxicities

Table 7-1 visit evaluation schedule

7.1.5 Follow up periods

8.1.1 Safety reporting

8.2.2 Reporting (of SAEs)

10.5.3 Safety objectives (definition of on-treatment and post-treatment periods)

Section 7.2.2.5.7 Pregnancy and assessment of fertility and Table 7-1: Pregnancy testing 
added at 120 and 150 days following end of treatment.

Exclusion Criteria 23 and 24: Requirement for women of child-bearing potential and 
sexually active males to use contraception increased from 90 to 150 days following end of 
treatment.

Table 7-4 Local lab: LDH added for Phase 2 melanoma patients to align with other trials 
in the PDR001 program

Protocol Summary Table: Population language corrected to align with body text
Study Status
The CLAG525X2101C study is currently ongoing in the Phase 1 study part.


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IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 05 (12-Apr-2016)
Amendment rationale
The purpose of this amendment is to incorporate the following modifications of the exclusion 
criteria requested by a regulatory authority:

Exclusion Criteria 02: Revised to exclude patients with history of severe hypersensitivity 
reactions to study treatment ingredients or other mAbs

Exclusion Criteria 07: Criterion added to exclude patients with a history of drug-induced 
pneumonitis or current pneumonitis

Exclusion Criteria 23: Clarified the definition of women who are considered post-
menopausal and not of child bearing potential
Additional changes to the protocol:

Exclusion Criteria 13: Washout period requirements for anti-cancer therapies have been 
split for clarification. Four-week washout period requirement for recent immunotherapies 
has been added.

Table 6-4: Clarified footnote regarding DLT observation window

Section 6.1.2 and Table 6-5: Clarified wording regarding infusion reactions

Table 7-1: Formatting corrected to clarify that capturing AEs and concomitant 
medications continues through the safety follow-up period

Table 7-2: Clarified that bone scans or other disease assessment methods allowed per 
RECIST 1.1 may be used

Section 10.1.4: Clarified minimum exposure for DDS for Q3W and Q4W schedule to 
align with Section 6.3.2

Section 10.4.4, 10.7, 10.8, and 14.3.2: corrected wording to reference 12 Phase 2 groups
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 04 (12-Feb-2016)
Amendment Rationale
The purpose of this amendment is to include a Japanese dose escalation arm for single-agent 
LAG525 with the goal of informing subsequent clinical development opportunities in Japan.
The single agent dose escalation part of this study is already underway globally with the 
exception of Japan. At the time of writing this amendment patients are being treated with single-
agent LAG525 at doses higher than the starting dose (1 mg/kg Q2W). In order to ensure that 
the safety and pharmacokinetic profiles of single-agent LAG525 are adequately characterized 
in Japanese patients at more than one LAG525 dose, a Japanese-specific dose escalation of 
single-agent LAG525 has been included in the protocol. The Japanese dose escalation will run 
separately from the ongoing dose escalation with a starting dose for single-agent LAG525 in 
Japanese patients of 1 mg/kg Q2W. Dose escalation decisions will be guided by a BLRM.
If the recommended dose of single agent LAG525 is the same in Arms A* and C**, patients 
enrolled in Japan may be recruited into the Phase II single agent part of the study. In addition, 
if the recommended dose of PDR001 for Japanese patients in the PDR001X1101 study is the 
same as that determined in study PDR001X2101, Japanese patients may also enter the 
combination parts of study LAG525X2101 at whichever dose is being tested at that time.
*Arm A: single-agent LAG525
**Arm C: single-agent LAG525 dose escalation in Japanese patients
Additional changes to the protocol:
The landscape of treatment with immunomodulatory therapy in oncology is evolving rapidly. 
In response to the growing number of patients with renal cancer receiving anti-PD-1/PD-L1 
therapy, expansion arms have been added for patients with renal cancer who are refractory to 
or have relapsed following prior treatment with PD-1/PD-L1 inhibitors to explore whether 
LAG525 alone or in combination with PDR001 can overcome PD-1/PD-L1 resistance.
In order to provide more flexibility in the palliation of symptoms caused by some tumor lesions 
and allow patients to continue the study treatment, the prohibited concomitant therapy section 
was updated to allow localized radiotherapy for non-target lesions.
Because the determination of EGFR, ALK, or BRAF V600 status is not performed routinely as 
part of standard assessment of disease in all countries or study sites, this amendment includes 
the determination of these molecular parameters by a local laboratory, at screening, for patients 
with a tumor of unknown status. However, the test results will not be used for eligibility of 
enrollment.
List of changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 1.2.2.2 Clinical Experience

Added a summary of PDR001X2101 study.

Section 2.2: Rationale for the study design:


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
Added a statement to include Japanese dose escalation arm for single-agent LAG525.

A new section (Section 2.2.2) was created to describe Japanese dose escalation.

Statement of recruitment of Japanese patients to the Phase II part was added to section 
2.2.3.

Section 3: Objectives and end points.

Primary objective was updated to include Japanese patients treated with single- agent 
LAG525.

Section 4.1 Description of Study Design:

The study design was updated to include a separate Japanese dose escalation.

Figure 4-1 was updated to include a separate Japanese dose escalation arm with 
single-agent LAG525 (Arm C).

Updated treatment group after adding renal cell carcinoma pre-treated with PD-1/PD-
L1 in the Phase II expansion part.

Section 4.1.1 Phase I dose escalation.

Added single dose escalation arm (Arm C) for Japanese patients.

Section 4.1.3 Study period

Added collection of EGFR, ALK, BRAF V600 status

Section 5.2: Inclusion criteria.

Updated for Japan only: written consent is necessary both from the patient and his/her 
legal representative if he/she is under the age of 20 years age for Japanese patients.

Section 5.3 Exclusion criteria

Removed one item in the exclusion criteria, which is prior PD-1 or PD-L1 directed 
therapy for renal cell carcinoma

Changed washout period from 6 weeks to 8 weeks for patients receiving anticancer 
immunotherapies such as CTLA-4 antagonists.

Section 6.2. Dose escalation guidelines

Added Arm C throughout the section

Section 6.2.3: Guidelines for dose escalation and determination of MTD/RP2D

Added Arm C to include Japan single agent dose escalation.

Section 6.3.4 Permitted concomitant therapy requiring caution and/or action

Updated to allow all types of anti-coagulation be included as permitted concomitant 
therapy, not just warfarin and heparin

Section 6.3.5 Prohibited concomitant therapy:

Clarified that limited-field palliative radiotherapy to non-target lesion(s) may be 
allowed after documented discussion with Novartis.

Section 7.1 Study flow and visit schedule

Added wording to explain category “D” and “S” in Table 7-1

Table 7-1 Visit evaluation schedule

Added collection of EGFR, ALK, BRAF V600 status


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
Pregnancy test was updated to reflect that during the safety follow-up period, a 
pregnancy test can be performed at home if patients are not coming to the clinic for 
the safety follow up visits

Added every 3 week dosing schedule to “study drug administration”

Section 7.1.1.2 Patient demographics and other baseline characteristics

Clarified MSI, EGFR, ALK, or BRAF V600 status to be collected at baseline as 
appropriate.

Section 7.1.2 Treatment period

A statement was added that for Japan only, patients enrolled in dose escalation are 
required to be hospitalized during the DLT evaluation period

Section 7.1.5 Follow up period: 90-day safety follow up period

A statement was added to clarify that during the safety follow up period, if patients 
are not coming to the clinic for the safety follow-up visits, a pregnancy test may be 
conducted at home if patients are not coming to the clinic for the safety follow up.

Table 7-2: Disease assessment collection plan

Table 7-2 was updated with detailed assessment collection plan.

Section 7.2.2.5.7 Pregnancy and assessment of fertility

A statement was added to clarify that during the safety follow up period, if patients 
are not coming to the clinic for the safety follow-up visits, a pregnancy test may be 
conducted at home if patients are not coming to the clinic for the safety follow up 
visits

Table 7-6: Pharmacokinetic blood collection log

Updated to provide specifications on some of the blood samples for Q2W, Q3W and 
Q4W schedules.

Footnote was updated that the sample collection may be stopped if sufficient data 
have been collected

Section 8: Safety monitoring and reporting

Updated section 8 throughout to reflect eSAE reporting procedure at Novartis

Section 10: Statistical Methods and data analysis.

Updated to include data analysis rules throughout the section; statistical hypothesis; 
model; and method of analysis for the Japanese-specific single agent LAG525 dose 
escalation.

Section 14: Appendices.

Added a new Section14.4: “Statistical details of Phase I Bayesian logistic regression 
model (BLRM) in Japanese patients treated with single agent of LAG525”.


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IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 03 (04-Dec-2016)
Amendment Rationale
The purpose of this amendment is to incorporate the following revision requested by a 
regulatory authority:

To specify that if required by a Regulatory Authority, recruitment to combination dose 
levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for patients 
from those countries.

To specify that for the combination arm, the first dose for the first two patients treated at 
each untested dose level will be staggered by 24 hours.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 2.3 Rationale for dose and regimen selection

Specified that if required by a Regulatory Authority, recruitment to combination dose 
levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for 
patients from those countries

Section 4.1 Description of study design:

Specified that for the combination arm, the first dose for the first two patients treated 
at each untested dose level will be staggered by 24 hours.

Added that if required by a Regulatory Authority, recruitment to combination dose 
levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for 
patients from those countries.

Section 6.1.1 Dose regimen

Specified that for the combination arm, the first dose for the first two patients treated 
at each untested dose level will be staggered by 24 hours.

Section 6.2.1 Starting dose rationale:

Added that if required by a Regulatory Authority, recruitment to combination dose 
levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for 
patients from those countries

Table 6-3 Provisional dose levels (Ph I Arm B: combinations of LAG525 and PDR001

Updated the footnote to specify that if required by a Regulatory Authority recruitment 
to combination dose levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 
mg/kg PDR001) for patients from those countries

Section 6.2.3 Guidelines for dose escalation and determination of MTD/RP2D

Added that if required by a Regulatory Authority, recruitment to combination dose 
levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for 
patients from those countries

Table 6-5 Recommended Dose Modifications for LAG525 and PDR001


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
Added a footnote to Pancreatitis to explain: asymptomatic enzyme increases do not 
require delay of study treatment or dose reduction
 

Section 7.2.2.5: Laboratory Evaluations

Clarified that cytokine release syndrome testing will be conducted centrally for sites 
not capable of local testing.
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 02 (14-Sep-2015)
Amendment Rationale
The goal of this amendment is as follows:
1. To focus the Phase II expansion on three main cancers: NSCLC, melanoma and renal cell 
carcinoma, both single agent and combination Phase II expansion will be conducted in 
cancers which are known to be responsive to single-agent PD-1 inhibition, to determine 
the efficacy of single-agent LAG525 and the combination of LAG525 with PDR001 in 
both the PD-1/PD-L1 pre-treated and naive settings.
a. Expansion arms for patients in the PD-1/PD-L1 naïve setting will explore antitumor 
activity of single-agent LAG525 and the combination of LAG525 with PDR001.
b. Expansion arms have been added for patients with NSCLC and melanoma who are 
refractory to or have relapsed following prior treatment with PD-1/PD-L1 inhibitors 
to explore whether LAG525 can overcome PD-1/PD-L1 resistance.
c.
 
 
 
 
 
2. Modify the inclusion criteria in the phase II part of the study for patients with NSCLC and 
melanoma who are naïve to PD-1/PD-L1 treatment, to align with study CPDR001X2101 
where PDR001 is being tested as a single-agent in the same patient populations.
3. Allow the option to test alternate dosing (i.e. flat dosing) within single agent dose 
escalation and/or Phase II expansion if flat dosing is supported by emerging PK data 
generated during the study. Flat dosing may also be tested in the combination part of the 
study for both LAG525 and PDR001.
a. Flat dosing decreases operational complexity with easier study drug preparation and 
may reduce the possibility of dosing errors.
4. Allow the option to test two doses of LAG525 during Phase II expansion
5. Allow collection of a blood sample for cytokine assessment (IL-6 
) for all 
patients at screening. This baseline sample will serve as a comparator for those patients 
who require follow-up assessment of cytokines (i.e. in case of an adverse event suspected 
to be cytokine release syndrome).
6. Clarification of certain exclusion criteria, and prohibited concomitant medications
7. Align the collection and analysis of 
 with preclinical 
evidence on the timing of immune response in tumor after therapy with PD-1 blocking 
antibodies
 
8. Changed safety monitoring / reporting and follow up window from 30 days to 90 days 
throughout the document. During the safety follow up period, safety evaluations, 


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pregnancy test need to be performed on 30, 60 and 90 days after the last dose of the study 
drug.
9. To align this protocol with the latest Novartis guidelines for the prevention of pregnancies 
in participants in clinical trials and their partners, the exclusion criteria were updated to 
exclude sexually active male subjects who are not willing to use a condom during the 
study.
Additional Changes to the protocol
Section 2.2.2 Phase II:

Updated patient populations to include those treated with prior PD-1 or PD-L1 inhibitors.
Section 2.3 Rationale for dose and regimen selection

Introduced alternative dosing (flat dose [mg]) which may be implemented during the study
Section 4.1: Description of study design:

Modified figure 4-1 study design

Modified Arm A to include group 4 and 5 for the single dose expansion part

Modified Arm B to include NSCLC and Melanoma patients who have received prior PD-1 
or PD-L1. Removed patients with gastric, CRC, NPC and renal cell carcinoma with 
previous treatment of PD-1 / PD-L1.
Section 4.1.3 Study period

Clarified biopsy requirements, i.e. in dose escalation part, it mandatory, in dose expansion 
part, it is optional.
Section 5.1 Patient population

Updated patient populations in the expansion phase.
Section 5.2: Inclusion criteria

Added detailed patient population criteria for the patients to be enrolled in the Phase II 
part of the study.

 
Section 5.3: Exclusion criteria

Added language about certain diseases /conditions that require steroid treatment are 
permitted to be enrolled

RCC patients who have received prior PD-1/PD-L1 are now excluded from the Phase II 
expansion. Clarified that the topical use of steroids are not prohibited.

Addition of exclusion criterion 24, which excludes sexually active male subjects who do 
not use a condom during intercourse
Section 6.1.1 Dosing regimen

Clarified how to handle a dosing delay for PDR001 within the combination arm if 
clinically indicated (e.g. if an infusion reaction occurs after LAG525 administration). 


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Emphasized that the break between LAG525 and PDR001 infusions can be up to 4 hours 
if clinically indicated. If PDR001 cannot be administered safely within 4 hours after 
LAG525 administration, the dose must be omitted.

Clarified there is a 7-day window for a dose delay of either single agent or combination 
treatment.

Alternate dosing (i.e. a flat dose) may be implemented after at least one cohort has been 
tested using a weight-based dosing paradigm

Introduced an option in the Phase II expansion to test 2 dose levels
Section 6.2.2 Provisional dose levels

Modified Table 6-2 and Table 6-3 to add flat doses
Section 6.2.3

Added flat dose in “mg” may be explored for single agent by opening new cohorts in the 
escalation part
Section 6.2.4

Added DLT window for Q3W dosing schedule. It will 21 days for patients in Q3W dosing 
schedule.

Clarified the duration of rash and/or photosensitivity should be 7 days instead of 14 days.
Section 6.3.1

Removed the statement about maximum number of dose reductions allowed from Table 6-
5 and placed the modified statement in the text, which allows more than 2 dose reductions 
of either drug if a patient is experiencing clinical benefit.
Section 6.3.2 Follow-up for toxicities

Changed the follow-up window from 30 days up to 90 days. Safety evaluations will be 
conducted on 30, 60, and 90 days after the last doses of LAG525 and/or PDR001
Section 7.1 Study flow and visit schedule

Added assessments for the cytokines IL-6 
 at baseline

Modified fresh tumor biopsy sample collection time, and changed the collection time point 
from cycle 2 to cycle 3.
Section 7.2.2.5.6 Cytokines

Added baseline cytokines

Added cytokine sample storage condition
Section 7.2.3 Pharmacokinetics and immunogenicity assessments
 

Deleted the columns with dose reference ID

Provided a footnote to analytes in Table 7-6.


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Section 9.3 data collection

Clarified PK and biomarker samples will be analyzed in central labs only, not in local 
labs.
Section 10: Statistical methods and data analysis

Study groups were updated to reflect the new study design.

Added alternative dose (flat dose in mg) and dosing schedule (Q4W) may be implemented 
during the study
Section 10.4.2 Statistical hypothesis, model, and method of analysis

Clarified that DLT data from single agent LAG525 cohorts will be used in the BLRM for 
combo of LAG525 and PDR001

Added BLRM for flat dosing

Updated Phase II analysis
Section 10.8 sample size calculation

Updated sample size justification for the phase II part
Section 14 Appendices

Updated Appendix 14.3.2 for phase II statistical analysis


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Amendment 01 (27-Apr-2015)
Amendment rationale
The purpose of this amendment is to incorporate the following revision requested by a 
regulatory authority:

Revise the DLT criterion for thrombocytopenia to include CTCAE grade 3 
thrombocytopenia with clinically significant bleeding as a DLT
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Section 6.2.4 Definitions of dose limiting toxicities (DLTs):

Added grade 3 thrombocytopenia with clinically significant bleeding to hematology 
section of Table 6-4.
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Immunotherapies that target immune checkpoints have recently shown strong efficacy and are 
emerging as key agents in cancer therapy. Antibodies targeting CTLA-4 (ipilimumab [BMS]) 
and PD-1 (e.g. nivolumab [BMS] and pembrolizumab [Merck]) demonstrate durable anti-tumor 
effects and an acceptable safety profile. While single agent treatments demonstrate promising 
efficacy, combinations of immunotherapy approaches suggest that synergistic blockade of co-
inhibitory proteins demonstrates greater antitumor activity than the single agent (Wolchok 
2013). Preclinical studies of the combination of PD-1 and LAG-3 demonstrate that 
simultaneous inhibition of both inhibitory receptors may have synergistic antitumor activity 
(Drake 2014; Woo 2012).
PD-1 (Programmed Death-1, CD-279) is a critical co-inhibitory receptor that is upregulated on 
T cells upon activation (Freeman 2008). It is also expressed by B cells, NK cells, dendritic cells, 
and activated monocytes. The ligands for PD-1, Programmed Death-Ligand 1 (PD-L1) and 
Programmed Death-Ligand 2 (PD-L2), are expressed by macrophages and monocytes, and can 
be induced on numerous cell types (T cells, endothelial cells, and tumor cells) during 
inflammation (Keir 2008). Engagement of PD-1 by its ligands transduces a signal that inhibits 
T-cell proliferation, cytokine production, and cytolytic function (Riley 2009). During 
tumorigenesis, cancer cells from a wide range of tumor types exploit immune checkpoint 
pathways, such as PD-1, to avoid detection by the adaptive immune system (Murphy 2011). 
Blockade of the PD-1 pathway has been shown to lead to both accumulation and increased 
activity of antitumor effector T cells and a reduced numbers of regulatory T cells (Tregs) at the 
tumor site (Wang 2009, Mangsbo 2010, Mkrtichyan 2011, Rosenblatt 2011).
LAG-3 (Lymphocyte Activation Gene-3, CD223) is a cell surface molecule expressed on 
activated CD4+ and CD8+ T effector cells, multiple populations of regulatory T cells, NK cells, 
B cells and plasmacytoid dendritic cells (Huard 1994, Triebel 1990, Kisielow 2005). LAG-3 
binds its ligand MHC Class II, and this interaction negatively regulates T cell signaling 
(Workman 2011). Blockade of LAG-3 has been shown to increase T cell proliferation and 
cytokine secretion, most notably IFN-γ (Huard 1997, Workman 2003). LAG-3 expression is 
also correlated with increased suppressive function in both FoxP3-positive natural regulatory T 
cells and induced FoxP3-negative regulatory cells (Huang 2004, Camisaschi 2010, Scurr 2014).
Preclinical studies in the Sa1N fibrosarcoma and MC38 colon carcinoma models demonstrated 
tumor growth inhibition with anti-LAG-3 as a monotherapy with enhanced tumor growth 
inhibition observed with the combination of anti-LAG-3 and anti-PD-1 immunotherapy (Woo 
2012). Expression analysis in human tumor infiltrating lymphocytes (TILs) from cancer 
patients supports this conclusion, with LAG-3 and PD-1 co-expression identified on tolerized 
TILs in patients with ovarian cancer and microsatellite high colorectal carcinoma (MSI-H CRC) 
(Chen 2014).


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1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of LAG525
LAG525 is a high-affinity, ligand-blocking, humanized anti-LAG-3 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of the known LAG-3 ligand MHC class II to LAG-3. 
LAG525 is cynomolgus cross-reactive and shows functional activity.
1.2.1.1
Non-clinical experience with LAG525
LAG525 binds specifically and with high affinity to human LAG-3. In Biacore assays, the KD
of LAG525 on human LAG-3 is 0.109 nM and in cell binding assays, LAG525 binds CHO-
hLAG-3 expressing cells with an affinity of 1.9 nM. LAG525 does not cross-react with rat or 
mouse LAG-3, and therefore cannot be evaluated in murine tumor models. It does cross-react 
with cynomolgus monkey LAG-3 (affinity of 2.3 nM on cynomolgus LAG-3-expressing cells), 
making cynomolgus monkey a relevant species and the only species for toxicology studies. A 
GLP tissue cross reactivity study was conducted with both human and cynomolgus monkey 
tissue specifically to assess the potential for off target binding. There was no binding observed 
even for tissues known to express LAG-3. This was likely due to reagent sensitivity issues and 
possibly the lower expression of the target.
Safety was evaluated in a five week repeat dose GLP toxicology study as well as in a limited 
panel in a single dose PK study, both in cynomolgus monkeys. In the single dose study, clinical 
observations, clinical chemistry, and hematology endpoints were evaluated as part of an in-life 
assessment of safety. There were no findings related to LAG525 administration in this single 
dose study.
In the five week GLP toxicology study, repeat administration of LAG525 to monkeys 
(3/sex/main and 2/sex/recovery groups) at doses of 6, 25, and 100 mg/kg was well tolerated at 
all doses tested. After the fifth dose, the eight week recovery period began for control and high 
dose animals assigned to recovery. Animals assigned to the main phase were sacrificed seven 
days after the last dose was administered. Minimal increases in fibrinogen at 100 mg/kg and 
globulin (relative change from pretest only) in males at 25 and 100 mg/kg were noted. 
Association with LAG525 administration is unclear but cannot be excluded. A female animal 
in the 6 mg/kg group displayed a hypersensitivity reaction soon after the third dose, consisting 
of vomiting and clinical signs of a swollen muzzle and flushed face. The animal was 
subsequently treated with diphenhydramine and the symptoms resolved shortly after treatment. 
This animal was then pre-treated with diphenhydramine prior to the last two doses and no 
further intervention was required. It was confirmed that this animal was positive for the 
presence of anti-drug antibodies. A statistically significant increase in proliferating CD4+ T 
cells was observed in animals given 100 mg/kg/week compared to control animals, a 
pharmacodynamic effect observed in vitro with LAG-3 blockade (Huard 1997; Workman 2003). 
There were no other test article related effects. The highest non-severely toxic dose (HNSTD) 
and the ‘no observed adverse effect level’ (NOAEL) was 100 mg/kg. LAG525 has a favorable 
safety profile in monkeys that supports the proposed human starting dose of 1 mg/kg.


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1.2.1.2
Clinical experience with LAG525
This is the first in human (FIH) study for LAG525. Please refer to the [LAG525 Investigator’s 
Brochure] for more details.
1.2.2
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 is cynomolgus 
cross-reactive and shows functional activity in vitro and ex vivo. For further details, please 
consult the most recent edition of the [PDR001 Investigator’s Brochure].
1.2.2.1
Non-clinical experience PDR001
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the KD of 
PDR001 on human PD-1 is 0.083 nM. In ex vivo lymphocyte stimulation assays using human 
blood, PDR001 enhances IL-2 production by approximately 2-fold in response to super antigen 
stimulation with Staphylococcal enterotoxin B (SEB). PDR001 does not cross-react with rodent 
PD-1, and cannot be evaluated in murine tumor models. It does cross-react with cynomolgus 
monkey PD-1, and is functionally active, making cynomolgus monkey a relevant species for 
toxicology studies. A GLP tissue cross reactivity study using frozen human and cynomolgus 
monkey tissues was also done in support of the safety of PDR001. There was no unexpected 
binding observed.
The non-clinical toxicology of PDR001 was evaluated in a five week GLP toxicology study in 
cynomolgus monkeys with safety pharmacology endpoints and an eight week recovery. Repeat 
administration of PDR001 to monkeys was well tolerated at all doses tested in the GLP 
toxicology study. No test article-related in-life, mortality, organ weight changes, or 
macroscopic findings were noted. There were no PDR001-related effects seen in any of the 
safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 100 
mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the
injection site blood vessel (saphenous vein) in a few animals given 25 mg/kg/week. These 
PDR001-related microscopic changes were fully reversible after an eight week recovery.
The following changes were noted in main phase and recovery treated animals as well as control 
recovery animals. Mostly low grade changes were noted in several tissues in the form of 
mononuclear infiltrates in the vascular and perivascular space. In general, in most organs, 
vascular/perivascular changes were limited to one or a few blood vessels in each organ and 
sometimes involved a segment of a blood vessel with occasional vessel wall degeneration. No 
evidence of parenchymal damage was associated with the vascular/perivascular changes in any 
of the organs examined and the changes were not associated with any frank tissue injury. While 
these effects were not exclusive to treated animals, because of their nature and close association 
with the expected pharmacology of PD1 blockade, a potential PDR001 related effect cannot be 
excluded and possibly explained by mild enhanced pharmacology of PDR001. There were no 
test article related effects seen in the cardiovascular (CV) assessments. All other microscopic 
findings were considered spontaneous or otherwise unrelated to PDR001 administration.


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Dose-dependent exposure to PDR001 in each dose group was confirmed. A pharmacodynamic 
ex vivo superantigen stimulated whole blood assay measuring IL-2 release was performed. 
Blood from untreated control animals showed augmentation of IL-2 release when PDR001 was 
added ex vivo, whereas blood from treated animals at all doses did not show augmented IL-2 
release, indicating target engagement and inability to further dis-inhibit the SEB induced 
response with the further addition of PDR001. The HNSTD dose in this study was 100 mg/kg.
1.2.2.2
Clinical experience
The CPDR001X2101 study started enrollment on 27 April 2015 and is ongoing. As of 17 
December 2015, a total of 58 patients had been treated in the study at the dose levels of 1, 3 and 
10 mg/kg Q2W and 3 and 5 mg/kg Q4W. No patients have experienced a DLT. The PK analysis 
of the dose escalation data using a population approach and the expected wide therapeutic index 
of PD-1 inhibitors support the use of flat dosing for PDR001 of 400 mg Q4W or 300 mg Q3W. 
The expected PDR001 Ctrough concentrations using either dosing regimen exceed the EC50 
for PD-1 blockade by approximately 75-fold in an ex vivo assay in PBMCs. Based on the 
available PK and safety data, the RP2D of PDR001 has been declared as 400 mg i.v. Q4W or 
300 mg i.v. Q3W for combination treatment regimens for which this may be more convenient. 
For further details, please consult the most recent edition of the [PDR001 Investigator’s 
Brochure].
PDR001 is currently being studied alone or in combination with other agents in ongoing phase 
I/Ib/II clinical trials. The preliminary toxicity profile appears to be similar to that of marketed 
inhibitors of PD-1 including the type, severity and frequency of occurrence of immune-
mediated adverse events. As observed with other PD-1 inhibitors, immune-mediated toxicities 
observed with PDR001 are reversible in many cases. In some cases, they may require treatment 
with corticosteroids. Certain toxicities are expected to be lifelong and may require replacement 
therapy with hormones, for example in the case of hypothyroidism. Based on the preliminary 
data, PDR001 is well tolerated with a safety profile similar to those of other marketed anti-PD-
1 antibodies. . For further details, please consult the most recent edition of the [PDR001 
Investigator’s Brochure].
1.2.3
Overview of the combination of LAG525 and PDR001
1.2.3.1
Nonclinical experience with the combination of LAG525 and PDR001
Woo (Woo 2012) described a series of experiments with dual LAG-3/PD-1 knockout (KO) 
mice evaluating both tumor efficacy and the KO phenotype in these animals. Compared to wild-
type (WT), the dual KO mice developed an early onset (4 weeks of age) of a lethal autoimmune 
condition that resulted in approximately 80% of the mice moribund by approximately 10 weeks. 
The major histopathologic manifestations included diffuse fibrosing lymphohistiocytic 
endocarditis, myocarditis, and pancreatitis. In contrast, LAG-3 and PD-1 single KO mice lacked 
any disease manifestations or histopathology over this period of observation. These results show 
that the PD-1 and LAG-3 pathways synergistically regulate immune self-reactivity. These 
results demonstrate a theoretical risk of the simultaneous disinhibition of both the LAG-3 and 
PD-1 receptor pathways. However, intermittent blocking of both receptors in patients where the 
pathways have been biologically and physiologically intact since birth seems unlikely to 
produce such a severe clinical picture. In addition, in the setting of a clinical trial with intense 


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safety monitoring and clear guidance on drug interruption and withdrawal, the management of 
immune adverse events should be possible. Any theoretical risk is also balanced by the well-
documented efficacy of these agents, both alone and in combination, in a host of tumor models 
and for PD-1 inhibition in the clinical setting.
1.2.3.2
Clinical experience with the combination of LAG525 and PDR001
As of a data cut-off date of 15-Nov-2016, a total of 198 patients were treated on the first-in-
human clinical study of LAG525 as a single agent and in combination with PDR001. The Phase 
I part of the study is ongoing for both single agent and combination. In the single-agent part of 
the study 106 patients were treated with LAG525 at doses ranging from 1 to 15 mg/kg on Q2W 
and Q4W schedules. Preliminary PK parameters demonstrated approximately dose-
proportional increases in exposure observed from 1 to 15 mg/kg with low to moderate 
interpatient variability. The observed median half-life for LAG525 ranged from 7.4 to 15.4 days.  
In the combination part of the study, 92 patients were treated with LAG525 in combination with 
PDR001.  PDR001 or LAG525 in combination with showed comparable PK to the single-agent 
data at the same dose levels from the ongoing PDR001 studies. The observed median half-life 
for PDR001 ranged from 7.2 to 23.8 days, which was similar to the results from the ongoing 
CPDR001X2101 study.
2
Rationale
2.1
Study rationale and purpose
This is a FIH, phase I/II clinical study of single agent LAG525 and in combination with PDR001.
The goal of immunotherapy in cancer is to sustain or rescue an existing tumor antigen-specific 
immune response capable of eradicating the disease. Recent advances in cancer immunology 
revealed extensive interaction between the host immune system and the tumor suggesting that 
clinically evident tumors have evaded potentially effective antitumor responses. Tumor antigen-
specific CD8+ and CD4+ T cells isolated from human tumors often display impaired effector 
function manifested by ineffective cytotoxicity and impaired cytokine secretion. The 
dysfunction of these tumor specific T cells is thought to result from the immunosuppressive 
tumor microenvironment and comprises T cell intrinsic and extrinsic mechanisms. T cell 
extrinsic mechanisms include suppressor cells (e.g. regulatory T cells (Treg), myeloid derived 
suppressor cells, MDSC) and soluble cytokines (e.g. IL-10). T cell intrinsic suppression is 
coordinated via a series of membrane receptors on T cells which can be categorized into (1) 
those transducing negative activation signals (co-inhibitory receptors or “checkpoints” e.g. 
CTLA-4 or PD-1) and (2) those transducing positive signals for cell activation (co-stimulatory 
receptors, e.g. GITR, 41BB) (Leen 2007). The balance between the signals from co-stimulatory 
and co-inhibitory receptors controls T cell activation.
Expression patterns of co-inhibitory and co-stimulatory receptors on tumor-specific T cells vary 
by both the maturation stage of the T cell as well as the location of the T cell (peripheral 
circulation v. intra-tumoral) (Baitsch 2012, Woo 2012). These patterns of expression together 
with early studies of the effects of signaling suggest that the network of co-receptors may 
deliver differential signals (Baitsch 2012). Tumor antigen-specific T cells isolated from the 


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tumor-draining lymph nodes of melanoma patients have an activation profile, whereas T cells 
derived from the tumor bed display an exhausted phenotype with strong expression of multiple 
checkpoints, impaired cytokine secretion and activity (Matsuzaki 2010).
Checkpoint inhibitors have been successfully introduced to clinical practice with the recent 
approval of the antagonists to the CTLA-4 checkpoint (ipilimumab, BMS) and PD-1 (e.g 
nivolumab [BMS] and pembrolizumab [Merck]). Although the checkpoint inhibitors generally 
result in similar enhanced anti-tumor T cell activation, their effects are mediated by distinct 
pathways and they demonstrate enhanced activity in combination. The combination of 
ipilimumab and nivolumab is more active than either single agent in advanced melanoma 
(Wolchok 2013). LAG-3 is a distinct co-inhibitory receptor which may cooperate with PD-1 to 
dampen immune responses. In preclinical studies, the combined inhibition of PD-1 and LAG-3 
checkpoints synergistically enhances antitumor responses over inhibition of either checkpoint 
alone (Drake 2014, Woo 2012). Taken together, these data suggest that combined inhibition of 
LAG-3 and PD-1 in the clinic may have significant anti-tumor activity.
The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and anti-tumor activity of LAG525 as a single agent and in 
combination with PDR001, an antibody directed against PD-1 under investigation in a separate 
study [PDR001X2101]. PD-1 blockade has proven clinical efficacy in various disease settings, 
such as melanoma, non-small cell lung cancer (NSCLC), mesothelioma (Alley 2017), TNBC
(Nanda 2016) and renal cell carcinoma.
Following determination of the maximum tolerated dose (MTD) or recommended Phase 2 dose 
(RP2D) of LAG525 as a single agent, and of LAG525 in combination with PDR001, 
preliminary anti-tumor activity of single agent LAG525 and the combination of LAG525 and 
PDR001 will be assessed in melanoma, NSCLC, mesothelioma, TNBC and renal cancer in the 
expansion part. The RP2D will be determined from the collective experience in the clinic 
considering the safety data, pharmacokinetic data, pharmacodynamic data and any early 
antitumor activity observed along with the statistical inference from the Bayesian Logistic 
Regression Model (BLRM).
Expansion cohorts testing single agent LAG525 will open once the RP2D or MTD of single 
agent LAG525 is identified. Expansion cohorts testing the combination of LAG525 and 
PDR001 will open for enrollment once the RP2D or MTD of the combination is determined.


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Figure 2-1
Blockade of PD-1/PD-L1 and LAG-3 by PDR001 and LAG525
2.2
Rationale for the study design
This is an open-label, phase I/II study of parallel cohorts with single-agent LAG525 or the 
combination of LAG525 and PDR001. The study consists of two parts: two parallel dose 
escalations with staggered starts in the Phase I part and Phase II cohorts at the maximum 
tolerated dose (MTD), or the recommended phase 2 dose (RP2D), if that is lower than the MTD, 
for the single agent arm and the combination arm in the Phase II part.
This study includes a Japanese dose escalation for single-agent LAG525 with the goal of 
informing subsequent clinical development opportunities in Japan (see Section 2.2.3).
2.2.1
Phase I
In the Phase I part, three dose escalations will be explored in advanced solid tumors: a single-
agent dose escalation of LAG525 (Arm A), a separate single-agent dose escalation of LAG525 
in Japanese patients (Arm C), and combination dose escalation of LAG525 and PDR001 (Arm 
B).
Dose escalation with combination of LAG525 and PDR001 will begin after the completion of 
at least the first two dose level cohorts of single agent LAG525. Then, the dose escalation arms 
(single agents and combination) may proceed in parallel. The design of the phase I part was 
chosen in order to establish the MTD/RP2D of LAG525 as a single agent and LAG525 in 
combination with PDR001 in patients with solid tumors amenable to immunotherapy. The dose 
escalation decision making will be guided by a Bayesian logistic regression model (BLRM) 
with overdose control (EWOC) principle based on DLT data in the context of available safety, 
PK and PD information. For details of the dose escalation, please refer to Section 6.2.


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This open-label dose escalation study design using a BLRM is a well-established method to 
estimate the MTD, or identify a lower RP2D in cancer patients. The adaptive BLRM with 
EWOC principle controls the risk of DLT in future patients on study. The decisions on the 
single dose of LAG525 (during the single agent escalation) or in combination with PDR001 
(during the combination escalation) are made by the Investigators and Novartis study personnel 
and will be based upon the dose identified to satisfy the EWOC criterion under the appropriate 
BLRM, patient tolerability and safety, PK and PD data available at the time of the decision 
Section 6.2.3.
2.2.2
Japanese single-agent dose escalation (Arm C)
The purpose of the Japanese dose escalation is to ensure that the safety and pharmacokinetic 
profiles of single-agent LAG525 are adequately characterized in Japanese patients at more than 
one LAG525 dose. The Japanese dose escalation for single-agent LAG525 will run separately 
from the ongoing dose escalation with a starting dose for single-agent LAG525 in Japanese 
patients of 1 mg/kg Q2W. Dose escalation decisions will be guided by a BLRM.
2.2.3
Phase II
Once the RP2D or MTD is determined for either single-agent LAG525 (Arm A) or the 
combination of LAG525 with PDR001 (Arm B), the respective phase II part of the study will 
begin. The primary objective of the phase II part is to estimate the preliminary anti-tumor 
activity of single agent LAG525 and in combination with PDR001.
The Phase II part of the study will be conducted in five diseases that are known to be potentially 
responsive to single-agent PD-1 inhibition: NSCLC, melanoma, mesothelioma, TNBC and 
renal cancer. The efficacy of single-agent LAG525 and the combination of LAG525 with 
PDR001 in these diseases will be assessed in both the PD-1/PD-L1 pre-treated and naive 
settings.
A Bayesian design will be used in order to estimate the overall response rate (ORR) in each 
disease area with single agent LAG525 or in combination with PDR001, evaluated at the RP2D 
of both single-agent LAG525 and the combination of LAG525 with PDR001 identified during 
phase I. The Phase II arms are designed to detect efficacy signals indicating a population where 
further study of either single-agent LAG525 or the combination of LAG525 with PDR001 is 
warranted. If the recommended dose of single-agent LAG525 is the same in Arms A and C, 
patients enrolled in Japan may be recruited to the Phase II single-agent part of the study. In 
addition if the recommended dose of PDR001 for Japanese patients in the PDR001X1101 study 
is the same as that determined in study PDR001X2101, Japanese patients may also enter the 
combination parts of study LAG525X2101 at which ever dose is being tested at that time.
2.3
Rationale for dose and regimen selection
The starting dose of LAG525 in the clinical setting was determined from toxicology studies as 
well as observed toxicity and efficacy from agents in the clinic with the similar mechanism of 
action of checkpoint inhibition (e.g. CTLA-4 and PD-1 inhibitors). The HNSTD dose from the 
cynomolgus monkey for LAG525 was 100 mg/kg. As LAG525 will be administered i.v., and it 
is generally accepted that antibody therapeutics allometrically scale according to body weight, 
the human equivalent dose (HED) of the HNSTD is 100 mg/kg. Based on the ICH S9 guidance, 


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a factor of six can be used to determine the maximum allowable starting dose, with an estimated 
maximum starting dose of 17 mg/kg administered weekly. LAG525 will be administered via 
i.v. infusion every 2 weeks, consistent with a schedule commonly used for humanized 
monoclonal antibodies with an expected half-life of approximately 10-20 days. Based on the 
pharmacologically active doses of 2-10 mg/kg in the clinic with agents having a similar 
mechanism of action (checkpoint inhibitors, CTLA-4 and PD-1 inhibitors, Topalian 2014, 
Wolchok 2013, Robert 2014) and with the intent to fully characterize the safety, 
pharmacokinetics, pharmacodynamics and preliminary efficacy at multiple dose levels, the 
starting dose of LAG525 is 1 mg/kg every 2 weeks. For the combination of LAG525 with 
PDR001 in dose escalation, the starting dose of PDR001 is 1 mg/kg and of LAG525 is 1 mg/kg 
administered intravenously once every 2 weeks and is based on the preclinical safety, 
tolerability, and PK data observed in the cynomolgus monkey with both PDR001 and LAG525 
as described in Section 6.2.1. If required by a Regulatory Authority, recruitment to combination 
dose levels will begin at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001) for patients 
from those countries
For both LAG525 single agent and the combination of LAG525 with PDR001, alternative 
dosing (e.g. flat dose [mg]) and dosing schedules (e.g. less frequent dosing) may be 
implemented during the study based on emerging clinical toxicity and preliminary PK, PD and 
efficacy data.
2.4
Rationale for choice of combination drugs
In vivo studies have demonstrated a synergistic effect in antitumor activity of the dual blockade 
of the LAG-3 and PD-1 co-inhibitory receptors when compared to the inhibition of either 
checkpoint alone. CD4+ and CD8+ TIL from Sa1N fibrosarcoma, MC38 colon carcinoma and 
B16 melanoma have previously been shown to co-express PD-1 and LAG-3; Woo and 
colleagues demonstrated some single agent activity of anti-LAG-3 treatment in both Sa1N 
fibrosarcoma and MC38 colon carcinoma. Importantly, combined LAG-3 and PD-1 blockade 
led to rapid and complete regression of established tumors in 70% of Sa1N fibrosarcoma and 
80% of MC38 colon carcinoma within 50 days of the initiation of therapy. Using the maximum 
likelihood model, this demonstrated synergy of co-blockade over single agent activity. Both 
TIL and lymphocytes from draining lymph nodes harvested from treated mice had increased 
numbers of CD8+IFN-gamma+ TIL, further supporting the anti-tumor role of co-blockade 
(Woo 2012).
The growth of syngeneic tumors was also studied in LAG-3 and PD-1 double deficient mice 
(Lag3-/-Pdcd1-/-). While combination blockade (using murine antibody reagents) did not show 
efficacy in B16 melanoma, both Pdcd1-/- and doubly deficient mice showed inhibited tumor 
growth. Depletion of CD4+ and CD8+ T cells led to restoration of normal tumor growth, 
demonstrating the dependency of the phenotype on T cell alteration. MC38 colon carcinoma 
implanted in doubly deficient mice showed 80% reduction (compared to 40% in Pdcd1-/- mice), 
confirming the synergistic action of PD-1 and LAG-3 seen in the co-blockade experiments 
(Woo 2012).
Taken together, these preclinical data demonstrate that co-blockade of the PD-1 and LAG-3 
pathways leads to anti-tumor activity superior to blockade of either inhibitory protein alone. 
(Woo 2012).


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3
Objectives and end points
Objectives and related endpoints are described in Table 3-1 below and apply to all patients 
enrolled and treated unless otherwise stated.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Section 10.4.1
Phase I part:
To estimate the RP2D or MTD for:
●
Single-agent LAG525 (including Japanese patients)
●
Combination of LAG525 and PDR001.

The incidence of dose limiting toxicities (DLTs) during the first 
cycle of treatment with single agent LAG525. For the 
combination treatment of LAG525 and PDR001, the DLT 
window will be 2 cycles of the treatment.
Phase II part:
To estimate the overall response rate per RECIST V1.1
●
Single-agent LAG525
●
Combination of LAG525 and PDR001

Overall response rate per “Response Evaluation Criteria in 
Solid Tumors (RECIST) V 1.1”
Secondary
Section 10.5
Phase I and Phase II parts:

To characterize the safety and tolerability of single-agent 
LAG525 given alone and in combination with PDR001
●
Safety incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs) including changes in laboratory 
parameters, vital signs and ECGs
●
Tolerability: Dose interruptions, reductions and dose intensity.

To characterize the pharmacokinetic profile of single-agent 
LAG525 given alone and in combination with PDR001
●
Serum PK parameters (e.g. AUC, Cmax, Tmax, t1/2 half-life)

To assess emergence of anti-LAG525, and anti-PDR001 
antibodies following one or more intravenous (i.v.) infusions of 
single-agent LAG525 given alone or in combination with 
PDR001
●
Presence and/ or concentration of anti-LAG525 and anti-
PDR001 antibodies


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Objective
Endpoint
Analysis
Phase I part:
●
To evaluate the preliminary antitumor activity of single-agent 
LAG525 given alone or in combination with PDR001
●
ORR, progression free survival (PFS), duration of response 
(DOR) and disease control rate (DCR)
Section 10.5
Phase II part:
●
To evaluate the preliminary antitumor activity of single-agent 
LAG525 given alone or in combination with PDR001
●
ORR per immune related Response Criteria (irRC), PFS, 
DOR, DCR per RECIST V1.1 and per irRC


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4
Study design
4.1
Description of study design
This study is a phase I/II, multi-center, open-label study which consists of 2 dose escalation 
parts (Arms A and B) with a staggered start, each followed by an expansion part. The first 
escalation will be conducted with single-agent LAG525 in advanced solid tumors. Once the 
MTD/RP2D of single-agent LAG525 is determined, the study will continue with a Phase II 
expansion part with single-agent LAG525 in defined patient populations. The second dose 
escalation part will be performed with the combination of LAG525 and PDR001 in advanced 
solid tumors followed by a Phase II expansion part with the combination in defined patient 
populations. The dose escalation of the combination of LAG525 and PDR001 will not begin 
until a cohort of 3 mg/kg single-agent LAG525 has been completed. If the single-agent LAG525 
dose of 3 mg/kg satisfies the EWOC criterion, the combination dose will begin with the planned 
starting dose as specified in Section 6.2.2. For the combination treatment arm, the first dose for 
the first two patients treated at each untested dose level will be staggered by 24 hours. If 3 
mg/kg with single agent does not satisfy the EWOC criterion, or if required by a Regulatory 
authority, then the combination dose will begin with a lower dose level (please refer to Section 
6.2.3 for details of the dose escalation process).
A separate Japanese dose escalation (Arm C) will be performed in order to ensure that the safety 
and pharmacokinetic profiles of single-agent LAG525 are adequately characterized in Japanese 
patients at more than one LAG525 dose. The Japanese dose escalation will run separately from 
the ongoing dose escalation with a starting dose for single-agent LAG525 in Japanese patients 
of 1 mg/kg Q2W. Dose escalation decisions will be guided by a BLRM. If the recommended 
dose of single agent LAG525 is the same in Arms A and C, patients enrolled in Japan may be 
recruited into the Phase II single-agent part of the study. In addition, if the recommended dose 
of PDR001 for Japanese patients on the PDR001X1101 study is the same as that determined in 
study PDR001X2101, patients in Japan may also enter the combination parts of the study at 
whichever dose is being tested at that time. After Japanese patients have enrolled in the 
combination dose escalation arm, and if during review of safety data (either in a Dose Escalation 
Meeting or during a regular safety review) Novartis and the enrolling Investigators consider the 
safety profile of Japanese patients treated in the combination arm to be potentially worse than 
that of patients treated in the rest of the world, an additional 3 to 6 Japanese patients may be 
recruited to a lower dose combination (previously studied in dose escalation) to further 
characterize the safety and tolerability of the combination in patients enrolled in Japan. If after 
review of safety data at the lower dose level, Novartis and the enrolling Investigators feel that
re-escalation to a higher combination dose level is acceptable, Japanese patients may be treated 
at the same dose as patients in the rest of the world. If re-escalation is not acceptable, any 
additional Japanese patients recruited to the combination dose escalation will be treated at the 
lower dose. The combination dose escalation in the rest of the world may continue as planned.
Both PDR001 and LAG525 will be administered i.v. once every two weeks until a patient 
experiences unacceptable toxicity, progressive disease as per immune related Response Criteria 
(irRC) or treatment is discontinued at the discretion of the investigator or the patient. In the 
combination cohorts, the two antibodies will be administered separately with a break of 30 


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minutes between administrations. The study design is summarized in Figure 4-1. Alternative 
dosing schedules (e.g. less frequent dosing) may be implemented during the study based on 
clinical toxicity and preliminary PK,
 and efficacy findings, including data from study 
PDR001X2101.
Figure 4-1
Study design
Note: In the single-agent LAG525 dose escalation (Arm A) at least 21 patients are required to define the 
RP2D; in the combination dose escalation (Arm B) at least 15 patients are required to define the RP2D 
and in the Japanese single-agent LAG525 dose escalation (Arm C) at least 12 patients are required to 
define the RP2D.
The primary clinical study report (CSR) will be based on all patients’ data from both phase I 
and phase II parts, up to the time when all patients have completed at least six cycles of 
treatment or discontinued the treatment. Patients who are on study beyond cycle 6 may remain 
on treatment as per the protocol. Any additional data (after the data cut-off date for the primary 
CSR) will be further summarized at completion of the study, as defined in Section 4.3.


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Study treatment group to be analyzed in Phase II expansion cohorts
Arm A: Single-agent LAG525 cohorts

Group 1: single-agent LAG525, NSCLC (naïve to PD-1/PD-L1 )

Group 2: single-agent LAG525, Melanoma (naïve to PD1/PD-L1)

Group 3: single-agent LAG525, Renal cancer (naïve to PD-1/PD-L1)

Group 4: single-agent LAG525, NSCLC (pre-treated with PD-1/PD-L1)

Group 5: single-agent LAG525, Melanoma (pre-treated with PD-1/PD-L1)

Group 11: single-agent LAG525, Renal cancer (pre-treated with PD-1/PD-L1)
Arm B: Combination LAG525 + PDR001 cohorts

Group 6: combination LAG525+PDR001, NSCLC (naïve to PD-1/PD-L1)

Group 7: combination LAG525+PDR001, Melanoma (naïve to PD-1/PD-L1)

Group 8: combination LAG525+PDR001, Renal cancer (naïve to PD-1/PD-L1)

Group 9: combination LAG525+PDR001, NSCLC (pre-treated with PD-1/PD-L1)

Group 10: combination LAG525+PDR001, Melanoma (pre-treated with PD-1/PD-L1)

Group 12: combination LAG525+PDR001, Renal cancer (pre-treated with PD-1/PD-L1)

Group 13:  combination LAG525+PDR001, Mesothelioma (naïve to PD-1/PD-L1)

Group 14:  combination LAG525+PDR001, TNBC (naïve to PD-1/PD-L1)

Group 15:  combination LAG525+PDR001, Mesothelioma (pre-treated with PD-1/PD-L1)

Group 16:  combination LAG525+PDR001, TNBC (pre-treated with PD-1/PD-L1)
4.1.1
Phase I dose escalation
Single-agent LAG525 (Arm A)
During the phase I single-agent dose escalation, patients with any advanced solid tumor will be 
treated with single-agent LAG525 until the MTD is reached or a lower RP2D is established. At 
least 21 patients are required during dose escalation to define the MTD/RP2D.
Combination of LAG525 with PDR001 (Arm B)
During the phase I combination dose escalation, patients with any advanced solid tumor will be 
treated with LAG525 in combination with PDR001 until the MTD is reached or a lower RP2D 
is established. It is expected that an RP2D will be established before the MTD is reached. At 
least 15 patients are required during dose escalation to define the MTD/RP2D.
For all dose escalation arms, to assure that the RP2D does not exceed the MTD, the dose 
escalation will be guided by an adaptive Bayesian logistic regression model (BLRM) following 
the EWOC principle. For further details, please refer to Section 6.2.3.


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Single-agent LAG525 in Japanese Patients (Arm C)
The Japanese dose escalation Arm C will be run separately from Arm A. At least 12 patients 
are required during dose escalation to define the MTD/RP2D. Dose escalation decisions will be 
guided by a separate BLRM to estimate the MTD /RP2D in Japanese patients (see Appendix 
14.4).
4.1.2
Phase II expansion
Once the MTD and/or RP2D have been determined in the escalation parts, additional patients 
will be enrolled in the respective phase II expansion parts in order to assess the preliminary 
anti-tumor activity of single-agent LAG525 and LAG525 in combination with PDR001. Phase 
II Expansion cohorts testing single-agent LAG525 will open once the RP2D or MTD of single-
agent LAG525 is identified. Phase II Expansion cohorts testing the combination of LAG525 
and PDR001 will open for enrollment once the RP2D or MTD of the combination is determined.
Novartis may elect not to initiate any given treatment arm based on emerging data (including 
but not limited to preliminary anti-tumor activity).
In the phase II part, patients will be assigned to different groups depending on the tumor type 
as shown in Figure 4-1. Please refer to Section 5.1 and Section 7.1.1 for further details. Each 
group will enroll approximately 20 patients, unless enrolling 20 patients to any of these groups 
is not logistically feasible, in which case enrollment may be stopped before 20 patients are 
treated in that group. Details of the sample size calculations leading to the patient numbers are 
provided in Section 10.8. The sample size in any group may be expanded to approximately 40 
patients, if at least 3 patients (or if at least 2 patients for TNBC) have an objective response (PR 
or CR) per RECIST 1.1 or irRC in that group. A Bayesian design will be used in order to 
estimate ORR within each disease group (see Section 10.8 for details of sample size).
4.1.3
Study Periods
Screening period
The screening period begins once the patient has signed the study informed consent. Patients 
will be evaluated against study inclusion and exclusion criteria Section 5.2 and Section 5.3.
Status of MSI (high or low) for patients with CRC will be collected during screening. In addition, 
EGFR, ALK or BRAF V600 status is to be collected at baseline as appropriate. If known, BRCA 
status will be collected at baseline
 
 
 
 
Treatment period
The treatment period will begin on Cycle 1 Day 1. For the purpose of scheduling and 
evaluations, a treatment cycle will consist of 28 days (21 days for patients on Q3W dosing 
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Further details are provided in Table 7-1 and Section 7.1.2.
150-day follow-up (FU) period
Patients will be followed up for safety evaluations on 30, 90, and 150 days after the last dose of 
study treatment. Please refer to Table 7-1 and Section 7.1.5 for further details.
Disease progression FU
Patients who discontinue the study for any reasons other than disease progression as per irRC 
will be followed for progression of disease. Please refer to Section 7.1.5 for further details.
 
4.2
Timing of interim analyses and design adaptations
No formal interim analyses are planned. However, in the phase I part, the dose-escalation design 
foresees that decisions based on the current data will be taken before the end of the study. In 
the phase II part, the number of tumor responses will be monitored to determine if the 
enrollment in any group should be expanded from 20 to approximately 40 patients. Please refer 
to Section 10.7 for further details.
4.3
Definition of end of the study
The end of study will be when:

80% of the patients per disease group in the phase II part have completed the follow-
up for disease progression or discontinued the study for any reason, and all patients 
have completed treatment and the 150 day safety follow-up period
or

If the study is terminated early
or

Another clinical study becomes available that can continue to provide study treatment 
in this patient population, and all patients ongoing are transferred to that clinical study.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative treatment option to patients who, in the opinion of the 
investigator, are still deriving clinical benefit.
See Section 10 Statistical Methods and Data Analysis for details of timing of the primary 
analysis and final reporting of data.
4.4
Early study termination
The study or any treatment group of the study can be terminated at any time for any reason by 
Novartis. Should this be necessary, the patient should be seen as soon as possible for End of 


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Treatment (EoT) visit and the assessments for EoT should be performed as described in 
Section 7.1.3 for a discontinued or withdrawn patient. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
In the phase I part of the study, both single and combination escalation will be conducted in all 
types of advanced solid tumors regardless of PD-1/PD-L1 treatment history.
In the phase II part of the study, both single agent and combination expansion arms will be 
conducted in patients with NSCLC, melanoma, and renal cancer as outlined in Figure 4-1.  The 
combination arm will also be conducted in patients with mesothelioma and TNBC as outlined 
in Figure 4-1, 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any procedures
For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.
2. Age ≥ 18 years
3. Phase I part: Patients with advanced/metastatic solid tumors, with measurable or non-
measurable disease as determined by RECIST version 1.1 (refer to Appendix 1), who have 
progressed despite standard therapy or are intolerant of standard therapy, or for whom no 
standard therapy exists.
4. Phase II part: Patients with advanced/metastatic solid tumors, with at least one measurable 
lesion as determined by RECIST version 1.1, who have had disease progression. 
Additionally, the following must apply:
a. NSCLC:
i.
Disease recurrence or progression during or after no more than one prior platinum 
doublet-based chemotherapy regimen for advanced or metastatic disease. Prior 
maintenance therapy is allowed (considered pemetrexed, erlotinib, bevacizumab).
ii. Patients must have been tested for mutations affecting EGFR and ALK. (Patients 
with a known mutation in one gene need not be tested for the other.) Patients with 
ALK or EGFR-positive NSCLC must have had recurrent or progressive disease 
after treatment with the corresponding inhibitor and no more than one platinum 
doublet-based chemotherapy, in any sequence.
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i.
Patients with BRAF V600 mutation-positive disease must have objective evidence 
of progression of disease after treatment with a BRAF inhibitor alone or in 
combination with other agents.
ii. Patients with BRAF wild-type disease must have objective evidence of progression 
of disease but are not required to have received prior therapy.
c.
Renal:
i.
Patients must have objective evidence of progression of disease during or 
following at least one regimen of treatment for advanced renal cancer.
d.
Mesothelioma
i.
Patients must have objective evidence of progression of disease during or 
following at least one prior line of systemic chemotherapy for advanced disease.
e.
TNBC
i.
Patients must have objective evidence of progression of disease during or
following no more than 2 prior lines of systemic chemotherapy for advanced
disease. Patients must have received a prior taxane-containing regimen.
5. ECOG Performance Status ≤ 1
6. Phase I Part: Patients enrolled in the Phase I part of the study must provide a new tumor 
biopsy at baseline and during treatment if medically feasible.
Phase II part: Patients enrolled in the phase II part of the study must provide a new tumor 
biopsy at baseline and during treatment, if medically feasible.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases 
that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing 
doses of corticosteroids within the prior 2 weeks. Patients with treated brain metastases 
should be neurologically stable for at least 4 weeks prior to study entry and off steroids for 
at least 2 weeks before administration of any study treatment.
2. History of severe hypersensitivity reactions to study treatment ingredients or other mAbs
3. Patient with out-of-range laboratory values defined as:

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40 
mL/min

Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are 
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN

Alanine aminotransferase (ALT) > 3 x ULN 

Aspartate aminotransferase (AST) > 3 x ULN

Absolute neutrophil count (ANC) < 1.0 x 109/L

Platelet count < 75 x 109/L

Hemoglobin (Hgb) < 9 g/dL

Potassium, magnesium, calcium or phosphate abnormality CTCAE > grade 2


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4. Clinically significant cardiac disease or impaired cardiac function, including any of the 
following:

Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension or clinically 
significant arrhythmia

QTcF >470 msec on screening ECG or congenital long QT syndrome

Acute myocardial infarction or unstable angina pectoris < 3 months prior to study 
entry
5. Active, known or suspected autoimmune disease.  Patients with vitiligo, type I diabetes 
mellitus, residual hypothyroidism due to an autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or other conditions not 
expected to recur, are permitted to enroll. Patients previously exposed to anti-PD-1 / PD-
L1 treatment who are adequately treated for skin rash or who are receiving replacement 
therapy for endocrinopathies should not be excluded. 
6. Patients who required discontinuation of treatment due to treatment-related toxicities with 
prior therapy directed against the same target as the drug(s) under study in this protocol.
7. History of drug-induced pneumonitis or current pneumonitis.
8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic 
antibiotics for infection must have completed therapy before screening is initiated.
9. HIV infection. Testing for HIV status is not necessary unless clinically indicated.
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for HBV or 
HCV status is not necessary unless clinically indicated or the patient has a history of HBV 
or HCV infection.
11. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers; any malignancy considered to be indolent and that has never required 
therapy; and completely resected carcinoma in situ of any type.
12. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results.
13. a. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment.
b. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C, nitrosoureas or 
more recent immunotherapies, 4 weeks is indicated as washout period.
c. For patients receiving a CTLA-4 antagonist or vaccine as anticancer therapy, 8 weeks is 
indicated as the washout period.
14. Patients receiving chronic treatment with systemic steroid therapy (> 10 mg/day 
prednisone or equivalent) within 7 days of the first dose of study treatment, other than 
replacement-dose steroids in the setting of adrenal insufficiency. Topical, inhaled, nasal
and ophthalmic steroids are not prohibited.
15. Patients receiving systemic treatment with any immunosuppressive medication that would 
interfere with the action of the study drugs, other than replacement-dose corticosteroids in 
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16. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment.
17. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery).
18. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass. To allow evaluation of response to treatment, patients enrolled in the Phase II 
part must have remaining measurable disease that has not been irradiated.
19. Participation in an interventional, investigational study within 2 weeks prior to the first 
dose of study treatment.
20. Presence of CTCAE ≥ grade 2 toxicity (except alopecia, peripheral neuropathy and 
ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy.
21. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M-CSF) ≤ 
2 weeks prior to the first dose of study treatment. Patients must have completed therapy at 
least 2 weeks prior to the first dose of study treatment with any hematopoietic colony-
stimulating growth factors. An erythroid stimulating agent is allowed as long as it was 
initiated at least 2 weeks prior to the first dose of study treatment.
22. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test.
23. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 150 days after the last dose of LAG525 and/or PDR001. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had over 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (age 
appropriate (e.g. generally 40-59 years), history of vasomotor symptoms (e.g. hot flushes) in 


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the absence of other medical justification or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential.
24. Sexually active males unless they use a condom during intercourse while taking the drug 
and for 150 days after stopping study treatment and should not father a child in this period. 
A condom is required to be used also by vasectomized men as well as during intercourse 
with a male partner in order to prevent delivery of the drug via seminal fluid
6
Treatment
6.1
Study treatment
For this study, the investigational drugs refer to LAG525 and PDR001. Both study drugs will 
be provided by Novartis. PDR001 will be supplied in lyophilized powder formulation. LAG525 
will be supplied as a liquid formulation.
All dosages prescribed and dispensed to patients and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study
treatments
Pharmaceutical form and route 
of administration
Dose*
Frequency and/or 
Regimen**
LAG525
Liquid in vial for i.v. infusion
1 mg/kg (starting dose)
Every 2 weeks
PDR001
Powder for solution for infusion
1 mg/kg (starting dose)
Every 2 weeks
*Flat dosing may be tested based on the review of emerging PK data generated during the study
**Alternate dosing regimens may be implemented to assess a less frequent dosing regimen
For the combination arm of the study, the first dose for the first two patients treated at each 
untested dose level will be staggered by 24 hours. LAG525 and PDR001 will be administered 
via i.v. infusion over 30 minutes once every 2 weeks. They will be administered separately in 
the same fashion with at least a 30-min break between the two antibody infusions. Infusions of 
each antibody can be extended to up to 2 hours if clinically indicated and the break between 
LAG525 and PDR001 antibody infusions can be up to 4 hours if clinically indicated.
Both study drugs may be infused using the same i.v. access site. LAG525 will be given first 
followed by PDR001. The same administration sequence must be followed for all participants, 
i.e. LAG525 is infused first. If an infusion reaction occurs after administration of LAG525, the 
subsequent PDR001 infusion must be delayed until it is safe for the patient to receive PDR001 
based on the clinical discretion of the investigator. The delay between LAG525 and PDR001 
infusions can be up to 4 hours if clinically indicated. If PDR001 cannot be administered safely 
within 4 hours after LAG525 administration, the dose must be omitted.
A scheduled dose (of either single-agent LAG525 or the combination of LAG525 and PDR001) 
may be delayed to recover from an unresolved AE. If a patient requires a dose interruption of > 
21 days from the intended day of the scheduled dose due to an unresolved AE related to study 


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drug(s), then the patient must be discontinued from the study, unless the patient is receiving 
clinical benefit and in the opinion of the investigator it is in the patient’s best interest to remain 
on study. The patient may restart treatment after discussion with Novartis. Dose modifications 
should be followed described in Section 6.3.1 and Section 6.3.2.
If a significant number of patients require dose delays due to drug-related toxicities, the dosing 
regimen for the study may be changed to once every 21 or 28 days. This will be discussed in a 
dose escalation teleconference at the time of the proposed change and documented in the 
minutes of this meeting accordingly Section 6.2.3.1. Alternative dosing regimens (flat dose, mg) 
or a less frequent dosing regimen (e.g. Q3W or Q4W) may also be considered based on 
emerging clinical toxicity and preliminary PK 
 and efficacy data generated during the 
study. A treatment cycle is defined as 28 days (21 days for patients on Q3W dosing regimen) 
with the potential to extend the cycle an additional 7 days if necessary for recovery of toxicities, 
as described above. Missed doses will not be made up. The first dose of LAG525 or combination 
of LAG525 and PDR001 is Cycle 1 Day 1 which defines the patient’s treatment cycles for the 
study.
Flat dosing may also be investigated in the combination part of the study for both LAG525 and 
PDR001.
Optional testing of two dose levels during phase II expansion
After a preliminary assessment of safety data in dose escalation, a decision may be made to 
investigate a second dose of LAG525 alone during the phase II expansion to further assess 
safety and efficacy. This would be performed in one disease setting. The two dose levels will 
be assigned in an alternating fashion to patients of the same disease group across all the sites in 
this global study. The number of patients required to be tested at this second dose level will be 
equivalent to the number of patients to be enrolled in this disease setting at the RP2D.
6.1.2
Ancillary treatments
Patients should not receive any pre-medications before the first infusion of the investigational 
drug LAG525 and/or PDR001. If a patient experienced an infusion reaction, he/she may receive 
pre-medications on subsequent dosing days after consultation with the Novartis Medical 
Monitor. Pre-medications should include but are not limited to paracetamol/acetaminophen and 
an antihistamine. The use of corticosteroid pre-medication will be at the discretion of the 
principal investigator in consultation with the Novartis Medical Monitor.
If ≥ 2 patients experience moderate to severe acute infusion reactions in a dose escalation cohort 
on C1D1 or if >25% of patients experience mild infusion reactions in the dose escalation, then 
mandatory primary prophylaxis regimens (i.e. before dosing on C1D1) will be instituted after 
discussion and agreement among principal investigators and Novartis. Prophylaxis regimens 
will include both paracetamol/acetaminophen and an antihistamine.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade ≥3 anaphylactic/anaphylactoid
reaction, the patient will be discontinued from the study. Such acute allergic reactions will be 
reported to the Sponsor in an expedited manner. These should be designated as reportable as a 


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SAE regardless of hospitalization as medically important events. Please refer to SAE reporting 
section for details.
Patients should be treated in a facility equipped for cardiopulmonary resuscitation. Appropriate 
resuscitation equipment should be available at the bedside and a physician readily available.
Guidelines on management of LAG525 or PDR001 infusion reactions are provided in
Section 6.3.1 and Table 6-5.
The CTCAE category of “Infusion related reaction” should be used to describe LAG525 and/or 
PDR001 infusion reactions, unless the investigator considers another category, such as 
“Allergic reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a 
specific situation.
6.1.3
Treatment duration
A patient may continue treatment with LAG525 until the patient experiences unacceptable 
toxicity, confirmed disease progression per irRC and/or treatment is discontinued at the 
discretion of the investigator or the patient. Refer to Section 7.1.3 and Section 7.1.5.
If more than 2 consecutive doses of LAG525 or combination of LAG525 and PDR001 have to 
be skipped due to drug-related toxicities, then the drugs should be permanently discontinued. If 
a patient who misses more than 2 consecutive doses due to a drug-related toxicity is 
experiencing clinical benefit, and in the opinion of the investigator it is in the patient’s best 
interest to remain on study, then the patient may continue the treatment(s) after discussion with 
Novartis.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
Starting dose of LAG525 as a single agent (Arm A and Arm C)
The starting dose of LAG525 selected for this study is based on 4-week GLP toxicology studies 
performed in cynomolgus monkeys as LAG525 cross reacts with monkey LAG-3 but not rat or 
murine LAG-3. LAG525 is a monoclonal antibody that does not have agonist activity, and will 
be administered to patients with advanced malignancies; therefore the starting dose is based on 
the ICH S9 guidance. In the cynomolgus monkey study, the HNSTD dose was 100 mg/kg. The 
human equivalent dose (HED) of the HNSTD is 100 mg/kg. Based on the ICH S9 guidance, a 
factor of six can be used to determine the maximum allowable starting dose, with an estimated 
maximum starting dose of 17 mg/kg administered weekly. Based on the pharmacologically 
active doses of 2-10 mg/kg in the clinic with agents having a similar mechanism of action 
(checkpoint inhibitors, CTLA-4 and PD-1 inhibitors, Topalian 2014, Wolchok 2013, Robert 
2014) and with the intent to fully characterize the safety, pharmacokinetics (PK), 
 and preliminary efficacy at multiple dose levels, the starting dose of 
LAG525 is 1 mg/kg every 2 weeks.


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Starting dose of LAG525 and PDR001 combination (Arm B)
PDR001 cross reacts with monkey PD-1 and thus, the starting dose of PDR001 selected for this 
study is based on 4-week GLP toxicology studies performed in cynomolgus monkeys and prior 
clinical experience with nivolumab and pembrolizumab (Topalian 2014, Robert 2014). It is 
anticipated that PDR001 will have similar PK/PD properties to these comparators; PDR001 is 
expected to demonstrate antitumor activity at doses of 2-3 mg/kg dosed every 2-3 weeks. The 
HNSTD of PDR001 was 100 mg/kg, administered i.v., once weekly. The human equivalent 
dose (HED) of the HNSTD is 100 mg/kg. The maximum permitted starting dose in patients is 
1/6 x 100 mg/kg, or 17 mg/kg administered weekly.
In order to evaluate the safety, PK 
, and antitumor activity of PDR001 in combination 
with LAG525 across a range of doses, the starting dose in the combination study is 1 mg/kg of 
PDR001 and 1 mg/kg of LAG525 i.v. administered every 2 weeks (Q2W). If required by a 
Regulatory Authority, recruitment to combination dose levels will begin at dose level -1 (0.3 
mg/kg LAG525 with 1 mg/kg PDR001) for patients from those countries.
For details of dose escalation please refer to Section 6.2.3.
6.2.2
Provisional dose levels
There will be three dose escalation arms in this study; Table 6-2 and Table 6-3 describe the 
starting doses and the provisional dose levels of single-agent LAG525 and the combinations of 
LAG525 and PDR001, respectively, that may be evaluated during this trial. With the exception 
of starting dose level 1, actual dose levels will be determined based on available toxicity, 
pharmacokinetic 
 data, guided by the BLRM, following a discussion with 
participating Investigators during dose escalation teleconferences Section 6.2.3. Dose 
escalation will continue until one or more MTDs or/RP2Ds are determined.
Table 6-2
Provisional dose levels (Ph I Arm A and Arm C: single-agent LAG525)
Dose level
Proposed dose LAG525*
Weight adjusted dose (Flat dose)****
Increment from previous dose
-1**
0.3 mg/kg (20 mg)***
-70%
1 (starting dose)
1 mg/kg (80 mg)***
0
2
3 mg/kg (240 mg)***
<300%
3
10 mg/kg (800 mg)***
< 333%
*It is possible for additional and/or intermediate dose levels to be added during the course of the study Cohorts 
may be added at any dose level below the MTD in order to better understand safety, PK 
 Multiple dose 
levels below the MTD may be evaluated simultaneously in order to obtain PK 
 data across a range of 
doses.
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level.
***Alternate dosing may be explored (i.e. flat dose, mg). If an alternate dosing regimen is used the dose may 
need to be adjusted to achieve an equivalent exposure per cycle.
****1 mg/kg corresponds to a flat dose of 80 mg


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Table 6-3
Provisional dose levels (Ph I Arm B: combinations of LAG525 and 
PDR001)
Dose level
Proposed dose LAG525*
Weight adjusted dose(flat dose)****
Proposed dose PDR001*
Weight adjusted dose (Flat dose****)
-2**
0.3 mg/kg ( 20 mg)
0.3 mg/kg ( 20 mg )
-1**
0.3 mg/kg (20 mg)
1 mg/kg (80 mg)
1 (starting dose)
1 mg/kg (80 mg )
1 mg/kg ( 80 mg)
2
1 mg/kg (80 mg)
3 mg/kg (240mg)
3
3 mg/kg (240mg)
3 mg/kg (240mg)
4
3 mg/kg (240mg)
10 mg/kg ( 800 mg)
5
10 mg/kg (800 mg)
10 mg/kg ( 800 mg)
*It is possible for additional and/or intermediate dose levels to be added during the course of the study Cohorts 
may be added at any dose level below the MTD in order to better understand safety, PK 
. Multiple dose 
levels below the MTD may be evaluated simultaneously in order to obtain PK 
 data across a range of 
doses.
**Dose level -2 and -1 represent treatment doses for patients requiring a dose reduction from starting dose 
level. If required by a Regulatory Authority, recruitment to combination dose levels will begin at dose level -1 
(0.3 mg/kg LAG525 with 1 mg/kg PDR001) for patients from those countries.
***Alternate dosing may be explored (i.e. flat dose, mg). If an alternate dosing regimen is used the dose may 
need to be adjusted to achieve an equivalent exposure per cycle.
****1 mg/kg corresponds to a flat dose of 80 mg
6.2.3
Guidelines for dose escalation and determination of MTD/ RP2D
The maximum tolerated dose (MTD) is defined as:

Arm A and Arm C (single-agent LAG525): for patients enrolled in the single agent arm 
with administration of single agent LAG525, the highest drug dosage that is unlikely (< 25% 
posterior probability) to cause DLT in 33% or more of the treated patients in the first cycle 
of study treatment under that schedule. The DLT window for Arm A and C is one cycle 
(28 days, 21 days for patients on Q3W dosing schedule). Patients enrolled in this arm 
must receive at least two doses (Q2W schedule) of LAG525 to be considered evaluable for 
toxicity. For the Q3W and Q4W schedule, one dose must be received.

Arm B (combination of LAG525 and PDR001): for patients enrolled in the combination 
treatment arm in the dose escalation part with administration of both LAG525 and PDR001, 
the highest combination drug doses that is unlikely (< 25% posterior probability) to cause 
DLT in 33% or more of the treated patients in the first two cycles of study treatment under 
that schedule. The DLT window for Arm B is two cycles (56 days, 42 days for patients 
on Q3W dosing schedule). Patients must receive at least three doses (Q2W schedule) of 
both study drugs during the first two cycles (DLT observation window) to be considered 
evaluable for toxicity. For the Q3W and Q4W schedule, patients must receive 2 doses of 
both study drugs during the first two cycles.
During the dose escalation of combination agents, only 1 of the 2 study drugs can be escalated 
at a time.
Adverse events and laboratory abnormalities considered to be DLTs are defined in Table 6-4.
For Arm B, since several combinations may correspond to this definition, more than one MTD 
may be identified with different doses of the study drugs. One (or more) of these MTDs or a 
suitable lower dose combination will then be selected as the RP2D(s).


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The applied adaptive Bayesian methodology provides an estimate of the single-agent LAG525 
and the combinations of LAG525 and PDR001 not exceeding the MTD. Typically the MTD is 
a tested dose (or combination) with maximum probability of targeted toxicity (DLT rate 
between 16% and <33%). The use of the EWOC principle limits the risk that a potential next 
dose will exceed the MTD Section 10.4.2.
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level in the arm of treatment (Arm A and C
refers to single agent and Arm B refers to combination treatment). Multiple cohorts may be 
sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD(s)/ RP2D(s) for further elaboration of 
safety, pharmacokinetic 
 parameters as required.
The dose escalation will proceed as follows:

Arm A (Single-agent LAG525): The first cohort enrolled in the study will be treated with 
the starting dose of 1 mg/kg LAG525 as a single agent in Arm A. Once this cohort is 
complete and the dose escalation decision has been determined collectively between the 
Sponsor and the participating investigators to escalate, the second cohort in Arm A will 
open with 3 mg/kg. Once a cohort of 3 mg/kg is complete and demonstrated to satisfy the 
EWOC criterion (< 25% posterior probability to cause DLT in 33% or more of the treated 
patients in the first cycle of study treatment), combination dosing will begin (Arm B) at the 
planned starting dose. In the event that the single-agent LAG525 dose of 3 mg/kg does not 
satisfy the EWOC criterion, then combination dose escalation may only proceed at a dose 
level one level below the LAG525 dose deemed safe (i.e. combination dose level -1, 0.3 
mg/kg LAG525 with 1 mg/kg PDR001).

Arm B (LAG525 and PDR001 combination): The combination dose escalation (Arm B) 
will proceed provided that the single-agent LAG525 dose of 1 mg/kg did not exceed the 
MTD. The starting dose for the combination will be 1 mg/kg of LAG525 combined with 1 
mg/kg of PDR001, unless the second dose level of single-agent LAG525 at 3 mg/kg is not 
tolerated or if required by a Regulatory Authority, in which case combination dose 
escalation will proceed at dose level -1 (0.3 mg/kg LAG525 with 1 mg/kg PDR001). The 
dose escalation of the combination Arm B will then proceed in parallel with the remaining 
dose escalation of Arm A.

Arm C (Japan single-agent LAG525): The same guidelines will be applied to dose 
escalation of single-agent LAG525 in Japanese patients. The first cohort of patients enrolled 
in the Japanese sub-population will be treated with a starting dose of 1 mg/kg LAG525 Q2W 
as a single agent. Once this cohort is complete and the dose escalation decision has been 
determined collectively between the Sponsor and the participating investigators to escalate 
the dose, the second cohort will open at a dose of up to 3 mg/kg Q2W (or flat dose equivalent) 
that satisfies EWOC criterion. The dose escalation will then proceed until the RP2D or MTD 
is determined. The Japanese dose escalation Arm C will be run separately from Arm A. 
Dose escalation decisions will be guided by the BLRM to estimate the MTD / RP2D in 
Japanese patients in the context of available safety and PK information.
Arm A and Arm B in dose escalation may enroll patients in an alternating fashion if two cohorts 
in the arms are open in parallel. If only one cohort is open at a given time, patients will enroll 
only into the open cohort and enrollment will pause until an additional cohort in either arm is 


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opened for enrollment. Patients identified for enrollment in dose escalation will be assigned to 
the appropriate cohort by Novartis.
For the purposes of dose escalation decisions, patients can be considered evaluable in each arm 
after having met the following criteria:

Arm A and Arm C: Patients must complete a minimum of 1 cycle of treatment with the 
minimum safety evaluation and drug exposure (at least two doses of LAG525) or have had 
a DLT within the first cycle of treatment to be considered evaluable for dose escalation 
decisions.

Arm B: Patients must complete a minimum of two cycles of treatment with the minimum 
safety evaluation and drug exposure (at least three doses of both study drugs) or have had a 
DLT within the first two cycles of treatment to be considered evaluable for dose escalation 
decisions.
Dose escalation decisions will be made by investigators and Novartis study personnel. For each 
arm, decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1 (arm A and Arm C), and cycles 1 and 2 (arm B), PK, 
 data 
from evaluable patients. The recommended dose for the next cohort of subjects will be guided 
by the BLRM with EWOC principle (Section 2.2) and determined by a synthesis of all available 
data from the cohort.
The adaptive Bayesian methodology provides an estimate of all dose levels of LAG525 and 
PDR001 that do not exceed the MTD and incorporates all DLT information at all dose levels 
for this estimation. In general, the next dose will have the highest chance that the DLT rate will 
fall in the target interval [16-33%) and will always satisfy the EWOC principle. In all cases, the 
dose for the next cohort will not exceed a 333% (1/2 Log10) increase from the previous dose. 
Smaller increases in dose may be recommended by the Investigators and Sponsor upon 
consideration of all of the available clinical data.
If the first 2 patients in a previously untested dose level experience a DLT, further enrollment 
to that cohort will stop and the BLRM will be updated with this new information. Re-evaluation 
of the available safety, PK, 
 data will occur. By incorporating information gained at the 
preceding dose levels, additional patients may be enrolled at this dose level or a lower dose 
level as agreed by Investigators and Novartis personnel and if the BLRM predicts that the risk 
that this dose exceeds the MTD remains below 25% (EWOC).
Dose escalation for each arm (Arm A and Arm C, single-agent LAG525 or Arm B, combination 
of LAG525 and PDR001) will continue until identification of the RP2D or the MTD of the 
single-agent or combination.


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The MTD/RP2D will be determined if the following conditions are met:
1. at least 6 patients have been treated at this dose
2. this dose satisfies one of the following conditions:
a. the posterior probability of targeted toxicity at this dose exceeds 50%, or
b. minimum of 21 patients for the single agent Arm A or 15 patients for the combination 
Arm B, or 12 patients for the Japanese dose escalation Arm C have already been 
treated on the trial for this arm.
3. it is the dose recommended for patients, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, see
Section 6.2.3.1.
To better understand the safety, tolerability, PK 
 of single-agent LAG525 or 
combinations of LAG525 and PDR001, additional cohorts of patients may be enrolled at 
preceding dose levels, or to intermediate dose levels before or while proceeding with further 
dose escalation.
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the DLT window, then the BLRM 
will be updated with this new information before any additional patients are enrolled at that 
higher dose level. Subjects ongoing will continue treatment at their assigned dose levels.
If the circumstance arises that a MTD is not reached in either single agent LAG525 escalation 
or that of the combination, then the RP2D of that arm will be determined from a synthesis of 
all data available, including safety and tolerability, pharmacokinetic 
 
assessments and any preliminary antitumor activity observations.
Change of schedule:
In the event of a change in dosing schedule, then a new BLRM will be used to evaluate this new 
schedule. This new BLRM will incorporate down-weighted existing dose escalation data in the 
prior distribution.
The starting dose for the new regimen will be determined based on the available data, including 
safety, and will be subject to the EWOC criterion under the newly constructed model. The new 
regimen will be less frequent than the Q2W schedule.
Change to flat dose:
Flat dosing (in mg) may be explored for single-agent LAG525 by opening a new cohort(s) in 
the escalation part of this study. The combination of LAG525 and PDR001 utilizing flat dosing 
may also be explored from the start of the combination dose escalation. Please refer to Table 6-
2 and Table 6-3.
Additional BLRMs will be developed to evaluate the flat dosing for single-agent LAG525 and 
its combination with PDR001. Those BLRMs will incorporate down-weighted dose escalation 
data from the weight-based dosing cohorts in an informative prior distribution.
The starting dose for the flat dose will be determined based on the available data, including 
safety, and will be subject to the EWOC criterion under the newly constructed model. The 
equivalent weight based dose should have been tested and shown to satisfy the EWOC criterion.


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6.2.3.1
Implementation of Dose Escalation Decisions
To implement dose escalation decisions, the available toxicity information (including all safety 
data, AEs Grade ≥ 2 and laboratory abnormalities that are not DLTs), the assessment of those 
doses satisfying the EWOC criterion from the BLRM, and the available PK 
 information 
will all be evaluated by the Investigators and Novartis study personnel (including the study 
physician and statistician) during a dose decision meeting by teleconference. All occurrences 
of DLT will be discussed and agreed at the dose decision teleconference among participating 
investigators and Novartis study personnel.
Cohort enrollment and drug administration at the next higher dose level may not proceed until 
the investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level 
with written confirmation of the next higher dose level to be tested.
6.2.3.2
Intra-Patient dose escalation
Intra-patient dose escalation is not permitted at any time within the first 4 cycles of treatment. 
After the 4th cycle is completed, individual patients may be considered for treatment at a dose 
of single agent LAG525 or in combination with PDR001, higher than the dose to which they 
were initially assigned. Only one of the study drugs will be escalated at any one time. Study
drugs will be escalated as detailed in Section 6.2.2. In order for a patient to be treated at a higher 
dose of either single agent LAG525 or in combination with PDR001, he or she must have 
tolerated the lower dose combination for at least 4 cycles of therapy (e.g., he or she must not 
have experienced at the lower dose level originally assigned a toxicity of CTCAE grade ≥ 2 
considered related to study drug). Moreover, the new, higher dose combination with which the 
patient is to be treated must be a dose combination that has completed evaluation in a dose-
escalation meeting and satisfies the EWOC criterion under the Bayesian model given all 
available data.
There is no limit to the number of times a patient may have his or her dose of LAG525 increased 
as a single agent or in combination with PDR001. Any further increases after the initial intra-
patient dose escalation are subject to the same rules as for the initial intra-patient escalation. 
Consultation with Novartis must occur prior to any intra-patient dose escalation occurring. 
These changes must be recorded on the Dosage Administration Record CRF.
6.2.3.2.1 Switch to LAG525 in combination with PDR001 for patients treated 
with LAG525 single-agent
Upon disease progression, patients assigned to LAG525 monotherapy during dose escalation 
may switch to LAG525 + PDR001 at a combination dose level that uses the patient’s same 
LAG525 dose and has been determined safe and tolerable in previous dose escalation patients.  
If there is no combination dose level that includes the patient’s LAG525 monotherapy dose, the 
patient may receive a lower dose level of LAG525 when switching to LAG525 in combination 
with PDR001; alternatively, the patient may switch to the LAG525 + PDR001 recommended 
Phase II dose, once the RP2D has been established. Patients switching to combination therapy 
must have completed at least 4 cycles of LAG525 monotherapy with no toxicity of CTCAE 
grade ≥ 2 considered related to study treatment.


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PDR001 may be added to LAG525 treatment only after documented discussion and agreement 
between Novartis and the Investigator, based on each patient’s condition and review of the 
planned dose and schedule.
Patients will start LAG525 in combination with PDR001 on Day 1 of the cycle during which 
the switch is made and patients will resume their standard scheduled visits per Table 7-1. For 
patients who switch from single-agent LAG525 to LAG525 in combination with PDR001, 
patients will resume the standard visit schedule; hematology/chemistry labs and vital signs will 
be collected on Days 8 and 15 as unscheduled assessments for the first cycle upon switch to the 
LAG525 in combination with PDR001. Cycle 1 will start based on the patient’s first dose of the 
original LAG525 monotherapy. After switching to combination therapy, patients will continue 
to have efficacy assessments as per protocol; however, the response data from these patients 
will not be incorporated into the ORR. No additional biopsies will be required. For patients who 
switch from single-agent LAG525 to LAG525 in combination with PDR001, immunogenicity 
samples will be collected as unscheduled assessments (instead of their standard PK collection 
schedule) on Day 1 pre-dose for the first 6 cycles upon switch to the LAG525 in combination 
with PDR001, and PK blood samples will be collected on Days 1 (pre-infusion) and 8 as 
unscheduled assessments (instead of their standard PK collection schedule) for the first cycle 
upon switch to the LAG525 in combination with PDR001.  Patients who switch from single 
agent LAG525 to LAG525 in combination with PDR001 will need to complete an additional 
End of Treatment Phase Disposition CRF, but the EOT tests/procedures are not required until 
discontinuation of LAG525 in combination with PDR001.
6.2.4
Definitions of dose-limiting toxicities (DLTs)
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of 
CTCAE grade ≥ 3 assessed as having a suspected relationship to study drug, and unrelated to 
disease, disease progression, inter-current illness, or concomitant medications that occurs 
within the first cycle of treatment with single agent LAG525 or within the first two cycles of 
treatment with the combination of LAG525 and PDR001, and meets any of the criteria included 
in Table 6-4.
DLT window:

Arm A and Arm C with single agent LAG525: 28 days (one cycle) (21 days for patients 
on Q3W dosing schedule).

Arm B with combination of LAG525 and PDR001: 56 days (two cycles) (42 days for 
patients on Q3W dosing schedule).
Emerging data from the new field of immune-immune combination studies suggest that some 
immune-related adverse events have a prolonged latency (Wolchok 2013). As such, the DLT 
window for the combination arm in this trial is extended to the length of two cycles or 56 days.
National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
version 4.03 will be used for all grading unless otherwise specified. For the purpose of dose-
escalation decisions, DLTs will be considered and included in the BLRM.


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The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade ≥ 2 adverse events will be reviewed for all patients at the current dose level.
Table 6-4
Criteria for defining dose-limiting toxicities
During dose escalation, any Grade 3 or Grade 4 AEs related to study treatment occurring in 
cycle 1 (applies to dose escalation Arm A and Arm C) , and in cycles 1 and 2 (applies to dose 
escalation Arm B) are DLTs, EXCEPT:  
Fatigue
Grade 3 fatigue that resolves to ≤ Grade 1 within 7 days.
Fever, Infection
Grade 3 infection or fever, in the absence of neutropenia,that resolves within 
7 days.  
Hypertension
Grade 3 hypertension that resolves within 7 days after starting anti-
hypertensive therapy.
Gastrointestinal
Grade 3 nausea and vomiting that resolves to ≤ Grade 1 within 48 hours of 
starting optimal anti-emetic therapy. 
Grade 3 diarrhea that resolves within 7 days after starting optimal anti-
diarrhea treatment, where colitis is not suspected.
Hepatic
Grade 3 ALT or AST in the absence of significantly increased bilirubin that 
resolves to ≤ Grade 1 within 7 days.
Amylase and lipase
Asymptomatic Grade ≥3 amylase or lipase.
Dermatologic
Grade 3 non bullous rash without epidermal detachment that resolves to ≤ 
Grade 1 within 7 days of starting treatment.
Hematologic
Grade 3 neutropenia without fever or other clinical symptoms that resolves 
to ≤ Grade 1 within 7 days.
Grade 3 thrombocytopenia without clinically significant bleeding. 
Grade 3 anemia that resolves within 7 days in the absence of transfusion.
Lymphopenia of any grade is not a DLT.
Electrolytes
Grade 3 electrolyte abnormalities that resolve to ≤ Grade 1 within 7 days 
after starting supplementation.
Musculoskeletal
Grade 3 asymptomatic increase in creatine kinase that resolves within 14 
days in the absence of evidence of cardiac involvement.
Immune-related toxicities*
In general, a Grade 3 immune-related AE that resolves to ≤ Grade 1 within 7 
days of starting appropriate treatment is not a DLT.  


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The following Grade 2 AEs related to study treatment are considered DLTs:
Ocular disorders
Grade 2 eye pain or reduction of visual acuity are DLTs if they do not 
respond to topical therapy and do not improve to Grade 1 severity within 2 
weeks of the initiation of topical therapy, OR if they require systemic 
treatment.
Pneumonitis
Grade 2 pneumonitis is a DLT if it does not resolve to ≤ Grade 1 within 7 
days of starting corticosteroids. 
Myocarditis 
Grade 2 myocarditis is a DLT.
Colitis
Grade 2 colitis is a DLT if it persists > 7 days despite treatment with 
corticosteroids.
Hepatic
Grade 2 ALT or AST accompanied by bilirubin >1.5 x ULN is a DLT.
Dermatologic
Grade 2 bullous disease that does not resolve to ≤ Grade 1 within 7 days of 
starting corticosteroids is a DLT.
Other adverse events
Other clinically significant toxicities, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 7 days within 
the DLT window, may be considered to be DLTs by the Investigators and 
Novartis, even if not CTCAE grade 3 or higher. Infusion reactions will not be 
considered as dose limiting because they are idiosyncratic and not related 
to dose.
* Depending on the nature of the AE, there may be cases where immune-related Grade 2-3 AEs of any 
duration warrant declaration of a DLT and permanent study discontinuation (e.g. Stevens-Johnson Syndrome 
(SJS)).  DLT determination not already outlined in this table will be made on a case-by-case basis after 
Investigator discussion with the Novartis Medical Monitor.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose or schedule 
adjustments are permitted in order to allow the patient to continue the study treatment. The 
following guidelines need to be applied:

If a patient experiences an AE meeting the criteria for DLT as outlined in Section 6.2.4
(including events occurring after cycle 1 for Arm A and C or including events occurring 
after cycle 2 for Arm B), treatment should be withheld at the onset of the AE. Following 
resolution of the toxicity to grade 1 or to the patient’s baseline value, the patient may 
resume study treatment after discussion with Novartis. If the investigator considers it to 
be in the patient’s best interest to resume therapy before the toxicity has resolved to 
grade 1 or to the patient’s baseline value, this may be permitted on a case by case basis 
after discussion with Novartis.

For clinical management of suspected immune-related events, reference to consensus 
management guidelines is recommended such as those provided in the National 
Comprehensive Cancer Network (NCCN) Guidelines for the Management of 
Immunotherapy-Related Toxicities (available at : 
https://www.nccn.org/professionals/physician_gls/default.aspx#immunotherapy), the 
American Society for Clinical Oncology clinical practice guideline for Management of 
Immune-Related Adverse Events in Patients Treated With Immune Checkpoint 


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Inhibitor Therapy (Brahmer 2018) or the European Society for Medical Oncology 
(ESMO) Clinical Practice Guidelines for Management of Toxicities from 
Immunotherapy (Haanen 2017).  Note that in general, study treatment should be 
interrupted for grade 3 and 4 toxicities and for a subset of lower grade toxicities.

Consider early referral to specialists with expertise in the diagnosis and management 
of immune-related AEs to thoroughly investigate events of uncertain etiology.

Events not included in the study protocol or the reference guidance documents should 
be managed per institutional preference.
A scheduled dose (of either single-agent LAG525 or the combination of LAG525 and PDR001) 
may be delayed to recover from an unresolved AE. If a patient requires a dose interruption of > 
21 days from the intended day of the scheduled dose due to an AE related to study drug(s), then 
the patient must be discontinued from the study, unless the patient is receiving clinical benefit 
and in the opinion of the investigator it is in the patient’s best interest to remain on study. The 
patient may restart treatment after discussion with Novartis.
Patients who discontinue the study for a study related AE or a study-related abnormal laboratory 
value must be followed as described in Section 6.3.2.
Table 6-5 outlines the recommended dose modifications for selected toxicities. 
All interruptions or change to study drug administration must be recorded on the Dose 
Administration Record eCRF.
Table 6-5
Recommended Dose Modifications for LAG525 and PDR001
Worst toxicity CTCAEa grade
Recommended Dose Modification
Infusion reaction or hypersensitivity reaction
Grade 1
Decrease infusion rate until recovery from the symptoms.
Grade 2
Stop infusion immediately, and keep line open. 
Follow institutional guidelines for the management and follow-up of 
infusion reaction.
Restart infusion at 50% of previous rate under continuous observation. 
Ensure that there is a minimum observation period of 1 hour prior to 
restarting the infusion.
If the AE recurs at the reinitiated slow rate of infusion, and despite oral 
pre-medication, then permanently discontinue study treatment.
Grade 3 and Grade 4
Discontinue infusion immediately, and discontinue study treatment.
Provide supplemental oxygen, fluids, and other resuscitative measures 
as needed. Monitor vital signs (e.g. blood pressure, pulse, respiration, 
and temperature) every 15 ± 5 minutes until resolution.
Cytokine Release Syndrome (CRS)
Grade 2
See instructions for Grade 2 Infusion Reaction above.
Grade 3 or Grade 4
Discontinue study treatment.
Follow-up CRS as per institutional guidelines.
Take blood for cytokine measurements as specified in Section 8.4.1 –
Laboratory evaluations.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Ocular (uveitis, eye pain, blurred vision)
Grade 1
Continue study treatment without dose modification.
Ophthalmology consultation.
Grade 2
Hold study treatment.
Urgent ophthalmology consultation.
Upon resolution to ≤ Grade 1 may consider resuming study treatment 
without dose reduction after discussion with the Novartis Medical 
Monitor and in consultation with ophthalmology.
Grade 3 or Grade 4
Discontinue study treatment.
Urgent ophthalmology consultation.
Pulmonary (pneumonitis)
Grade 1
Consider study treatment hold.
Manage per institutional practice.
Consider resuming study treatment upon radiographic evidence of 
improvement.
Grade 2
Hold study treatment.
Pulmonary and infection workup.
Upon resolution to ≤ Grade 1, may resume study treatment without
dose modification.
Grade 3 or Grade 4
Discontinue study treatment.
Cardiovascular
ECG QTc-Interval prolonged; hypertension
Grade 3
Hold study treatment. 
Upon resolution to Grade ≤ 1 or baseline (hypertension, QTc) or < 30 
msec difference from baseline (QTc) within ≤ 7 days, may resume 
study treatment without dose modification after discussion with the 
Novartis Medical Monitor. Baseline ECG refers to the ECG(s) collected 
at screening.
Grade 4
Discontinue study treatment.
Other cardiovascular disorders
Grade 2 (except myocarditis)
Hold study treatment.
Upon resolution to Grade ≤ 1 or baseline, may resume study treatment 
without dose modification after discussion with the Novartis Medical 
Monitor.
Grade 2 myocarditis, or 
Grade ≥ 3 other cardiac disorders 
related to study treatment
Discontinue study treatment.
Gastrointestinal
Diarrhea/colitis*
Grade 1
May continue study treatment without dose modification.  Manage per 
institutional standard guidelines which should include anti-diarrheal 
treatment, consideration of corticosteroid therapy, and hydration.
Grade 2
Hold study treatment.
GI consultation.
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to ≤ 
10 mg prednisone per day, resume study treatment without dose 
modification after discussion with the Novartis Medical Monitor.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Grade 3
Hold study treatment.
GI consultation.
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to ≤ 
10 mg prednisone per day, consider resuming study treatment after 
discussion with the Novartis Medical Monitor.
Grade 4
Discontinue study treatment.
AST and/or ALT elevation
Grade 2 AST and/or ALT
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1 or baseline, consider resuming study 
treatment without dose modification.
Grade 2 transaminitis with 
bilirubin >1.5 x ULN (unless Gilbert’s 
syndrome)
Discontinue study treatment.
Grade 3 AST and/or ALT
Hold study treatment.
Manage per institutional practices.
Upon resolution to ≤ Grade 1 or baseline within 7 days, consider 
resuming study treatment without dose modification after discussion 
with the Novartis Medical Monitor.
Otherwise, discontinue study treatment.
Grade 4 AST and/or ALT
Discontinue study treatment.
Isolated total bilirubin elevation**
Grade 2
Hold study treatment. 
Upon resolution to ≤ Grade 1 or baseline, may continue study treatment 
without dose modification.
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 1 or baseline, may consider resuming study 
treatment after discussion with the Novartis Medical Monitor.  
Grade 4
See footnote**.  Otherwise, discontinue study treatment.
Asymptomatic amylase and/or lipase elevation***
Grade 3 or Grade 4, not associated 
with symptoms or clinical 
manifestations of pancreatitis***
Continue study treatment. 
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial 
report, hold study treatment.
Upon resolution to ≤ Grade 2, may resume study treatment without 
dose modification, after discussion with the Novartis Medical Monitor.
Pancreatitis
Grade 2/radiologic evidence
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without 
dose modification, if no clinical evidence of pancreatitis and after 
discussion with the Novartis Medical Monitor.
Grade 3 or Grade 4
Discontinue study treatment.
Renal
Serum creatinine
Grade 2
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without 
dose modification after discussion with the Novartis Medical Monitor.
Grade 3 or 4
Discontinue study treatment.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Musculoskeletal
Grade 2 or Grade 3
Hold study treatment.
Consider resuming study treatment without dose modification upon 
resolution to ≤ Grade 1 with appropriate management.
Grade 4
Discontinue study treatment.
In some cases, resuming study treatment may be considered after 
discussion with the Novartis Medical Monitor and consultation with a 
rheumatologist.
Endocrine
Hypothyroidism or hyperthyroidism
Grade 2
May continue study treatment without dose modification.
Management according to institutional practice.
Grade 3
Hold study treatment. 
Upon resolution to Grade ≤ 1 with appropriate management, may 
resume study treatment without dose modification.
Grade 4
May resume therapy following resolution or control with physiologic 
hormone replacement.
Other endocrine disorders
Grade 2 and Grade 3
Hold study treatment. 
Upon resolution to Grade ≤ 1 with appropriate management, may 
resume study treatment without dose modification.
Grade 4
Hold study treatment.
Grade 4 treatment-related endocrinopathies, such as 
adrenal insufficiency, adrenocorticotropic hormone 
(ACTH) deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling 
agents, respectively, may not require discontinuation after discussion 
with and approval from the Novartis Medical Monitor.
Neurology
Grade 1
Consider study treatment hold, particularly for clinical 
suspicion of Guillain-Barre syndrome, encephalitis, aseptic meningitis, 
transverse myelitis, or peripheral neuropathy.
Grade 2
Hold study treatment.  
In some cases, resuming study treatment may be 
considered after discussion with the Novartis Medical 
Monitor.
Grade 3 or Grade 4
Discontinue study treatment.
Dermatology (rash)
Grade 1
Continue study treatment without dose modification. Topical steroids, 
antihistamines, topical emollients
Grade 2
Consider holding study treatment.
Topical or oral steroids, antihistamines.
If study treatment is held and resolution to ≤ Grade 1, resume study 
treatment without dose modification.
Grade 3 or Grade 4
Hold study treatment.
Manage per institutional practice.
After resolution to ≤ Grade 1, consider resuming study treatment after 
discussion with the Novartis Medical Monitor.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Bullous dermatitis
Hold study treatment.
Grade 1-2 bullous dermatitis: discussion with the Novartis Medical 
Monitor is required before considering resuming study treatment.  
Grade 3 bullous dermatitis: consider resuming therapy after expert 
consultation and documented discussion with the Novartis medical 
monitor.
Grade 4 bullous dermatitis: discontinue study treatment
Stevens-Johnson syndrome (SJS), or 
Lyell syndrome/toxic epidermal 
necrolysis (TEN)
Permanently discontinue study treatment
Hematology
Neutropenia (ANC)
Grade 3 or Grade 4
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification, after discussion with the Novartis 
Medical Monitor.
Febrile neutropenia
Grade 3 or Grade 4
Hold study treatment.
Upon resolution of fever and improvement of neutropenia to ≤ Grade 2 
or baseline, resume study treatment without dose modification, after 
discussion with the Novartis Medical Monitor.
Thrombocytopenia
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 2 or baseline, resume study treatment 
without dose modification.
For Grade 3 associated with major bleeding, discontinue study 
treatment.
Grade 4
Discontinue study treatment.
Anemia
Grade 3 or Grade 4
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification.
Lymphopenia
Any grade
Treatment-related lymphopenia does not require study treatment hold 
or discontinuation.
Other laboratory adverse events, not specified elsewhere in table and not included in the consensus 
guidelines
Grade 3
Hold study treatment. 
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification.
Grade 4
Isolated Grade 4 electrolyte abnormalities not associated with clinical 
sequelae and corrected after appropriate management within 72 hours 
of their onset do not require discontinuation.
In the case of Grade 4 electrolyte imbalances associated with clinical 
sequelae, or not resolved to ≤ Grade 1 within 72 hours despite 
appropriate management, discontinue study treatment.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Other non-laboratory adverse events, not specified elsewhere in table and not included in the consensus 
guidelines
Grade 2
Consider study treatment hold, at Investigator discretion.
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification.
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 1, resuming study treatment must be 
discussed with the Novartis Medical Monitor.
Grade 4
Discontinue study treatment.
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE)
*Note: anti-diarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea.
**Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis 
as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then delay study treatment until resolved ≤ Grade 1, and resume study treatment at 
the discretion of the investigator.
***Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within one week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. 
6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed-up at least once a week (or more if clinically 
indicated) for 4 weeks, and subsequently at approximately 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. 
The emergence of Immune-Related AE (irAE) may be anticipated based on the mechanism of 
action of immunomodulatory therapies.
An irAE is any clinically significant adverse event affecting any organ that is associated with 
study drug exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. Serologic, 
histologic (tumor sample) and immunological assessments should be performed as deemed 
appropriate by the Investigator or specialist consultant to verify the immune-related nature of 
the AE. An empiric trial of corticosteroids may also contribute to understanding the etiology of 
a potential irAE. 
Consensus management algorithms for irAEs have been developed and are available to assist 
investigators in assessing and managing irAEs (refer to Section 6.3.1 Dose modifications).
In case of a toxicity suspected to be a cytokine release syndrome, the assessments outlined in 
Section 7.2.2.5.6 must be performed.
All patients must be followed up for irAEs, AEs, and SAEs for 150 days following the last 
doses of LAG525 and/or PDR001.
6.3.3
Permitted concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed.


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For patients with hormone resistant prostate cancer receiving luteinizing hormone-releasing 
hormone agonists or antagonists, or for patients with metastatic carcinoid tumors receiving 
somatostatin analogs to control symptoms of carcinoid syndrome, these treatments must have 
been initiated ≥4 weeks prior to first dose of study treatment and may be continued throughout 
the study. 
Bisphosphonates are generally allowed for the management of bone metastases and 
osteoporosis. However, chronic concomitant bisphosphonate therapy for the prevention of bone 
metastasis is not permitted.  If bisphosphonate therapy is to be started after the first dose of 
study drug, prior consultation and approval by Novartis is required and the reason for its use 
must be clearly documented.
Patients must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. All 
medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed on the Prior and Concomitant Medications or the Surgical and Medical Procedures 
CRF. Prior antineoplastic therapies including medications, radiotherapy, and surgery are to be 
recorded on the separate Prior Antineoplastic Therapy eCRF during screening.
6.3.4
Permitted concomitant therapy requiring caution and/or action
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) may not be initiated during the DLT observation window (see Section 6.2.3) in the dose 
escalation part of the study, unless the patient has already experienced a DLT. Treatment with 
erythroid stimulating agents (ESAs) may not be initiated during the DLT observation window 
in the dose escalation part of the study, unless the patient has already experienced a DLT. If a 
patient is using ESA prior to enrollment (at least 2 weeks prior to the first dose of study 
treatment), they may continue at the same dose.
Anticoagulation is permitted if the patients are already at stable doses for >2 weeks at time of 
first dose and INR should be monitored as clinically indicated per investigator’s discretion. 
However, ongoing anticoagulant therapy should be temporarily discontinued to allow tumor 
biopsy according to the institutional guidelines.
Antihypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with the study 
drugs including LAG525 or its combination with PDR001.
6.3.5
Prohibited concomitant therapy
During the course of the study, patients may not receive other additional investigational drugs, 
agents, devices, chemotherapy, or any other therapies that may be active against cancer. 
However, limited-field palliative radiotherapy to non-target lesion(s) may be allowed as 
concomitant therapy after documented discussion with Novartis. Such local therapies 
administered during the study treatment must be listed on the corresponding CRF. Additionally, 
no other therapeutic monoclonal antibodies and no immunosuppressive medication may be 


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administered while on this study. Denosumab may be used for the management of bone 
metastases. 
The use of systemic steroid therapy (at doses greater than 10 mg/day prednisone or equivalent) 
and other immunosuppressive drugs is not allowed, with the exception of: 

Prophylactic use for patients with imaging contrast dye allergy.

Replacement-dose steroids (defined as 10mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids) in the setting of adrenal insufficiency. 

Transient exacerbations of chronic inflammatory conditions such as COPD. Steroids must 
be reduced to 10 mg/day (or lower dose) of prednisone or equivalent dose of 
corticosteroids prior to the next treatment with LAG525 and/or PDR001.

Upon treatment of LAG525 and/or PDR001 infusion reactions or LAG525 and/or 
PDR001-related irAEs, steroids must be reduced to 10 mg/day (or lower dose) of 
prednisone or equivalent dose of corticosteroids prior to the next treatment with LAG525 
and/or PDR001.
Topical, inhaled, nasal and ophthalmic steroids are allowed. The use of live vaccines is not 
allowed through the whole duration of the study. Inactivated vaccines are allowed.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first pre-screened (if applicable) or when the patient is enrolled for screening. The 
subject number is retained as the primary identifier for the patient throughout his/her entire 
participation in the trial. The Subject No. consists of the Center Number (Center No. is assigned 
by Novartis to the investigative site) with a sequential patient number suffixed to it, so that each 
subject is numbered uniquely across the entire database. Upon signing the informed consent 
form, the patient is assigned to the next sequential Subject No. available to the investigator 
through the Oracle Clinical RDC interface.
6.4.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort will be coordinated by the sponsor. No 
randomization will be performed in this study.
6.5
Study drug preparation and dispensation
LAG525 is supplied as liquid in vial (100 mg per vial). PDR001 100 mg is formulated as powder
for solution for infusion. Further instructions for the preparation and dispensation of LAG525 
and PDR001 are described in the [Pharmacy Manual].
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record CRF.


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6.5.1
Study drug packaging and labeling
LAG525 100 mg liquid in vial.
PDR001 (100 mg powder for solution for infusion) will be supplied by Novartis to Investigator 
as open label bulk medication.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but will not supply information about 
the patient.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, LAG525 and PDR001 should be stored according to 
the instructions specified on the drug labels.
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Study treatment will be administered to the patient by the study site staff at the study sites. 
Compliance will be assured by administration of the study treatment under the supervision of 
investigator or his/her designee.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment according to local institutional drug accountability processes. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
study.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table (“Category” column) indicates which assessments produce data to be 
entered into the clinical database (D) or remain in source documents only (S).


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No CRF will be used as a source document.
Screening/baseline evaluations must be performed ≤ 21 days before Cycle 1 Day 1, except for 
baseline radiological evaluations which must be done within 28 days. Assessments required on 
Cycle 1 Day 1 that are performed as part of the screening evaluations and within 72 hours prior 
to the first dose of study treatment, do not need to be repeated on Cycle 1 Day 1. Laboratory 
and radiological assessments performed as part of standard of care prior to signing informed 
consent may be used if performed within the screening time window.
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 7 days is allowed. If the infusion of LAG525 or its combination 
with PDR001 is delayed, the assessments will be shifted accordingly. On PK collection days 
the windows are provided in Section 7.2.3.
Radiological assessments must be performed +/- 7 days of the scheduled date of the assessment.


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Table 7-1
Visit evaluation schedule
Screening 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
Safety Follow-
Upg
Disease 
Progression 
F/U
Day of cycle
-21 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
Obtain Informed Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion criteria
D
5.2 / 5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and extent of 
cancer
D
7.1.1.2
X
MSI status if applicable
D
7.1.1.2
X
EGFR, ALK, BRAF V600 
status (if applicable) and 
BRCA (if known)
D
7.1.1.2
X
Prior antineoplastic therapy
D
7.1.1.2
X
Prior/concomitant medications
D
7.1.1.2
X
Continuous
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
Xh
X
Performance status
D
7.2.2.4
X
X
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
Xh
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
Xh
X
Coagulation
D
7.2.2.5.3
X


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Screening 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
Safety Follow-
Upg
Disease 
Progression 
F/U
Day of cycle
-21 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
Urinalysis
D
7.2.2.5.4
X
Thyroid function
D
7.2.2.5.5
X
X
X
X
X
X
Cytokines (
IL-6)
D
7.2.2.5.6
X
In case of a suspected cytokine release syndrome
Pregnancy test
D
7.2.2.5.7
X
X
X
X
X
S
7.2.2.5.7
Xg
Antineoplastic therapies since 
discontinuation of study 
treatment
D
7.1.5
X
X
X
Tumor evaluation as per 
RECIST 1.1 and as per irRC.
D
7.2.1
X
Every 8 weeks ± 1 week after Cycle 1 Day 1 until 40 weeks, then every 12 weeks until 
progression of disease per irRC or patient withdrawal.
For disease progression f/u, every 8 weeks ± 1 week until 40 weeks, then every 12 weeks ± 1 
week until progression of disease per irRC, or lost to follow-up.
ECG
D
7.2.2.6.1
X
X
X
X
Xa
Xj
Adverse events
D
8
Continuous


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Screening 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
Safety Follow-
Upg
Disease 
Progression 
F/U
Day of cycle
-21 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
Study Drug administration
D
6.1.1
i.v. every 2 weeks (potential alternative schedules, e.g., every 3 or 4 
weeks).
PK samplingc
D
7.2.3
X
X
X
X
X
X
X
X
X
X
X
Xa, i
Xk
Immunogenicity (IG) sampling
D
7.2.3
X
X
X
Xa, i
X
a. Cycles 4-6 only.
b. Anytime from Cycle 3 Day 1 through Cycle 3 Day 15.
c. Japanese patients enrolled in dose escalation are required to be hospitalized during the DLT evaluation period
 
 
 
g. Safety evaluations for 150 days after the last dose of study treatment with contacts at 30-, 90-, and 150-day. Pregnancy tests every month until the 150-day safety 
follow-up; can be performed at home or at a local doctor’s office if the patient is not coming to the clinic.
h. For patients who switch from single-agent LAG525 to LAG525 in combination with PDR001, patients will resume the standard visit schedule; hematology/chemistry 
labs and vital signs will be collected on Days 8 and 15 as unscheduled assessments for the first cycle upon switch to the LAG525 in combination with PDR001.
i. For patients who switch from single-agent LAG525 to LAG525 in combination with PDR001, immunogenicity samples will be collected as unscheduled 
assessments (instead of their standard PK collection schedule) on Day 1 pre-dose for the first 6 cycles upon switch to the LAG525 in combination with PDR001, and 
PK blood samples will be collected on Days 1 (pre-infusion) and 8 as unscheduled assessments (instead of their standard PK collection schedule) for the first cycle 
upon switch to the LAG525 in combination with PDR001.
j. After the primary CSR cut-off date is reached, EOT ECGs will be performed at the discretion of the investigator.
k. After the primary CSR cut-off date is reached, EOT PKs will not be performed.


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7.1.1
Screening
The study IRB/IEC informed consent form must be signed and dated before any screening 
procedures are performed, except for laboratory and radiological evaluations performed as part 
of standard of care within the screening window.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1. Screening assessments must be repeated if 
performed outside of the specified screening window Section 7.1. Patients are allowed to re-
screen after abnormal labs or symptoms are corrected or treated.
7.1.1.1
Information to be collected on screening failures
A patient who signed an Informed Consent Form but failed to be started on treatment for any 
reason will be considered a screen failure. If patients are found not eligible after signing the 
main study consent, the patients will be considered as screening failures, and data will be 
handled in the same manner.
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure patients. No other data will be entered into the clinical database for 
patients who are screen failures, unless the patient experienced a SAE during screening.
7.1.1.2
Patient demographics and other baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, prior medication, procedures, significant non-drug therapies and any other 
assessments that are done for the purpose of determining eligibility for inclusion in the study. 
For patients with CRC, the MSI status will be collected. If the MSI status determination is not 
performed routinely as part of the patient standard follow-up, it is requested to be determined 
locally during screening. In the phase II part of the study, for patients with NSCLC, the EGFR 
and ALK mutation status will be collected; for patients with melanoma, the BRAF V600 
mutation status will be collected; for patients with TNBC, if known, the BRCA status will be 
collected. If the EGFR, ALK or BRAF V600 status is not known, it is requested to be 
determined locally during screening. These test results are not required to qualify for enrollment.
7.1.2
Treatment period
A treatment cycle is defined as 28 days for the purposes of scheduling procedures and 
evaluations (21 days for patients on Q3W dosing schedule). Please refer to Table 7-1 for details 
of the timing of required assessments and Section 7.1 for visit windows. Based on emerging 
available safety, PK, 
 and efficacy data generated during the study, the treatment cycle length 
may be switched to 21 days.
For Japan only, patients enrolled in dose escalation are required to be hospitalized during the 
DLT evaluation period.
Patients will be treated until they experience unacceptable toxicity, progressive disease per irRC 
and/or treatment is discontinued at the discretion of the investigator or the patient, as described 
in Section 7.1.3 and Section 4.3.


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Patients may continue treatment with LAG525 or its combination with PDR001 until the patient 
experiences unacceptable toxicity that precludes any further treatment, disease progression, 
and/or treatment is discontinued at the discretion of the investigator or by patient request. 
Patients who have disease progression and have evidence of clinical benefit, such as disease 
shrinkage at other sites or symptomatic improvement, may continue treatment with LAG525 or 
its combination with PDR001. In addition, LAG525 or its combination with PDR001 treatment 
may be temporarily interrupted to permit local therapy for symptomatic metastases after disease 
progression has been documented. Patients who continue on treatment after disease progression 
should discontinue study treatment once they are no longer deriving benefit as assessed by the 
investigator.
7.1.3
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every effort 
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason.
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued if any of the following occur:

Adverse event

Lost to follow-up

Physician’s decision

Progressive disease per irRC, RECIST 1.1, or as determined clinically by the Investigator

Study terminated by the sponsor

Subject/guardian decision

Protocol deviations that result in significant risk to the patients’ safety

Technical problems
Patients will be withdrawn if any of the following occur:

Death

Pregnancy
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
and within 14 days of the last dose of study drug or within 14 days of the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the 
EOT visit will be performed (Table 7-1). If the decision to withdraw the patient occurs at a 
regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit. An End of Treatment Phase Disposition CRF page should be 
completed, giving the date and reason for stopping the study treatment. End of 
treatment/Premature withdrawal visit is not considered as the end of the study.


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Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact them as specified in Section 7.1.6. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. At that time, the reason for study completion 
should be recorded on the Study Phase Completion Disposition CRF page.
Patients who transfer into another study or an alternative treatment option to continue provision 
of study treatment will perform the end of treatment procedures.
7.1.3.1
Replacement policy
Phase I dose escalation part:
Patients will not be replaced on study. However, if a patient is considered to be non-evaluable 
for the Dose Determining Set (DDS), enrollment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrollment of new 
patients may be considered until at least the minimum number or at most the maximum number 
of evaluable patients is achieved within the cohort. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.3.
Phase II expansion part: during the phase II expansion part no replacements will be needed.
7.1.4
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study any longer, and 

Does not allow further collection of personal data
In this situation, the investigator should make reasonable effort (e.g. telephone, email, letter) to 
understand the primary reason for the patient's decision to withdraw his/her consent and record 
this information. Study treatment must be discontinued and no further assessments conducted. 
The data that would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient's study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient's sample until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and the 
informed consent form. 


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For European Union and Rest of World: All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
7.1.5
Follow up period
150-day safety follow up period
All patients must have safety evaluations 30 days, 90 days, and 150 days after the last dose of 
study treatment. The follow-up can be done by telephone call or a visit. Concomitant 
medications will be collected until the 30-day safety follow-up has been completed, or the start 
of a new antineoplastic therapy, whichever occurs first. Information related to AEs (including 
concomitant medication taken for on-going AEs) will be collected for 150 days after the last 
dose of study drug. All AEs suspected to be related to study treatment should be followed up 
weekly or as clinically indicated until resolution or stabilization.
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period. After initiation of new post-treatment antineoplastic therapy, only AEs 
suspected to be related to study treatment will be collected in the Adverse Events CRF.
For a female participant of child bearing potential, a pregnancy test will be performed on Days 
30, 60, 90, 120 and 150 after stopping the study treatment. If the patient is not coming to the 
clinic for the safety follow-up visits, a pregnancy test will be performed at home or at a local 
doctor’s office at each of the safety follow-up time points described above, and the results will 
be communicated to the site staff and will be recorded only in the source documentation, not in 
the CRF.
Disease progression follow up period
Patients who discontinue study treatment for any reason other than death, disease progression 
per irRC, lost to follow-up, consent withdrawal, start of new cancer therapy or study termination, 
also should return for tumor evaluation assessments every 8 weeks until 40 weeks, and then 12 
weeks until progression of disease per irRC. If patients refuse to return for these visits or are 
unable to do so, every effort should be made to contact them or a knowledgeable informant by 
telephone to determine if the patient had disease progression.
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period.
 
 
 
 
 
 


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7.1.6
Lost to follow up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be determined locally according to two sets of criteria:
1. RECIST v1.1 (Appendix 1)
2. irRC (Appendix 2)
The local investigator’s assessment will be used for the analysis of response according to both 
RECIST 1.1 and irRC, and for treatment decision making (study discontinuation due to PD as 
per irRC). Patients experiencing progressive disease per RECIST v. 1.1 criteria may continue 
to be treated according to irRC guidelines until progression is documented via irRC. Imaging 
data may be centrally collected and checked for quality by an imaging Contract Research 
Organization (CRO) designated by Novartis. The local investigator’s assessment will be used 
for the data analysis and for treatment decision making. Central review of the imaging data may 
be performed if deemed necessary. 
At screening, all patients will undergo CT with i.v. contrast of the chest, abdomen and pelvis. 
MRI should only be used to evaluate sites of disease that are not adequately imaged by CT. If 
a patient is intolerant of iodine-based contrast agents, CTs may be performed without contrast. 
MRI may be used to evaluate sites of disease where a CT without i.v. contrast is not adequate. 
Visible skin lesions and easily palpable subcutaneous tumors may be measured by physical 
examination using a ruler or calipers. Ultrasound should not be used to measure sites of disease. 
See Table 7-2 for further details.
Tumor assessments will be performed at the following time points:

Screening

Every 8 weeks ± 1 week after Cycle 1 Day 1 until 40 weeks, then every 12 weeks ± 1 
week until progression of disease per irRC or patient withdrawal. After EOT, during 
disease progression f/u, every 8 weeks ± 1 week until 40 weeks, then every 12 weeks ± 1 
week until progression of disease per irRC, or lost to follow-up.

PR or CR, per both RECIST 1.1 and irRC, will be confirmed by a new assessment after at 
least 4 weeks. Also PD, as per irRC, needs to be confirmed after at least 4 weeks.

At the End of Treatment, if a scan was not conducted within 30 days prior to End of 
Treatment
Disease progression follow-up should be performed as described in Section 7.1.5.


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Table 7-2
Disease assessment collection plan
Procedure
Screening/Baseline
During Treatment/Follow-up
CT or MRI
with contrast 
enhancement
(Chest, Abdomen, 
Pelvis)
Mandated
Every 8 weeks ± 1 week after Cycle 1 Day 1 until 40 
weeks, then every 12 weeks ± 1 week until 
progression of disease per irRC or patient 
withdrawal. After EOT, during disease progression 
f/u, every 8 weeks ± 1 week until 40 weeks, then 
every 12 weeks ± 1 week until progression of 
disease per irRC, or lost to follow-up
Brain CT or MRI with 
contrast
Mandated
If disease was detected at baseline, or if clinically 
indicated
Localized bone CT, 
MRI or x-ray
For any lesions identified on 
the bone scan that are not 
visible on the chest, abdomen 
and pelvis CT or MRI
If lesions were documented at baseline, follow same 
schedule as CT/MRI of chest, abdomen, and pelvis
Whole body bone 
scan
If clinically indicated
If clinically indicated
Any other procedure allowed as per RECIST 1.1 guidelines and not conflicting with this section


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7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, urinalysis, thyroid function, 
pregnancy, ECG, cytokine testing, as well as collecting of the AEs at every visit. For details on 
AE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
Physical examination will be performed according to Table 7-1.
At Screening and Cycle 1 Day 1, prior to LAG525 infusion, a complete physical examination 
will be performed and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
neurological system. If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed.
From Cycle 1 Day 8 onwards, a short physical examination will be performed. A short physical 
exam will include the examination of general appearance, vital signs (temperature, blood 
pressure [BP] and pulse) and body sites as directed by symptoms.
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History CRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event CRF page.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1 as per institutional standards.
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator if medically 
indicated, and will be recorded as unscheduled assessment.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured as indicated in Table 7-1.
7.2.2.4
Performance status
Performance status is determined as indicated in Table 7-3.
Table 7-3
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair


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7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally (except 
cytokine release syndrome testing, which will be performed and analyzed centrally for sites not 
capable of local testing). Refer to Table 7-4 for a summary of the parameters to be evaluated 
according to Table 7-1. On dosing days of LAG525 or its combination with PDR001, samples 
for these parameters will be collected prior to the infusion of LAG525 or its combination.
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges for that laboratory.
Table 7-4
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, 
Chloride, Creatinine, Glucose*
Magnesium, Inorganic Phosphate, Potassium, Sodium, Total Bilirubin (also measure 
direct and indirect bilirubin if total bilirubin is > grade 1), Blood Urea Nitrogen (BUN) or 
Urea, amylase, and lipase. 
Additionally for melanoma and TNBC patients: LDH 
Coagulation
Prothrombin time (PT) or International normalized ratio [INR]), activated partial 
thromboplastin time (APTT)
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific 
Gravity, White Blood Cells)
Thyroid
Total or free T4, TSH
Cytokines
 Interleukein-6 (IL-6)
*See Section 7.2.2.5.2 regarding fasting glucose testing
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1. Patients without pre-existing diabetes or previously determined to be 
normoglycemic shown to have an abnormal random blood glucose at screening must have a 
fasting blood glucose test performed and any subsequently diagnosed hyperglycemia should be 
managed appropriately as per Institutional guidelines.


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7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.4 Urinalysis
Urinalysis panel outlined in Table 7-4 will be performed as per the assessment schedule in Table 
7-1.
7.2.2.5.5 Thyroid function
Thyroid function panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1.
7.2.2.5.6 Cytokines
The cytokine panel outlined in Table 7-4 will be performed on an as needed basis in case a 
patient has an adverse event suspected to include cytokine release syndrome. This assessment 
is in addition to the pharmacodynamic cytokine panels described in Section 7.2.4.3.2.
Baseline cytokine samples must be collected at screening for all patients. If a suspected cytokine 
release syndrome occurs, additional sample(s) must be collected at the following time points:

within 5 hours after the occurrence of the adverse event

One week after the occurrence of the adverse event.

Samples collected for cytokine tests will be stored at -700C. The samples will be analyzed 
retrospectively in batches for those patients who experience an AE that is suspected to be 
cytokine release syndrome.
7.2.2.5.7 Pregnancy and assessment of fertility
Pregnancy tests will be performed for women of child bearing potential.
At screening, a serum pregnancy test must be performed within 72 hours before the first dose. 
During the study (Day 1 of each cycle starting with Cycle 2) a serum or urine pregnancy test 
must be performed. At End of Treatment, a serum or urine pregnancy test must also be 
performed.
Pregnancy test will also be performed during the follow-up period on Days 30, 60, 90, 120, and 
150 after stopping the study treatment. If the patient is not coming to the clinic for the safety 
follow-up visits, a pregnancy test will be performed at home or at a local doctor’s office at each 
of the safety follow-up time points described above, and the results will be communicated to 
the site staff and will be recorded only in the source documentation, not in the CRF.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1 and 
Table 7-5. Blood samples scheduled at the same time point should be taken after the ECGs are 


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completed. The ECGs on C1D1, C2D1, C3D1, C4D1, C5D1 and C6D1 must be performed in 
triplicate.
The post-dose ECGs in the combination arm will be collected after the completion of the last 
dose of infusion.
Table 7-5
12 Lead ECG collection plan
Cycle
Day
Time
Screening
-21 to -1
Anytime
1
1
*Pre-dose
1
1
*1h (±5 min) hour post dose
2
1
*Pre-dose
2
1
*1h (±5 min) hour post dose
3
1
*Pre-dose
3
1
*1h (±5 min) hour post dose
4
1
*Pre-dose
4
1
*1h (±5 min) hour post dose
5
1
*Pre-dose
5
1
*1h (±5 min) hour post dose
6
1
*Pre-dose
6
1
*1h (±5 min) hour post dose
EoT
-
Anytime
Unscheduled**
-
Anytime
*ECGs Performed in triplicate.
**A PK sample should be collected just after an ECG performed due to an unexpected cardiac signal.
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the ECG Manual.
After the primary CSR cut-off date is reached, ECGs will be performed at the discretion of the 
investigator and will be recorded on an unscheduled CRF page. These ECGs will not be 
reviewed by the central laboratory.
Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events CRF page. All eligibility and patient 
management decisions should be made based on the local reading of the ECG.
7.2.3
Pharmacokinetics and immunogenicity assessments
The following PK parameters will be determined for LAG525 alone, LAG525 in combination 
with PDR001 and PDR001 in combination with LAG525 using non-compartmental methods: 
Cmax, Tmax, AUC0-tlast (AUC0-336h - Cycle 1 Day 1 and Cycle 3 Day 1), time to last 
measurable concentration (Tlast), t1/2, and the accumulation ratio of LAG525 and PDR001. 
 
.
The data will be analyzed- using WinNonlin Phoenix (Pharsight Corporation; Mountain View, 
CA). PK profiles to assess PK properties of single-agent LAG525 and LAG525 in combination 


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with PDR001 will be collected from all enrolled patients. Please refer to Table 7-6 for details 
on PK and immunogenicity (IG) sample collections. For patients who switch from single-agent 
LAG525 to LAG525 in combination with PDR001, immunogenicity samples will be collected 
as unscheduled assessments (instead of their standard PK collection schedule) on Day 1 pre-
dose for the first 6 cycles upon switch to the LAG525 in combination with PDR001, and PK 
blood samples will be collected on Days 1 (pre-infusion) and 8 as unscheduled assessments 
(instead of their standard PK collection schedule) for the first cycle upon switch to the LAG525 
in combination with PDR001.
If the dosing of Cycle 3 Day 1 is delayed, the PK sampling for PK profile should be delayed 
accordingly to match the scheduled time points for cycle 3 as outlined in Table 7-6. PK and IG 
samples will be collected also at the End of Treatment Visit and in the event of a clinically 
significant AE (such as infusion reaction/anaphylaxis) or if IG is suspected, at which time those 
samples could be used to measure any relevant biomarkers, to understand the infusion 
reaction/adverse event better. After the primary CSR data cut-off date is reached, no additional 
PK and IG samples will be collected for the patients still on-going on the study.
 
 
 
Table 7-6
Pharmacokinetic blood collection log for LAG525 alone, LAG525 in 
combination with PDR001 and PDR001 in combination with LAG525 in 
all patientsb
Cycle
Day
Scheduled Time Point (h)a, f
Analytesc d
1
1
Pre-infusion of Cycle 1
mAb and IG
1
1
1h post infusion (± 5 min)
mAb
1
2e
24h post infusion (± 2h)*
mAb
1
8
168h post infusion (± 8h)*
mAb
1
11e
240h post infusion (± 24h)*
mAb
1
15
Q2W: Pre-infusion / 336h post infusion (±24h)*
Q3W: 336h post infusion (±24h)*
Q4W: 336h post infusion (±24h)* 
mAb
2
1
Q2W: Pre-infusion*
Q3W: Pre-infusion / 504h post infusion (±24h)*
Q4W: Pre-infusion / 672h post infusion (±24h)*
mAb and IG
2
1e
1h post infusion (± 5 min)
mAb
3
1
Pre-infusion of Cycle 3
mAb and IG
3
1
1h post infusion (± 5 min)
mAb
3
2e
24h post infusion (± 2h)*
mAb
3
8
168h post infusion (± 8h)*
mAb
3
11e
240h post infusion (± 24h)*
mAb
3
15
Q2W: Pre-infusion / 336h post infusion (±24h)
Q3W: 336h post infusion (±24h)
Q4W: 336h post infusion (±24h) *
mAb


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Cycle
Day
Scheduled Time Point (h)a, f
Analytesc d
4
1
Q2W: Pre-infusion
Q3W: Pre-infusion / 504h post infusion (±24h)
Q4W: Pre-infusion / 672h post infusion (±24h)* )
mAb and IG
5
1
Pre-infusion of Cycle 5
mAb and IG
5
1e
1h post infusion (± 5 min)
mAb
6
1
Pre-infusion of Cycle 6
mAb and IG
6
1e
1h post infusion (± 5 min)
mAb
EOT
mAb and IG
Unscheduledg
mAb and IG
a. Time points are taken from the infusion completion time.
b. PK samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will need 
to be flushed with 10 mL of saline.
c. Analytes for PK (mAb) will include LAG525 alone, LAG525 in combination with PDR001PDR001 in 
combination with LAG525, and analytes for IG will include LAG525 alone, LAG525 in combination with 
PDR001, PDR001 in combination with LAG525
 
e. PK samples to be collected at this timepoint for Phase I patients only
f.
For LAG525 in combination with PDR001 patients, the 1-hour post infusion sample should be taken after each
infusion
g. For patients who switch from single-agent LAG525 to LAG525 in combination with PDR001, immunogenicity 
samples will be collected as unscheduled assessments (instead of their standard PK collection schedule) on 
Day 1 pre-dose for the first 6 cycles upon switch to the LAG525 in combination with PDR001, and PK blood 
samples will be collected on Days 1 (pre-infusion) and 8 as unscheduled assessments (instead of their 
standard PK collection schedule) for the first cycle upon switch to the LAG525 in combination with PDR001.  
*Collection of these samples may be stopped if sufficient data have been collected
7.2.3.1
Bioanalytics
Bioanalysis for pharmacokinetic studies will employ 2 validated assays:
1. The assay to quantify LAG525 and PDR001 will be a validated LCMS. 
2. The assay to quantify and assess the IG against LAG525 and PDR001 will be using a 
validated homogeneous ELISA. 
7.2.3.2
PK and immunogenicity sample handling, labeling, and shipping 
instructions
Blood samples should be collected from the arm opposite from the investigational drug 
infusion, or from another site. A total of 5 mL of blood will be collected at each time point. 
For time points when LAG525 or PDR001 (mAb) PK and IG are to be measured, a single blood 
sample will be collected for both IG and PK. After clotting and centrifugation, the resulting 
serum will be separated in aliquots and will be stored frozen until analysis. Please see the 
Laboratory Manual for detailed instructions about collection, handling and shipment of samples.
The actual collection date and time of each sample will be entered on the 
Pharmacokinetics/Immunogenicity Blood Collection eCRF pages.


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 150 days following the last dose of study treatment. After initiation of 
new post-treatment antineoplastic therapy, only AEs suspected to be related to study treatment 
will be collected in the Adverse Events CRF. Adverse events (including lab abnormalities that 
constitute AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study but is collected as a seriousness 
criterion. Information about deaths will be collected through a Death form.


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The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC or as per RECIST), should not be reported as a serious adverse 
event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST or 
irRC. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event.
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study.
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
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If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE.
8.2.2
Reporting
For patients who sign the study ICF, SAE collection starts at time of main study informed 
consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 150 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. If a 
patient starts a post treatment antineoplastic therapy, then only SAEs suspected to be related to 
study treatment will be reported.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after this 150 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English [For Japan: sites participating in FIH studies must complete the SAE report 
form in English], and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the Novartis study treatment, an oncology Chief Medical Office and Patient Safety
(CMO&PS) department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 


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accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. After the mother has provided consent, these data will be 
collected for up to 12 months after the birth of the child.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology CMO&PS. Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment and any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.5
Data Monitoring Committee
A data monitoring board will not be used for this study. This is an open-label, Phase I-II study 
in which all patients receive either LAG525 or the combination of LAG525 with PDR001. 
Novartis will have access to the Safety Data on a regular basis. Novartis will host investigator 
teleconferences on a regular basis during the study. Further, during the phase I part of the study 
Novartis and the investigators will meet at the end of each treatment cohort to discuss and 
evaluate all of the gathered safety data. At the dose escalation teleconference the clinical course 
(safety information including both DLTs and all CTCAE Grade 2 or higher toxicity data during 
the DLT observation period, and PK data) for each patient in the current dose cohort will be 
described in detail. Updated safety data on other ongoing patients, including data in later cycles, 
will be discussed as well.
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the BLRM with EWOC, and a medical review of relevant clinical, PK and 
laboratory data. Novartis and the investigator parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or recruit an 
additional cohort of patients at the current dose level Section 10.4.2, Section 10.7.


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During the phase II part of the study Individual patient data will be reviewed on an ongoing 
basis. Overall response rate (ORR) per RECIST V1.1, ORR per irRC and aggregate safety data 
will be monitored quarterly by the study team across the duration of the trial. The data review 
and analysis will be based on the available investigator reported data in the clinical database at 
that time Section 10.7.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories. ECG data collected during the study will be 
reviewed and processed centrally by a specialist CRO. During the course of the study, Novartis 
may decide to have a central review of the radiological assessments performed. In such case, 
the investigator’s staff will be instructed on how to send data from these radiological 
assessments to a Contract Research Organization (CRO) for central review when needed. 
Designated investigational site staff will enter the information required by the protocol into the 
appropriate eCRF and/or designated laboratory requisition forms. Field monitors will review 
the eCRFs and laboratory paper requisition forms for accuracy and completeness and instruct 
site personnel to make any required corrections or additions. One copy of the requisition form 
will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff is 
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Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized using 
descriptive statistics (continuous data) and/or contingency table (categorical data) for 
demographic and baseline characteristics, efficacy measurements, safety measurements and all 
relevant PK 
 measurements. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented.
The study data will be analyzed and reported based on all patients’ data of the dose escalation 
and expansion parts up to the time when all patients have potentially completed at least six 
cycles of treatment or discontinued the study. Any additional data for patients continuing to 
receive study treatment past the data cutoff date for the primary Clinical Study Report, as 
allowed by the protocol, will be reported at completion of the study as defined in Section 4.3.
The following rules will be followed for reporting results unless stated otherwise:

For the phase I part data will be analyzed by Arm and cohorts treated with the same dose or 
dose combination (dose levels and schedules) will be pooled into a single treatment group 
by Arm. All summaries, listings, figures and analyses will be performed by treatment group 
and Arm. Arms to be analyzed are:

Arm A: Single-agent LAG525

Arm B: Combination LAG525 + PDR001

Arm C: Single-agent LAG525 dose escalation in Japanese patients

For the phase II, all summaries, listings, figures for primary efficacy analysis and safety 
analyses will be presented by disease group and/or by dose group for one or more disease 
groups whenever applicable. Patients from the expansion part will be classified according 
to the disease group to which they were assigned at baseline based on the disease type.

The different groups to be analyzed are:

Group 1: single-agent LAG525, NSCLC (naïve to PD-1/PD-L1)

Group 2: single-agent LAG525, Melanoma (naïve to PD-1/PD-L1)

Group 3: single-agent LAG525, Renal cancer (naïve to PD-1/PD-L1)

Group 4: single-agent LAG525, NSCLC (pre-treated with PD-1/PD-L1)

Group 5: single-agent LAG525, Melanoma (pre-treated with PD-1/PD-L1)


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
Group 11: single-agent LAG525, Renal cancer (pre-treated with PD-1/PD-L1)

Group 6: combo LAG525+PDR001, NSCLC (naïve to PD-1/PD-L1)

Group 7: combo LAG525+PDR001, Melanoma (naïve to PD-1/PD-L1)

Group 8: combo LAG525+PDR001, Renal cancer (naïve to PD-1/PD-L1)

Group 9: combo LAG525+PDR001, NSCLC (pre- treated with PD-1/PD-L1)

Group 10: combo LAG525+PDR001, Melanoma (pre-treated with PD-1/PD-L1)

Group 12: combo LAG525+PDR001, Renal cancer (pre-treated with PD-1/PD-L1)

Group 13: combo LAG525+PDR001, Mesothelioma (naïve with PD-1/PD-L1

Group 14: combo LAG525+PDR001, TNBC (naïve with PD-1/PD-L1)

Group 15: combo LAG525+PDR001, Mesothelioma (pre-treated with PD-1/PD-L1)

Group 16: combo LAG525+PDR001, TNBC (pre-treated with PD-1/PD-L1)
Patients in groups 1 to 5 and 11 will receive the recommended dose of single-agent LAG525; 
patients in groups 6 to 10 and 12 to 16 will receive the recommended combination doses of 
LAG525 and PDR001.
Note: patients from the dose escalation and the expansion will not be pooled in any analyses 
unless otherwise specified.
Alternative dosing (i.e. flat dose (mg) and/or dosing schedules (e.g. Q4W)) may be 
implemented during the study as described in Section 6.1.1. Patients treated with flat dosing 
(mg) or an alternative dosing schedule will be analyzed as separate treatment groups unless 
otherwise specified. Details on dose pooling will be provided in the reporting and analysis plan 
(RAP).
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.
10.1
Analysis Sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of assigned 
single-agent LAG525, or at least one full or partial dose of assigned combination of study drugs. 
Patients will be analyzed according to the planned treatment. The FAS will be used for all 
listings of raw data. Unless otherwise specified, the FAS will be the default analysis set used 
for all analyses.
10.1.2
Safety Set
The Safety Set includes all patients from the FAS who have received at least one dose of 
LAG525 or PDR001. Patients will be classified according to treatment received, where 
treatment received is defined as:
1. The treatment assigned if it was received at least once, or
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.


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The safety set will be used for the safety summary of the study.
10.1.3
Per-Protocol Set
The Per Protocol Set (PPS) consists of a subset of FAS patients in the phase II part who meet 
the following criteria:

Presence of at least one measurable lesion according to RECIST 1.1 as per Appendix 1

At least 2 post-baseline tumor assessments (unless disease progression is observed before 
that time)

Have received the planned treatment

Have not been pre- treated with PD-1 or PD-L1 inhibitors except patients in the pretreated 
groups, who must have previously received a PD-1- or PD-L1-directed therapy.
Patients will be classified according to planned treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint Section 10.4. If the PPS and the FAS are 
identical, then analyses described by the PPS below will not be performed.
10.1.4
Dose- Determining Analysis Set
Single-agent LAG525 escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during Cycle 1.
A patient is considered to have met the minimum exposure criterion if having received at least 
two of the planned dose of LAG525 during Cycle 1 for the Q2W schedule or at least one planned 
dose of LAG525 during Cycle 1 for the Q3W and Q4W schedules. Patients who do not 
experience a DLT during the first cycle are considered to have sufficient safety evaluations if 
they have been observed for ≥ 28 days following the first dose (21 days for patients on Q3W 
dosing schedule), and are considered by both the Sponsor and Investigators to have enough 
safety data to conclude that a DLT did not occur.
For patients who switch from single agent LAG525 to combination with PDR001, the DLTs 
occurring after the switch will not be considered in the BLRM.
Combination of LAG525 and PDR001 dose escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during the first two cycles.
A patient is considered to have met the minimum exposure criterion if both of the following 
criteria are met
1. The patient has received at least three doses of LAG525  during the first 2 cycles for the 
Q2W schedule or at least two doses of LAG525 during the first 2 cycles for the Q3W and 
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2. The patient has received at least three doses of PDR001  during the first 2 cycles  for the 
Q2W schedule or at least two doses of PDR001 during the first 2 cycles  for the Q3W and 
Q4W schedules
Patients who do not experience a DLT during the first two cycles are considered to have 
sufficient safety evaluations if they have been observed for ≥ 56 days following the first dose 
(42 days for patients on Q3W dosing schedule), and are considered by both the Sponsor and 
Investigators to have enough safety data to conclude that a DLT did not occur.
In the dose escalation part, patients who do not meet these minimum safety evaluation 
requirements will be regarded as ineligible for the DDS and an additional patient(s) may be 
recruited.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable PK data. The PAS will be used for all PK analyses.
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of analysis.
10.2
Patient demographics / other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be listed in detail.
Qualitative data (e.g. performance status) and quantitative data (e.g. weight) will be 
summarized by appropriate descriptive statistics for each treatment group in phase I and for 
each group in phase II.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
For each of LAG525 and PDR001, the actual dose and duration in days of treatment as well as 
the dose intensity (actual dose received/actual duration) and relative dose intensity (the ratio of 
dose intensity to planned dose/planned duration) will be listed and summarized by means of 
descriptive statistics by treatment group. Categories for relative dose intensity of LAG525 or 
PDR001 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The 
number and proportion of patients within each category will be presented by treatment group.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient and summarized by ATC term and treatment group.
The reason for discontinuation from treatment will be summarized and listed, along with dates 
of first and last dose of LAG525 and PDR001 (if applicable), duration of exposure to LAG525 
and PDR001 (if applicable) and date of discontinuation for each patient.
Compliance with the protocol will be assessed by the number and proportion of patients with 
protocol deviations. Protocol deviations will be identified prior to database lock and will be 
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10.4
Primary Objective
Phase I part:
To estimate the recommended phase 2 dose (RP2D) or the maximum tolerated dose (MTD) for 
single-agent LAG525 (including for Japanese patients) and for the combination of LAG525 and 
PDR001.
Phase II part:
To assess preliminary anti-tumor activity of single-agent LAG525 and combinations of 
LAG525 and PDR001.
10.4.1
Variable
Phase I
For the single-agent LAG525 dose escalation arm, the primary variable is the incidence of DLTs 
in the first cycle of treatment. For the combo dose escalation arm, the primary variable is the
incidence of DLTs in the first two cycles of treatment. Estimation of the MTD(s)/RP2D(s) will 
be based upon the estimation by the BLRM of the probability of a DLT in the DLT window for 
patients in the dose-determining set. In addition, the dose-exposure relationship for LAG525 
and PDR001 will be estimated and used to support dose decisions.
Phase II
The primary variable is the Overall Response Rate (ORR), defined as the proportion of patients 
with a best overall response of complete response (CR) or partial response (PR) based on local 
Investigator assessment, as defined in RECIST v1.1. Estimation of the true ORR in this part of 
the study will be based upon the observed ORR for patients in FAS, using a Bayesian analysis.
10.4.2
Statistical hypothesis, model, and method of analysis
Phase I
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used to make dose recommendations and estimate 
the MTD(s)/ RP2D(s) during the dose escalation part of the study. The BLRM will be fit on the 
dose-limiting toxicity data (i.e. absence or presence of DLT) during the DLT window 
accumulated throughout the dose escalation to model the dose-toxicity relationship. In the 
single-agent LAG525 dose escalation part, the dose-toxicity (DLT) relationship is described by 
the following 2-parameter BLRM:
logit(π1(d1)) = log(α1) + β1log(d1/d1*), α1>0, β1>0
where logit(π1(d1))= log (π1(d1)/(1-π1(d1))), and π1(d1) is the probability of a DLT at dose d1, 
where d1 represents the Q2W dose of LAG525. Doses are rescaled as d1/d1* with reference dose 
d1*=3 mg/kg of LAG525. As a consequence α1 is equal to the odds of DLT rate at d1*. Note 
that for a dose equal to zero, the probability of toxicity is zero.


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For Japanese patients, the same model as above will be applied to guide single agent dose 
escalation decisions. Currently available information about the dose-DLT relationships of 
single-agent LAG525 in Arm A will be used to derive informative priors for the BLRM 
parameters describing the dose-DLT relationships of this agent taking into consideration the 
heterogeneity between the global population and Japanese patients. For further details on the 
statistical model including the prior specification for the model parameters refer to in Appendix 
14.4 (Appendix 4)
In the dose escalation for the combinations, the dose-toxicity (DLT) relationship is modeled by 
a 5-parameter BLRM as follows. Let π1(d1) be the probability of DLT if LAG525 is given as a 
single agent at Q2W dose d1, and π2(d2) the probability of DLT if PDR001 is given as a single 
agent at Q2W dose of d2. π12(d1,d2) denotes the probability of DLT if LAG525 is given in 
combination with PDR001 at Q2W dose d1 of LAG525 and Q2W dose d2 of PDR001. The 
possibility of synergism or antagonism between the safety profiles of the two drugs is captured 
in the model of odds of DLT rate with combination doses.
LAG525: logit(π1(d1)) = log(α1) + β1log(d1/d1*)
PDR001: logit(π2(d2)) = log(α2) + β2log(d2/d2*)
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2))
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 3 mg/kg and d2*= 3 mg/kg are the reference 
doses of LAG525 and PDR001 respectively, α1, α2, β1, β2 > 0 and -∞ < η < ∞ is the interaction 
coefficient.
At the time of each LAG525+PDR001 dose escalation analysis, DLT data up to, and including, 
the last completed cohort from the single agent dose escalation will be included in the 
LAG525+PDR001 BLRM. Single agent LAG525 data will be incorporated directly into the 
BLRM since this data comes from the same study. Single agent PDR001 data from study 
PDR001X2101 dose escalation will also be utilized. In order to account for between study 
variability, the DLT data obtained from PDR001X2101 will be discounted (e.g. using down-
weighting approach).
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions for the BLRM are derived based on available pre-clinical data on 
LAG525 and PDR001 and also clinical data for nivolumab and pembrolizumab. For further 
details on the BLRM model including the prior specification for the model parameters, and 
examples of hypothetical decisions that may be followed during the dose escalation, refer to 
Appendix 14.3.1.
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels (or combinations) are obtained. Dose recommendation will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories:

[0,16%] under-dosing

[16%,33%] targeted toxicity

[33%,100%] excessive toxicity


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Dose recommendation will also be guided by the EWOC principle, which mandates the dose 
for the next cohort to have less than 25% chance of excessive toxicity. The final estimate of the 
MTD(s)/ RP2D(s) will also satisfy this condition.
In case of changes in dosing schedule during dose-escalation, a BLRM of the same functional 
form described in Appendix 14.3.1 will be used to estimate the dose-DLT relationship for each 
schedule based on a newly derived prior incorporating the historical trial data and the on-study 
data from previous schedule. At each time the model is updated, all available information on 
the dose-DLT relationship from all explored dosing schedules will be used. In order to account 
for between schedule variability in the assessment of a given dosing schedule, the DLT data 
obtained from other explored dosing schedules will be down-weighted. A similar approach will 
be taken in the event of a change from weight-based dosing to flat dosing. A new BLRM with 
the same functional form will be developed to evaluate the flat dose. All DLT data obtained 
from the weight-based dosing cohorts will be incorporated and down-weighted appropriately.
Phase II
A Bayesian design will be used in order to estimate ORR within each group as defined in 
Section 4.1, and it will be used to provide inferential summaries (e.g., mean, median, interval 
probabilities) in relation to the patient population.
Each group will enroll approximately 20 patients, and may be extended to 40 patients if at least 
3 patients have an objective response for NSCLC, renal cancer, melanoma and mesothelioma,
and at least 2 patients have an objective response for TNBC as the target ORR is lower for 
TNBC. The primary analysis will be performed when all patients have completed at least 6 
cycles of treatment or discontinued prior to that time for any reason.
For a Bayesian design, a prior distribution for the parameter of interest, ORR, must be specified. 
For the current study, the prior clinical assumption for single-agent LAG525 and its 
combination with PDR001 in the selected patient populations is used in order to derive a 
minimally informative unimodal Beta prior distribution that reflects the level of uncertainty 
around ORR before starting the current trial. The prior mean ORR is conservatively set to be 
equal to 20% and the parameters of the minimally informative Beta prior distribution of ORR 
have been set up as follows:

a/(a+b) = 0.2

a = 0.25

b = 1.0
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. See sample size estimation in section 10.8.
Single-agent LAG525 (groups 1 to 5 and group 11): Estimates of the ORR for each group 
along with mean, median, standard deviation, and 95% credible intervals and the interval 
probabilities for the true ORR lying within [0%, 10%], [10%, 20%], [20%, 30%], [30%, 50%] 
and [50%, 100%] will be presented.
If the observed ORR is equal to or greater than 20% for NSCLC and renal cancer (i.e. ≥ 8 
responses (CR or PR) out of 40 patients) and 30% for melanoma (i.e. ≥ 12 responses [CR or 


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PR) out of 40 patients), then this will be considered as preliminary evidence of antitumor 
activity of single-agent LAG525 in the respective patient groups.
Note that for a sample size of n = 40,

for NSCLC and renal cancer, if the observed ORR is 20% then the posterior probability of 
true ORR greater than 15% is 78.2%.

for melanoma, if the observed ORR is 30% then the posterior probability of true ORR 
greater than 20% is 92.3%.
LAG525+PDR001 combination (groups 6 to 10 and groups 12 to 16): Estimates of the ORR 
for each group along with mean, median, standard deviation, and 95% credible intervals and 
the interval probabilities for the true ORR lying within [0%, 20%], [20%, 30%],[30%, 45%], 
[45%, 60%] and [60%, 100%] will be presented.
If the observed ORR is equal to or greater than 30% for NSCLC, mesothelioma and renal cancer 
(i.e. ≥ 12 responses (CR or PR) of out 40 patients), 20% for TNBC (i.e. ≥ 8 responses [CR or 
PR] of out 40 patients) and 45% for melanoma (i.e. ≥ 18 responses [CR or PR] of out 40 
patients), then this will be considered as preliminary evidence of antitumor activity of 
LAG525+PDR001 in the respective patient group.
Note that for a sample size of n = 40,

for NSCLC, mesothelioma and renal cancer, if the observed ORR is 30% then the 
posterior probability of true ORR greater than 20% is 92.3%.

for TNBC, if the observed ORR is 20% then the posterior probability of true ORR greater 
than 10% is 96.6%.

for melanoma, if the observed ORR is 45% then the posterior probability of true ORR 
greater than 30% is 97.2% (See Section 10.8).
10.4.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the 
primary analysis, although their data will be used for all remaining analyses.
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be 
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST 1.1 as per Appendix 1.
Other missing data will simply be noted as missing on appropriate tables/listings.
10.4.4
Supportive analyses
For the phase I part, dose-exposure relationships will be estimated for LAG525 and PDR001 
via Bayesian linear models, in order to further guide the dose recommendation to targeted 
exposure of LAG525 and PDR001. Further details will be given in the RAP.

From the estimation of the two dose-exposure models, the following posterior summaries 
will be derived for each dose combination: Mean, median, standard deviation and 95%-
credible interval for the exposure of both drugs

The probability that the true AUC(0-336h) after first dose of treatment achieves the target 
exposure.


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For the phase II part, the primary analysis on ORR will be repeated using the PPS.
If there are a substantial number of patients receiving palliative radiotherapy, sensitivity 
analyses of ORR will be performed where the tumor response assessments are censored at the 
time of palliative radiotherapy. BOR is determined by the best response recorded between the 
date of first dose of treatment and date of objectively documented progression or date of 
subsequent anticancer therapy (including on-treatment palliative radiotherapy of non-target 
lesions), whichever occurs first.
In addition, a Bayesian hierarchical model will be applied to the overall response data from 
patients in the phase II part. Response rates j will be inferred for j = 1,…, 16, for groups 1 to 
16 respectively.
For each group j, the number of responders follows a binomial distribution
rj ~ Bin( nj, j )
We further let the parameters j = log(j /(1-j)) be either exchangeable with some of the other 
group parameters, or non-exchangeable with any of them. Based on the number of groups in 
the phase II part, we allow for two exchangeability distributions, which, for example, accounts 
for the case where some indication show no activity and some are promising.
Thus, for each group j three possibilities arise, with respective probabilities pj = ( pj1, pj2, pj3 ), 
as follows:
1. With probability pj1 the parameter j follows a normal distribution with exchangeability 
parameters 1 and 1:
j ~ N(1,12)
2. With probability pj2 , j follows a normal distribution with exchangeability parameters 
2 < 1 and 2:
j ~ N(2,22)
3. With remaining probability pj3 = 1pj1pj2, j follows a weakly-informative prior 
distribution
j ~ N(mw,vw)
For the detailed specifications of mw, vw, the a-priori weights pj (j=1,…,J), and the prior 
distributions for 1, 1, 2, and 2, see Appendix 14.3.2.
At completion of the study, the HM will be updated with all the data available from the patients 
in the FAS by group. All responses and progressions will be determined as per RECIST v1.1.
Single-agent LAG525 (groups 1 to 5 and group 11): For each of the groups where patients 
take the recommended dose of single agent LAG525, estimates of the ORR along with mean, 
median, standard deviation, and 95% credible intervals and the interval probabilities for the true 
ORR lying within [0%, 10%], [10%, 20%], [20%, 30%], [30%, 50%] and 50%, 100%] will be 
presented.
Success will be declared for the single agent LAG525 if both of the following two criteria are 
fulfilled:


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a. the true ORR for the indication has posterior mean of at least 20%, and
b. there is at least 90% posterior probability that the true ORR exceeds 10%.
LAG525+PDR001 combination (groups 6 to 10 and groups 12 to 16): For each of the groups 
where patients take the recommended combination doses of LAG525+PDR001, estimates of 
the ORR along with mean, median, standard deviation, and 95% credible intervals and the 
interval probabilities for the true ORR lying within [0%, 20%], [20%, 30%],[30%, 45%], [45%, 
60%] and [60%, 100%] will be presented.
Success will be declared for the combo of LAG525 and PDR001 if both of the following two 
criteria are fulfilled:
a. the true ORR for the indication has posterior mean of at least 30%, and
b. there is at least 90% posterior probability that the true ORR exceeds 20%.
Additional supportive 
 analyses will be conducted to support the primary 
objective, if appropriate, and the details of these analyses will be defined in the RAP.
10.5
Secondary Objectives
10.5.1
Key secondary objective(s)
Not applicable
10.5.2
Other secondary objectives
Analysis of efficacy endpoints will be performed separately for the single agent LAG525 arm 
and for the combo arm using the FAS.
Tumor response will be determined per local investigators’ assessment. All efficacy secondary 
endpoints will be defined and analyzed based on tumor assessment by RECIST 1.1 and irRC as 
described in Appendix 14.1 and Appendix 14.2, respectively.
Efficacy endpoints will include ORR, PFS, DOR and DCR for phase I and phase II. In Phase II 
secondary endpoints BOR and ORR will be defined based on irRC only. Definitions for these 
endpoints are provided in Appendix 14.1.
For irRC the key difference from RECIST in the assessments of these endpoints is the 
requirement for confirmation of PD no less than 4 weeks after the criteria for PD are first met. 
The date of the first of these two assessments is then the date of confirmed progression. For 
patients who have ended treatment without a valid confirmation assessment, for the purposes 
of analysis the single assessment of PD will be treated as a confirmed PD. A single assessment 
of PD followed by a subsequent assessment of SD or better will be considered as a pseudo-
progression, and will not be used for analysis.
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. BOR, PFS, DOR and DCR will be listed by patient.
BOR and ORR will be summarized by treatment group for all patients treated in the phase I 
part. The following analyses will be presented by disease group for patients treated in the phase 
II part. 


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
BOR will be summarized

ORR and DCR will be summarized with an accompanying [90%] exact binomial 
confidence interval (CI)

For PFS the survival function will be estimated using the Kaplan-Meier (KM) product 
limit method and displayed graphically. Median duration, with a two-sided [90%] CI, and 
25th and 75th percentiles (Brookmeyer et al 1982, Klein et al 1997) will be presented. KM 
estimates of survival proportions at specified time points, along with corresponding [90%] 
CIs (Greenwood’s formula, Kalbfleisch et al 1980) will also be provided.

For DOR, KM estimates may be provided if sufficient numbers of patients respond.
For patients switching from single-agent LAG525 to combination, efficacy endpoints (like 
BOR, ORR, PFS, etc.) will be censored at the time the patients start receiving PDR001. All 
efficacy assessments from these patients will be listed and the assessments performed under 
combination will be flagged.
Any additional analyses of efficacy endpoints will be described in the RAP.
10.5.3
Safety Objectives
10.5.3.1 Analysis set and grouping for the analyses
For summaries of DLTs, the DDS will be used. For all other safety analyses, the safety set will 
be used. All listings and tables will be presented by treatment group.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
Safety summaries will primarily be based on all data from the on-treatment period. Following 
last administration of study medication, adverse events (including serious adverse events), and 
new antineoplastic therapies are collected for a period of 150 days. Following start of new 
antineoplastic therapy, only study treatment related adverse events will be collected. Select 
summaries of related adverse events will be produced for the overall period starting from the 
first dose of study treatment until the end of the post-treatment period.  
For patients who switch from single-agent LAG525 to combination with PDR001, the on-
treatment period will be defined from day of first dose of study medication to 30 days after the 
last dose of single-agent LAG525.
All safety assessments from these patients will be listed and the assessments performed under 
combination will be flagged.
10.5.3.2 Adverse events (AEs)
Primary summary tables for AEs have to include only AEs that started or worsened during the 
on-treatment period, the treatment-emergent AEs. Additional select summaries will be 


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produced using all related AEs that started or worsened during the combined on-treatment and 
post-treatment periods. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of AE, relation to study treatment by treatment group.
Serious adverse events and non-serious adverse events will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 the study’s biostatistical and reporting team will grade laboratory data accordingly. 
For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values 
not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

Frequency table for newly occurring on-treatment grades 3 or 4 (see below for details).

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value.

Listing of all clinically relevant laboratory data with values flagged to show the 
corresponding CTCAE grades and the classifications relative to the laboratory normal 
ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP.
10.5.3.4 Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs
Definitions of notably abnormal results will be specified in the RAP.

shift table baseline to worst on-treatment result
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.


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10.5.3.6 Tolerability
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be 
listed by patient and summarized (Section 10.3).
10.5.3.7 Pharmacokinetics
The pharmacokinetic parameters that will be assessed are presented in Table 10-1.
Table 10-1
Pharmacokinetic Parameters to be analyzed
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL
The total body clearance of drug from the plasma (volume x time-1)
Vz
The apparent volume of distribution during terminal phase (associated with z) (volume)
AR
Accumulation Ratio=Cmax (multiple Dose)/Cmax (single dose)
PAS will be used in all pharmacokinetic data analysis and PK summary statistics. PK data from 
Japanese patients treated on the single agent Japanese dose escalation (Arm C) will be analyzed 
separately.
Pharmacokinetic variables:
The following pharmacokinetic parameters will be determined by profile using non-
compartmental method(s) for single agent LAG525, LAG525 in combination with PDR001and 
PDR001 in combination with LAG525:

AUCinf, AUClast (AUC0-336h), Cmax, Tmax, T1/2, CL, Vz and accumulation ratio.
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data listings. 
Concentrations below the limit of quantitation will be treated as zero in summary statistics.
Descriptive statistics of all pharmacokinetic parameters will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter.
Summary statistics will be presented for LAG525 serum concentrations at each scheduled time 
point. Descriptive graphical plots of individual serum concentration versus time profiles and 
mean concentration versus time profiles will be generated.
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation (LLOQ) will be handled as zero in summary statistics, and reported 
as is in data listings. Any missing pharmacokinetic parameter data will not be imputed.


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Further analyses may be conducted using population PK approaches.
 
 
Any analyses 
performed will be specified either in the RAP prior to clinical database lock or in a stand-alone 
analysis plan document. All analyses will be reported either in the CSR or a stand-alone report.
Dose proportionality
The analysis of dose proportionality will be conducted for AUC and Cmax of single agent 
LAG525, LAG525 in combination with PDR001 and PDR001 in combination with LAG525 
using a power model on log-transformed scale. The log-transformed PK parameters will each 
be regressed onto a fixed factor for log (dose). The 90% confidence interval (CI) of the slope 
for each PK parameter will be computed from the model and presented in a summary table.


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10.7
Interim Analysis
No formal interim analyses are planned.
However, in phase I, the dose-escalation design foresees that decisions based on the current 
data are taken before the end of the study. More precisely, after each cohort in the dose 


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escalation part, the next dose will be chosen depending on the observed data (based on safety, 
tolerability, PK, PD and efficacy data, guided by the recommendations from the BLRM of DLT 
using EWOC, and recommendations from participating investigators). Details of this procedure 
and the process for communication with Investigators are provided in Section 6.2.3.
Data from patients in the phase II part will be reviewed on an ongoing basis to monitor the 
safety and tolerability of the RP2D in that part of the study. The sample size in any of the 16
groups (1 to 16) may be extended to approximately 40 patients, if at least 3 patients have a 
response (PR or CR) per RECIST 1.1 or irRC for NSCLC, melanoma, renal cancer and 
mesothelioma, and if at least 2 patients have a response (PR or CR) per RECIST 1.1 or irRC 
for TNBC. The Investigators and Novartis study personnel will make the decision based on a 
synthesis of all relevant data available including safety, PK 
 information.
10.8
Sample size calculation
Phase I
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD(s)/ RP2D(s) level, as described in Section 6.2.3. Multiple cohorts may 
be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD(s)/ RP2D(s) for further elaboration of 
safety and pharmacokinetic parameters as required. At least 21 patients are required to be 
treated in the single agent LAG525 dose escalation (Arm A), at least 12 patients are required to 
be treated in the Japanese dose escalation (Arm C), and at least 15 patients are required to be 
treated in the combo dose escalation (Arm B), for the model to have reasonable operating 
characteristics relating to estimation of the MTD.
Phase II
Approximately 20 patients will be initially enrolled to each of the groups 1 to 16. Any of the 16
groups may be extended to approximately 40 patients.
Single-agent LAG525 (groups 1 to 5 and group 11):
Assume that efficacy will be claimed for single agent LAG525 if observing an ORR of ≥ 20% 
for NSCLC or renal cancer and ≥ 30% for Melanoma, the operating characteristics of the design 
are provided in Table 10-2, including the probability of stopping the enrollment at 20 patients 
(fewer than 3 responses in the first 20 patients), and the probabilities to extend the enrollment 
to 40 patients and observe an ORR ≥ 20% and ≥ 30%.
Specifically,

If the true ORR is 10% for NSCLC or renal cancer (i.e. in the unacceptable efficacy 
range), the probability of observing an ORR ≥ 20% is 3.8% (< 5%).

If the true ORR is 15% for melanoma (i.e. in the unacceptable efficacy range), the 
probability of observing an ORR ≥ 30% is 1.2% (< 5%).

If the true ORR is 30% for NSCLC or renal cancer (i.e. in the clinically significant 
efficacy range), the probability of observing an ORR ≥ 20% is 92.6%.


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
If the true ORR is 40% for melanoma (i.e. in the clinically significant efficacy range), the 
probability of observing an ORR ≥ 30% is 92.8%.
Table 10-2
Operating characteristics of the design (single agent LAG525)
True 
ORR
Probability to 
observe <3 
responses in first 
20 patients
Groups 1,3,4 and 11: NSCLC and Renal 
cancer
Groups 2 & 5: Melanoma
probability to observe an ORR ≥ 20% 
with 40 patients
probability to observe an ORR 
≥ 30% with 40 patients
10%
67.7%
3.8%
< 0.1%
15%
40.5%
22.5%
1.2%
20%
20.6%
53.1%
8.7%
25%
9.1%
78.8%
28.4%
30%
3.5%
92.6%
55.8%
40%
0.4%
99.5%
92.8%
Combination LAG525+PDR001 (groups 6 to 10 and groups 12 to 16):
Assume that efficacy will be claimed for the combination of LAG525 + PDR001 if observing 
an ORR of ≥ 30% for NSCLC or renal cancer or mesothelioma, ≥ 20% for TNBC and ≥ 45% 
for melanoma, the operating characteristics of the design are provided in Table 10-3 and Table 
10-4, including the probability of stopping the enrollment at 20 patients (fewer than 3 responses 
in the first 20 patients for NSCLC, renal cancer, melanoma and mesothelioma and fewer than 
2 responses in the first 20 patients for TNBC), and the probabilities to extend the enrollment to 
40 patients and observe an ORR ≥ 30% (for NSCLC, renal cancer, mesothelioma), 20% (for 
TNBC) and ≥ 45% % (for melanoma).
Specifically,

If the true ORR is 15% for NSCLC, mesothelioma or renal cancer (i.e. in the unacceptable 
efficacy range), the probability of observing an ORR ≥ 30% is 1.2% (< 5%).

If the true ORR is 30% for melanoma (i.e. in the unacceptable efficacy range), the 
probability of observing an ORR ≥ 45% is 3.2% (< 5%).

If the true ORR is 40% for NSCLC, mesothelioma or renal cancer (i.e. in the clinically 
significant efficacy range), the probability of observing an ORR ≥ 30% is 92.8%.

If the true ORR is 55% for melanoma (i.e. in the clinically significant efficacy range), the 
probability of observing an ORR ≥ 45% is 92.3%.

If the true ORR is 10% for TNBC (i.e. in the unacceptable efficacy range), the probability 
of observing an ORR ≥ 20% is 4.1% (< 5%).

If the true ORR is 30% for TNBC (i.e. in the clinically significant efficacy range), the 
probability of observing an ORR ≥ 20% is 94.2%.


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Table 10-3
Operating characteristics of the design (LAG525+PDR001)
True 
ORR
Probability to 
observe <3 
responses in first 
20 patients
Groups 6,8,9,12,13,15: NSCLC, renal and 
mesothelioma
Groups 7 & 10: melanoma
probability to observe an ORR ≥ 30% 
with 40 patients
probability to observe an ORR 
≥ 45% with 40 patients
15%
40.5%
1.2%
<0.1%
20%
20.6%
8.7%
<0.1%
30%
3.5%
55.8%
3.2%
40%
0.4%
92.8%
31.1%
45%
0.1%
98.2%
56.1%
55%
<0.1%
>99.9%
92.3%
Table 10-4
Operating characteristics of the design (LAG525 + PDR001)
True 
ORR
Probability to observe <2 
responses in first 20 
patients
Groups  14, 16: TNBC
probability to observe an ORR ≥ 20% with 40 patients
10%
39.2%
4.1%
15%
17.6%
24.1%
20%
6.9%
55.7%
25%
2.4%
81.3%
30%
0.8%
94.2%
40%
0.1%
99.8%
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/EC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
 
 
 
 
 
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov, before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 


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of study completion (i.e., LPLV) and those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
References (available upon request)
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Baitsch L, Legat A, Barbara L et al (2012). Extended co-expression of inhibitory receptors by 
human CD8 T-cells depending on differentiation, antigen-specificity and anatomical 
localization. PLoS One 7(8): e30852.
Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of Immune-Related Adverse 
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Camisaschi C, Casati C, Rini F et al (2010). LAG-3 expression defines a subset of 
CD4(+)CD25(high)Fox3(+) regulatory T cells that are expanded at tumor sites. J Immunol, 
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Chen J, Chen Z (2014) The effect of immune microenvironment on the progression and 
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Huang CT, Workman CJ, Flies D et al (2004) Roles if LAG-3 in regulatory T cells. Immunity 
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Huard B, Gaulard P, Faure F et al (1994) Cellular expression and tissue distribution of the 
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Huard B, Mastrangeli R, Prigent P et al (1997) Characterization of the major 
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Keir ME, Butte MJ, Freeman GJ, et al (2008) PD-1 and its ligands in tolerance and immunity. 
Ann Rev Immunol: 26:677–704
Kisielow M, Kisielow J, Capoferri-Sollami G et al (2005). Expression of lymphocyte 
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Leen AM, Rooney CM, Foster AE (2007). Improving T cell therapy for cancer. 2007: 25:243-
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Matsuzaki J, Gnjatic S, Beck A et al (2010) Tumor-infiltrating NY-ESO-1-specific CD8+ T 
cells are negatively regulated by LAG3 and PD1 in human ovarian cancer. Proc Natl Acad Sci 
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PD-1 synergistically regulate T-cell function to promote tumoral immune escape, Cancer 
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the expression of activated T cells. Eur J Immunol 33(4):970-9


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14
Appendices
14.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival 
 
 (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
 
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.28 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.4
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed 
by cytology/histology.
For patients without measurable disease see Section 14.1.26.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.


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
Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) 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.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly
identified by physical exam that is not measurable by reproducible imaging techniques.
14.1.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in Section 
14.1.26.
14.1.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.


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
For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.


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
Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.7
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.4.

Nodal target: See Section 14.1.4.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 


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diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.1.8
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.9
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
14.1.10
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.


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14.1.11
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.1.12
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3. Methodology change See Section 14.1.6.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 


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on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.


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
The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all 
non-nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters.
14.1.13
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline.
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD 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 CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 


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one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

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 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.6.
14.1.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.1.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).


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If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 150 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

-For non-randomized trials where response is the primary endpoint, confirmation is 
needed.

-For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required


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
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:


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
Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
14.1.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.1.19
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.


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14.1.21
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.1.22
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.1.23
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988).


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It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.1.24
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.23. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.


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
at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.25
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page 
 
).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 


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is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.26).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. 
 
If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.26
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.


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For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.1.27
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.1.25, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)


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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
1.=Definitions can be found in Section 14.1.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:


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
Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.28
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.1.29
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.30
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment


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
No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
14.1.31
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting 
.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.1.32
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the investigator or central reader’s response 
assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.


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14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.35
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.36
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.37
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.39
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page 
.


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For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.1.40
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.2
Appendix 2: Guidelines for immune-related response criteria 
(IrRC) using one-dimensional measurements (simulating RECIST 
1.1)
14.2.1
Introduction
The currently used immune-related response criteria (irRC) uses unidimensional measurements 
to assess tumor response and it is an adaptation of the original irRC published by Wolchok 
(Wolchol et al. 2009 and Nishino et al. 2013).
The purpose of this document is to summarize the irRC guidelines in details focusing on 
differences in tumor response assessments between irRC and RECIST v1.1.
The primary difference between irRC and RECIST 1.1 is the definition of progressive disease. 
The definitions of baseline target/non target lesions, number of lesions selected at baseline, the 
criteria for lesion measurement method of evaluation of response and definition of response are 
the same for irRC and RECIST 1.1 and are available in the RECIST 1.1 guidelines (Appendix 
14.1).
14.2.2
New Lesions and non-target lesions
In irRC a new lesion does not automatically indicate progressive disease.
New measurable lesions are added to the sum of diameters of the previously existing target 
lesions, and the sum of diameters is followed at each subsequent tumor assessment.
New measureable lesions are defined using the same criteria as for baseline target lesions in 
RECIST v1.1. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions.  Up to five new measurable lesions (and a 
maximum of two per organ) are allowed in total and will be included in the overall tumor 
assessment.
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 
at baseline and any new non-measurable lesions that have appeared during the study). If after 
worsening a non-target lesion becomes measurable, it should still be followed as a non-target 
lesion. Worsening of non-target lesions and new non-measurable lesions only indicate disease 
progression 
if 
there 
is 
unequivocal 
evidence 
of 
disease 
progression
(Table 14-6).
14.2.3
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions is calculated (at baseline 
and throughout the study). The diameters of any new measurable lesions are included in the 
sum of diameters at each assessment to provide the total tumor burden. At each assessment, 
percent change in the sum of diameters is calculated and compared to baseline or to nadir in 
order to evaluate the target lesion response (including new measurable lesions) (Section 14.2.4). 
This evaluation combined with the status of non-target lesions (baseline and new non-


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measurable lesions) is then used to determinate the overall lesion response. The measurement 
thresholds for irPR and irPD assessment are the same as for RECIST v1.1 (Table 14-6).
14.2.4
Definitions of response categories and evaluation of overall lesion 
response
In irRC, the overall response is primarily based on target lesions (baseline and new measurable 
lesions). The non-target lesions only contribute to define irCR, and irPD in the case of 
unequivocal progression, as shown below in Table 14-6.
Like in RECIST 1.1, irCR and irPR must be confirmed at a new assessment after at least 4 
weeks. Unlike RECIST 1.1, irPD also requires confirmation at a new assessment after at least 
4 weeks.
The response categories are defined as follows:

Immune related Complete Response (irCR): Disappearance of all non-nodal target 
lesions and non-target lesions in two consecutive observations not less than 4 weeks apart. 
In addition, any pathological lymph nodes assigned as target lesions must have a reduction 
in short axis to < 10 mm. (Sum of diameters may be greater than zero at the time of CR, if 
nodal lesions are included as target lesions).

Immune related Partial Response (irPR): At least a 30% decrease in the sum of 
diameters of all target lesions including new target lesions in two consecutive observations 
not less than 4 weeks apart, taking as reference the baseline sum of diameters.

Immune related Progressive Disease (irPD): At least a 20% increase in the sum of 
diameters of all measured target lesions including new measurable lesions. The irPD must 
be confirmed in a second evaluation not less than 4 weeks later, taking as reference the 
smallest sum of diameter of all target lesions recorded at or after baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. Worsening of non-target lesions (existing or new) only indicate 
PD when there is unequivocal evidence of progression, confirmed in a second evaluation 
not less than 4 weeks later.

Immune related Stable Disease (irSD): Neither a sufficient shrinkage to qualify for irPR 
or irCR, nor an increase in lesions which would qualify for irPD.

Unknown (UNK): Progression has not been documented and one or more target lesions or 
new measurable lesions observed at earlier assessment have not been/could not be
assessed or have been assessed using a method significantly different from baseline 
(target lesions) or assessment of first occurrence (for new measurable lesions) that 
prevents reasonable comparison to the prior assessments.
Table 14-6
Overall response at each assessment
Measurable response
Target and new measurable lesions 
(Tumor burden), * (%)
Non-measurable response
Non-target lesions
(both baseline and new non-measurable)
Overall response
Using irRC
- 100
Absent
irCRa
- 100
Stable/not evaluated
irPRa
≤-30
Absent/Stable/not evaluated
irPRa
>-30 and<+20
Absent/Stable/not evaluated
irSD


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≥+20
Any
irPDa
Any
Unequivocal progression
irPDa
*the diameter of new measurable lesions is included in the calculation of the sum of diameters.
a To be confirmed after at least 4 weeks.
If the evaluation of any of the target lesions could not be made during follow-up, the overall 
status must be ‘unknown’ unless progression was documented.
If the evaluation of any non-target lesions is not made, and all target lesions disappeared, irCR 
cannot be determined and overall response must be “irPR”.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the irCR.
14.2.5
Only non-measurable disease at baseline
For patients with only non-measurable disease at baseline, unequivocal progression of non-
target lesions will constitute an irPD (i.e. worsening of the overall tumor burden which is 
substantial enough to lead to discontinuation or change of therapy). In addition, the appearance 
of new lesions (measurable or non-measurable) consistent with unequivocal progression taking 
into account the overall disease burden will constitute an irPD. The absence of all non-target 
lesions and no new lesions will qualify for irCR. Otherwise the overall response will be 
considered as irNon-CR/Non-PD (irNCRNPD) similar to RECIST 1.1. Confirmation of irPD 
and irCR as specified above in (Section 14.2.4) is required. If any baseline non-target lesion or 
a new lesion observed at an earlier post-baseline evaluation was not/could not be assessed at a 
later post-baseline tumor evaluation then the overall response will be irUNK. No confirmation 
is required for irNCRNPD.
14.2.6
Reference (available upon request)
Wolchok JD, Hoos A, O'Day S et al (2009) Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res; 15:7412-20.
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013) Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-Related Response Criteria Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-3943.


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14.3
Appendix 3: Statistical details of Phase I Bayesian logistic 
regression models (BLRM) and Phase II hierarchical models
14.3.1
Phase I BLRM
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used to make dose recommendations and estimate 
the maximum tolerated dose (MTD) and/or identify the recommended dose for Phase II (RP2D)
during the dose escalation part of the study. The use of Bayesian response adaptive models for 
Phase I studies has been advocated by the EMEA guideline on small populations (2006) and by 
Rogatko (2007) and is one of the key elements of the FDA’s Critical Path Initiative.
In the single-agent LAG525 dose escalation part, the dose-toxicity (DLT) relationship is 
described by the following 2-parameter BLRM:
logit(π1(d1)) = log(α1) + β1log(d1/d1*), 
α1>0, β1>0
where logit(π1(d1))= log (π1(d1)/(1-π1(d1))), and π1(d1) is the probability of a DLT at dose d1, 
where d1 represents the Q2W dose of LAG525. Doses are rescaled as d1/d1* with reference dose 
d1*=3 mg/kg of LAG525. As a consequence α1 is equal to the odds of DLT rate at d1*. Note 
that for a dose equal to zero, the probability of toxicity is zero.
In the dose escalation for the combinations, the dose-toxicity (DLT) relationship is modeled by 
a 5-parameter BLRM as follows. Let π1(d1) be the probability of DLT if LAG525 is given as a 
single agent at Q2W dose d1, and π2(d2) the probability of DLT if PDR001 is given as a single 
agent at Q2W dose of d2. π12(d1,d2) denotes the probability of DLT if LAG525 is given in 
combination with PDR001 at Q2W dose d1 of LAG525 and Q2W dose d2 of PDR001. The 
possibility of synergism or antagonism between the safety profiles of the two drugs is captured 
in the model of odds of DLT rate with combination doses.
LAG525: logit(π1(d1)) = log(α1) + β1log(d1/d1*)
PDR001: logit(π2(d2)) = log(α2) + β2log(d2/d2*)
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2))
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 3 mg/kg and d2*= 3 mg/kg are the reference 
doses of LAG525 and PDR001 respectively, α1, α2, β1, β2 > 0 and -∞ < η < ∞ is the interaction 
coefficient.
The Bayesian approach requires the specification of prior distributions for all model parameters. 
This section provides details of the statistical model, the derivation of prior distributions for the 
model parameters, and the properties of the adaptive design (dosing recommendations for 
hypothetical data scenarios and operating characteristics).


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14.3.1.1 Prior specifications for single agent model parameters
Prior for PDR001 parameters (log(α2), log(β2)):
Because more clinical data are available on the class of anti-PD-1 antibody than the anti-LAG-
3 antibody, we first derive the prior for single-agent PDR001. This prior will be checked based 
upon the available single agent data of PDR from CPDR001X2101 study.
This study uses a mixture prior consisting of two components, as specified in Table 14-7. 
Component 1 is the distribution derived based on PDR001 preclinical data and clinical data on 
Nivolumab and Pembrolizumab, and is also the component that reflects the low toxicity profile. 
The assigned weight for component 1 is 80%. Component 2 allows for a case assuming higher 
toxicity. The assigned weight for component 2 is 20%.
Table 14-7
Prior distribution of model parameters – phase I single agent PDR001
Parameter
Means
Standard deviations
Correlation
Weight
Component 1: priors for a low toxicity profile
log(α2), log(β2)
-2.692, -1.26
1.0, 1.0
0
0.8
Component 2: priors for a more toxicity sensitive population
log(α2), log(β2)
-2.3, 0
2, 1
0
0.2
Component 1:
For the intercept parameter log(α2), the prior mean of -2.692 is derived based on the a-priori
median of an assumed 6.3% DLT rate at the reference dose d2*= 3 mg/kg. By setting the 
standard deviation of log(α2) =1, the respective upper bound of the 95% a-priori interval of the 
DLT rate at dose 3 mg/kg is 32.5%, lower than 33%, which represents the a-priori assumption 
that 3 mg/kg of PDR001 is a safe dose.
For the log-slope parameter log(β2), the prior mean of -1.26 and prior standard deviation of 1 
have the following interpretation: when tripling the dose, the odds of having a DLT are 
multiplied by a factor of 3β, i.e., by 1.4 for the median and approximately (1.0, 9.1) for the 95% 
interval. This reflects the a-priori assumption that the dose-DLT curve may be quite flat for the 
anti-PD1 antibody.
Component 2:
This weakly informative bivariate normal prior allows for a case with higher toxicity.
For the intercept parameter log(α2), the prior mean of -2.3 is derived based on the a-priori 
median of an assumed 9.1% DLT rate at the reference dose d2*= 3 mg/kg. By setting the 
standard deviation =2, the respective 95% a-priori interval at dose 3 mg/kg is wide (0.2%, 84%), 
which represents weak prior information.
For the log-slope parameter log(β2), the prior mean of 0 and prior standard deviation of 1 allow 
for very flat to very steep slopes. Therefore, it is a weakly informative prior. The interpretation 
is as follows: when tripling the dose, the odds of having a DLT are multiplied by a factor of 3β, 
i.e., by 3 for the median and (1.2, 2439.2) for the 95% interval.
For both components, the correlation between log(α2) and log(β2) is set to 0.


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Prior for LAG525 parameters (log(α1), log(β1)):
Before observing any clinical data, the DLT profile of single-agent LAG525 is expected to be 
similar to that of single-agent PDR001. Therefore, it is reasonable to use the same mixture prior 
defined in Table 14-7 for (log(α1), log(β1)).
Table 14-8, Table 14-9 and Table 14-10 summarize the DLT rates of the associated prior 
distribution. The doses not meeting the overdose criteria are bold in the table, i.e. it is not 
eligible at the start of the study (under the prior).
Table 14-8
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the mixture prior in Table 14-7)
LAG525 dose 
(mg/kg Q2W)
Prior probabilities that Pr(DLT) is in 
interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16,0.33)
[0.33, 1]
2.50%
50.00%
97.50%
0.3
0.939
0.047
0.014
0.049
0.076
0
0.024
0.252
1 (starting dose)
0.9
0.075
0.026
0.069
0.095
0.001
0.039
0.334
3
0.805
0.134
0.061
0.11
0.133
0.006
0.066
0.518
10
0.615
0.2
0.185
0.205
0.233
0.012
0.114
0.946
Table 14-9
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the Component 1 prior in Table 14-7)
LAG525 dose 
(mg/kg Q2W)
Prior probabilities that Pr(DLT) is in 
interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16,0.33)
[0.33, 1]
2.50%
50.00%
97.50%
0.3
0.948
0.046
0.006
0.048
0.059
0
0.028
0.216
1 (starting dose)
0.918
0.071
0.011
0.064
0.069
0.004
0.041
0.257
3
0.849
0.127
0.024
0.09
0.084
0.009
0.064
0.327
10
0.683
0.211
0.106
0.151
0.154
0.013
0.1
0.603
Table 14-10
Summary of prior distribution of DLT rates – phase I single agent 
LAG525 (derived from the Component 2 prior in Table 14-7)
LAG525 dose 
(mg/kg Q2W)
Prior probabilities that Pr(DLT) is 
in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16,0.33)
[0.33, 1]
2.50%
50.00%
97.50%
0.3
0.898
0.053
0.048
0.056
0.129
0
0.006
0.496
1 (starting dose)
0.821
0.09
0.089
0.095
0.167
0
0.022
0.653
3
0.624
0.162
0.214
0.193
0.231
0.002
0.092
0.838
10
0.345
0.154
0.501
0.42
0.346
0.006
0.332
0.999
Note: bold values indicate doses not meeting the overdose criterion (less than 25% chance of excessive 
toxicity) with the prior information only.
To check the performance of the model, the document summarizes some hypothetical dose 
escalation scenarios. Details regarding dose recommendation are described in Section 10.4.2 of 
the protocol.


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14.3.1.2 Hypothetical dose escalation scenarios for the single-agent LAG525 
arm
In order to show how the Bayesian model performs, different hypothetical dose escalation 
scenarios were investigated. The design should make reasonable dose-recommendations during 
the clinical trial based on the observed DLTs for hypothetical dose escalation scenarios. During 
the study, the decision to dose escalate after completion of a given cohort and the actual dose 
chosen for the subsequent cohort will depend on the recommendation of the BLRM per EWOC 
principle, estimated/predicted exposure at each dose level, and medical review of available 
clinical and laboratory data.
Some hypothetical dose escalation scenarios to illustrate the dose escalation up to the fourth 
dose cohort are listed in Table 14-11. The maximum dose increment allowed in the scenarios 
did not exceed 334% as per escalation rules defined in Section 6.2.3. The recommended next 
dose level satisfied the EWOC principle.
Table 14-11
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent LAG525
Scena
rio
LAG525 Dose level 
(mg/kg)
Np
at
Nt
ox
Next Dose Level 
(NDL)
P(Target) 
NDL
P(Over) 
NDL
Median DLT rate 
(NDL)
1
1
4
0
3
0.101
0.026
0.054
2
1
4
1
3
0.264
0.108
0.121
3
1
4
2
1
0.365
0.221
0.19
4
1
4
0
3
3
0
10
0.146
0.108
0.079
5
1
4
0
3
3
1
3
0.215
0.055
0.098
6
1
4
0
3
3
2
1
0.21
0.036
0.089
7
1
4
0
3
6
0
10
0.126
0.084
0.068
8
1
4
0
3
6
1
10
0.241
0.193
0.137
9
1
4
0
3
6
2
3
0.338
0.089
0.142


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Scena
rio
LAG525 Dose level 
(mg/kg)
Np
at
Nt
ox
Next Dose Level 
(NDL)
P(Target) 
NDL
P(Over) 
NDL
Median DLT rate 
(NDL)
10
1
4
0
3
3
1
3
3
0
10
0.241
0.193
0.137
11
1
4
0
3
3
1
3
3
1
3
0.338
0.089
0.142
12
1
4
0
3
3
1
3
3
2
1
0.254
0.034
0.103
13
1
4
0
3
3
2
1
3
0
3
0.337
0.248
0.191
14
1
4
0
3
3
2
1
3
1
1
0.367
0.064
0.143
15
1
4
0
3
3
2
1
3
2
1
0.506
0.212
0.222
16
1
4
1
3
3
0
10
0.274
0.118
0.128
17
1
4
1
3
3
1
3
0.38
0.15
0.168
18
1
4
1
3
3
2
1
0.416
0.179
0.192
19
1
4
1
3
3
1
3
5
0
10
0.364
0.137
0.16


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Scena
rio
LAG525 Dose level 
(mg/kg)
Np
at
Nt
ox
Next Dose Level 
(NDL)
P(Target) 
NDL
P(Over) 
NDL
Median DLT rate 
(NDL)
20
1
4
1
3
3
1
3
5
1
3
0.463
0.102
0.175
21
1
4
1
3
3
1
3
5
2
1
0.445
0.082
0.166
22
1
3
0
3
5
2
1
3
1
3
0.479
0.182
0.201
23
1
3
0
3
5
2
1
3
1
1
4
0
3
0.429
0.128
0.173
Overall, the model is showing appropriate behaviors, in agreement with clinical sense and 
decision making process. The dose levels investigated correspond to the provisional dose levels 
specified in Section 6.2.2.
14.3.1.3 Prior specifications for LAG525 + PDR001 combination model 
parameters
The 5-parameter BLRM used to guide the dose escalation for the combination of 
LAG525+PDR001 will use DLT information from both dose escalation arms: patients receiving 
the single-agent LAG525 and patients receiving the LAG525+PDR001 combo. At each dose 
escalation meeting, data from the last completed single agent cohort will be incorporated 
directly into the model, without down-weighting. The available single agent data from 
CPDR001X2101 study will also be used to check the prior information for the BLRM model.
The prior distributions of model parameters for single-agent LAG525 and single-agent PDR001 
have been derived in Section 14.3.1.1.
Prior for the interaction parameter η12:
A normal prior distribution for the interaction parameter η12 is to be derived to reflect the current 
uncertainty about the toxicity profile of the combination of LAG525 and PDR001. The risk of 
significant positive interaction between LAG525 and PDR001 cannot be totally excluded. The 
interaction parameter η12 was chosen accordingly but with a degree of uncertainty in order to 
allow for the possibility that the interaction may be positive or negative. Therefore the following 
assumption is made for the interaction parameter:


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
η12 is normally distributed and centered at log (1.5)*(d1/d1*)*(d2/d2*), i.e. 50% increase in 
odds of DLT due to interaction compared to independence at the anticipated combination 
reference dose d1* and d2*.

97.5th percentile of η12 is log (5)*(d1/d1*)*(d2/d2*), i.e.5-fold increase in odds of DLT due 
to interaction compared to independence at the combination reference dose d1* and d2*.
Therefore the prior mean for η12 is 0.405 and the prior standard deviation is 0.614. This allows 
for the potential of both synergism and antagonism between the safety profiles of the two drugs. 
Since the interaction is dose-dependent (see model definition in Section 10.4.2), the prior for 
the interaction parameter has a simple interpretation only at the anticipated combination 
reference dose of LAG525 = 3 mg/kg Q2W and PDR001 = 3 mg/kg Q2W.
Table 14-12 summarizes the prior distributions of the model parameters and Table 14-13
summarizes the corresponding prior distribution for the DLT rates at each provisional dose level.
Table 14-12
Prior distribution of model parameters – phase I LAG525 + PDR001
Parameters
Description
Means
Standard 
deviations
Correlation
Weight
log(α1),log(β1)
LAG525 parameters
-2.692, -1.26
1.0, 1.0
0
0.8
-2.3, 0
2, 1
0
0.2
log(α2),log(β2)
PDR001 parameters
-2.692, -1.26
1.0, 1.0
0
0.8
-2.3, 0
2, 1
0
0.2
η12
Interaction LAG525-
PDR001
0.405
0.614
Table 14-13
Summary of prior distribution of DLT rates – phase I LAG525 + 
PDR001
LAG525 dose 
(mg/kg Q2W)
Prior probabilities that Pr(DLT) is 
in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16,0.33)
[0.33, 1]
2.50%
50.00%
97.50%
PDR001 = 0.3 mg/kg Q2W
0.3
0.834
0.129
0.037
0.097
0.105
0.004
0.066
0.386
1
0.778
0.168
0.053
0.117
0.119
0.009
0.082
0.451
3
0.658
0.241
0.102
0.16
0.148
0.019
0.114
0.61
10
0.448
0.292
0.261
0.264
0.238
0.029
0.181
0.96
PDR001 = 1 mg/kg Q2W
0.3
0.778
0.169
0.053
0.117
0.118
0.009
0.083
0.448
1
0.709
0.216
0.075
0.14
0.13
0.015
0.102
0.509
3
0.556
0.3
0.144
0.191
0.161
0.026
0.143
0.673
10
0.309
0.288
0.403
0.339
0.259
0.033
0.264
0.975
PDR001 = 3 mg/kg Q2W
0.3
0.655
0.243
0.102
0.16
0.147
0.019
0.116
0.599
1 
0.551
0.303
0.146
0.192
0.161
0.026
0.144
0.663
3
0.35
0.329
0.321
0.282
0.208
0.035
0.226
0.831
10
0.211
0.135
0.654
0.534
0.339
0.013
0.556
0.997


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LAG525 dose 
(mg/kg Q2W)
Prior probabilities that Pr(DLT) is 
in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16,0.33)
[0.33, 1]
2.50%
50.00%
97.50%
PDR001 = 10 mg/kg Q2W
0.3
0.438
0.298
0.263
0.266
0.236
0.029
0.184
0.957
1 
0.302
0.287
0.411
0.341
0.258
0.033
0.268
0.972
3
0.208
0.137
0.655
0.535
0.339
0.013
0.561
0.997
10
0.21
0.04
0.75
0.71
0.398
0
0.981
1
Note: bold values indicate doses not meeting the overdose criterion (more than 25% chance of excessive 
toxicity) with the prior information only.
14.3.1.4 Hypothetical dose escalation scenarios for LAG525 + PDR001 
combination arm
Table 14-14 shows on-study dosing recommendations for some hypothetical data scenarios.
Note that the next dose combination is selected in concordance with the provisional dose levels 
specified in Section 6.2.2 of the protocol wherever it is allowed, to mimic possible on-study 
escalation steps.
Table 14-14
Hypothetical dose escalation scenarios for on-study decisions –
phase I LAG525 + PDR001
Scenario
Dose combination 
LAG525 (mg/kg Q2W) / 
PDR001 (mg/kg Q2W)
Npat
Ntox
Next dose 
combination 
(NDC)
P(target) 
NDC
P(over) 
NDC
Median DLT 
rate (NDC)
1
1/1
4
0
1/3
0.237
0.052
0.108
2
1/1
4
1
1/3
0.408
0.163
0.181
3
1/1
4
2
0.3/1
0.409
0.183
0.187
4*
1/0 (single agent cohort 
1)
1/1
3
4
0
2
1/1
0.444
0.183
0.195
5
1/1
1/3
4
3
0
0
3/3
0.32
0.129
0.144
6
1/1
1/3
4
3
0
1
1/3
0.364
0.082
0.148
7
1/1
1/3
4
3
0
2
1/1
0.358
0.064
0.141
8
1/1
1/3
4
5
1
0
3/3
0.395
0.191
0.187
9
1/1
1/3
4
5
1
1
1/3
0.481
0.104
0.18


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Scenario
Dose combination 
LAG525 (mg/kg Q2W) / 
PDR001 (mg/kg Q2W)
Npat
Ntox
Next dose 
combination 
(NDC)
P(target) 
NDC
P(over) 
NDC
Median DLT 
rate (NDC)
10
1/1
1/3
4
5
1
2
1/1
0.486
0.113
0.184
11
1/1
0.3/1
4
3
2
0
1/1
0.441
0.128
0.177
12
1/1
0.3/1
4
3
2
1
0.3/1
0.489
0.223
0.222
13
1/1
0.3/1
4
3
2
2
Stop
14*
1/0 (single agent cohort 
1)
1/1
0.3/1
3
4
3
0
2
2
0.3/0.3
0.495
0.241
0.231
15*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
0
0
0
3/3
0.293
0.088
0.127
16*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
0
0
1
3/3
0.4
0.235
0.205
17*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
0
0
2
1/1
0.276
0.032
0.117
18*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
1
1
1
1/3
0.526
0.189
0.217
19*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
1
1
2
1/1
0.543
0.173
0.214


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Scenario
Dose combination 
LAG525 (mg/kg Q2W) / 
PDR001 (mg/kg Q2W)
Npat
Ntox
Next dose 
combination 
(NDC)
P(target) 
NDC
P(over) 
NDC
Median DLT 
rate (NDC)
20*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
0
1
1
1/3
0.466
0.15
0.188


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Protocol No. CLAG525X2101C
Scenario
Dose combination 
LAG525 (mg/kg Q2W) / 
PDR001 (mg/kg Q2W)
Npat
Ntox
Next dose 
combination 
(NDC)
P(target) 
NDC
P(over) 
NDC
Median DLT 
rate (NDC)
21*
1/0 (single agent cohort 
1)
3/0 (single agent cohort 
2)
1/1
1/3
3
3
4
3
0
0
1
2
1/1
0.47
0.13
0.186
*PDR001 dose of 0 represents a single-agent LAG525 cohort. Data from patients receiving the single-agent 
LAG525 are incorporated directly into the model, without down-weighting
Within Table 14-14, P(Target) NDC represents the probability that the true DLT rate for the dose lies in the 
target interval (16%, 33%) while P(Over) NDC represents the probability that the true DLT rate for the dose 
exceeds 33%.
Within Table 14-14, it can be seen that the model generally leads to decisions that are in 
agreement with clinical sense. The dose levels investigated correspond to the provisional dose 
levels specified in Section 6.2.2.
14.3.1.5 Operating characteristics for LAG525 + PDR001 combination arm
Scenarios
In order to show how the design performs, 5 hypothetical scenarios were investigated:
1. For scenario 1, the odds of DLT are aligned with the prior information, i.e. the DLT rates 
for dose combinations are set to the median values derived from the prior.
2. For scenario 2, the odds of DLT are assumed to be 33% decrease from scenario 1
3. For scenario 3, the odds of DLT are assumed to be 25% increase from scenario 1
4. For scenario 4, the odds of DLT are assumed to be 2-folder increase from scenario 1
5. For Scenario 5, it was assumed all provisional combination doses are safe. The odds of 
DLT remain flat when the doses are escalated beyond 3 mg/kg of LAG525 and 3 mg/kg of 
PDR001.
The true probabilities used in the simulation are presented in the tables for each scenario above.
Scenario 1 – aligned with prior
Table 14-15
True underlying probabilities of DLT for Scenario 1
LAG525
(mg/kg, Q2W)
PDR001 (mg/kg, Q2W)
0.3
1
3
10
0.3
0.066
0.083
0.116
0.184
1
0.082
0.102
0.144
0.268
3
0.114
0.143
0.226
0.561
10
0.181
0.264
0.556
0.981
Bold values indicate dose combinations in the targeted toxicity interval [16%, 33%).


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Scenario 2 – Scenario 1 + 33% decrease in odds of DLT
Table 14-16
True underlying probabilities of DLT for Scenario 2
LAG525
(mg/kg, Q2W)
PDR001 (mg/kg, Q2W)
0.3
1
3
10
0.3
0.045
0.057
0.080
0.131
1
0.056
0.070
0.101
0.196
3
0.079
0.100
0.163
0.460
10
0.128
0.193
0.455
0.972
Bold values indicate dose combinations in the targeted toxicity interval [16%, 33%).
Scenario 3 – Scenario 1 + 25% increase in odds of DLT
Table 14-17
True underlying probabilities of DLT for Scenario 3
LAG525
(mg/kg, Q2W)
PDR001 (mg/kg, Q2W)
0.3
1
3
10
0.3
0.081
0.102
0.141
0.220
1
0.100
0.124
0.174
0.314
3
0.139
0.173
0.267
0.615
10
0.216
0.310
0.610
0.985
Bold values indicate dose combinations in the targeted toxicity interval [16%, 33%).
Scenario 4 - Scenario 1 + 2 folder increase in odds of DLT
Table 14-18
True underlying probabilities of DLT for Scenario 4
LAG525
(mg/kg, Q2W)
PDR001 (mg/kg, Q2W)
0.3
1
3
10
0.3
0.124
0.153
0.208
0.311
1
0.152
0.185
0.252
0.423
3
0.205
0.250
0.369
0.719
10
0.307
0.418
0.715
0.990
Bold values indicate dose combinations in the targeted toxicity interval [16%, 33%).
Scenario 5 – Misspecification of DLT relationship
Table 14-19 represents the hypothetical scenario that all provisional combination doses are safe. 
The odds of DLT are set the same as in scenario 1 for lower dose combinations and remain flat 
when the doses are escalated beyond 3 mg/kg of LAG525 and 3 mg/kg of PDR001.


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Table 14-19
True underlying probabilities of DLT for Scenario 5
LAG525
(mg/kg, Q2W)
PDR001 (mg/kg, Q2W)
0.3
1
3
10
0.3
0.066
0.083
0.116
0.184
1
0.082
0.102
0.144
0.268
3
0.114
0.143
0.226
0.268
10
0.181
0.264
0.264
0.268
Bold values indicate dose combinations in the targeted toxicity interval [16%, 33%).
Simulation parameters:
1000 trials were used to simulate each scenario. The starting dose combination was chosen as 
1 mg/kg for LAG525 and 1 mg/kg for PDR001, and the maximal dose to jump to was orthogonal, 
and follows the protocol specifications (Section 10.4.2 of the protocol). The number of patients 
to enroll in each cohort and stopping rules used to declare MTD were defined as:

Maximum number of patients treated: 60

Minimum cohort size: 3

Minimum number of patients treated at a given dose combination in order to declare 
MTD: 6

Posterior probability of targeted toxicity at this combination dose > 50% and is the highest 
among potential doses, or
Minimum number of patients treated in the trial: 15
Metrics
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were:
1. Average proportion of patients receiving a target dose combination on study (I)
2. Average proportion of patients receiving a dose combination with true P(DLT) ≥ 33% on 
study (II)
3. Average proportion of patients receiving a dose combination with true P(DLT) < 16% on 
study (III)
4. Proportion of trials that were recommended a target dose combination as the MTD 
(correct final decision) (IV)
5. Proportion of trials that were recommended a dose combinations with true P(DLT) ≥ 33% 
as the MTD (patient risk) (V)
6. Proportion of trials that were recommended a dose combination with true P(DLT) < 16% 
as the MTD (VI)
Results
Table 14-20 below summarizes the simulated operating characteristics of the model for the 5 
different scenarios studied, additionally showing the percentage of trials stopped before 
declaring MTD when all dose combinations were considered too toxic.


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Table 14-20
Results
Scenario
Metric
I
II
III
IV
V
VI
Stopped
1
0.418
0.003
0.579
0.573
0
0.420
0.007
2
0.527
0.018
0.454
0.787
0.009
0.203
0.001
3
0.672
0.002
0.326
0.915
0
0.075
0.010
4
0.745
0.201
0.054
0.785
0.162
0.019
0.034
5
0.434
0
0.566
0.602
0
0.392
0.006
The simulated operating characteristics presented show that the combination model performs 
well under the hypothetical scenarios investigated.
The proportion of patients treated at overly toxic dose combinations (metric II) is very low for 
all the scenarios. The probability of identifying a dose with P (DLT) > 0.33 as MTD (metric V) 
is low for all scenarios.
In scenarios 2, 3 and 4, the probability that the identified MTD falls within the target interval 
(metric IV) is more than 78%, showing excellent targeting of MTD.
In scenarios 1, the underlying P (DLT) is low and below 0.33 for most dose combinations except 
3/3, 3/10 and 10/3 for LAG525 in mg/kg / PDR001 in mg/kg; in scenario 5, none of the 
underlying P (DLT) is above 0.33. This explains why scenarios 1 and 5 have a relatively high 
proportion of patients receiving a dose with P (DLT) < 0.16 (metric III) and why the probability 
that the identified MTD falls within the under-dose interval (metric VI) is not very low.
The percentages of trials that were stopped when all dose combinations were considered too 
toxic are low (< 5%) in all scenarios.
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics.
14.3.2
Prior specifications for phase II hierarchical model
As a supporting analysis, for patients in phase II part, the ORR for each of 16 groups is estimated 
using a hierarchical model with two exchangeable groups and one non-exchangeable group (see 
Section 10.4.4) and data from all 16 groups.
The model is given in Section 10.4.4 and the details of prior specifications are provided here. 
Three results will be used in the below specifications:
a. For a probability , we construct a weakly-informative prior distribution on the logit-
scale, i.e. for log(/(1-)), as follows: the prior median is set to a plausible value m, and 
the “prior sample size” will be approximately one. For the latter, under a normal 
approximation, the resulting variance on the logit-scale is v= 1/m+ 1/(1- m). This 
leads to a weakly-informative normal prior distribution for log(/(1-)) with mean mand 
variance v.
b. For exchangeable group-specific parameters j = log(j /(1-j )), j ~ N(, 2), let the prior 
distributions be ~ N(mµ, vµ) and ~ HN(s). Here, HN(s) denotes the half-normal 
distribution with scale parameter s.


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c. Assume that the marginal (total) variance V() as well as the scale parameter s are known, 
where the first defines the a-priori uncertainty for the indication parameters, and the 
second defines the a-priori degree of borrowing across groups. From these specifications, 
the prior variance of follows from the law of total variance
V() = E(V(|,) + V(E(|,)) = E(2)+V() = s2 + vµ,.
From this, the variance of is vµ = V() s2.Based on these results, we specified the prior 
distributions for parameters in the hierarchical model as follows:
1. The group-specific normal priors for the non-exchangeable case, defined by mw and vw
were derived from (a) above. The prior median for the response probability was set as 0.2 
(a limited treatment effect), and the corresponding variance was derived as described in 
(a) above. This results in
mw = logit(0.2) = 1.386, vw = 1/0.2 + 1/(1 – 0.2) = 2.52
2. For the exchangeable cases, the specifications were as follows:
2.1 Applying (b) above, 1 and 2 were given a half-normal distribution with scale 0.5, 
implying a prior 95%-interval for as (0.016, 1.12), which allows for small to large 
between-indication heterogeneity (Spiegelhalter 2004).
2.2 1 and 2 were given normal prior distributions. For 1, the mean of the prior 
distribution was set to logit(0.1) = 2.197 corresponding to no treatment effect. For 
2, the mean was set to logit(0.3) = 0.847 corresponding to a substantial treatment 
effect.
2.3 Assume j belongs to the first exchangeability distribution. Applying (c) above, the 
total variance worth approximately one subject is 3.332. Since 1 ~ HN(0.5) the 
variance for the normal prior distribution for 1 becomes 3.2962. The same approach 
was used to derive the variance for the normal prior distribution for 2, yielding a 
variance of 2.1242.
3. Finally, for each group j, the prior mixture weights pj were chosen as
pj = (0.25, 0.25, 0.50),
j=1,…,16.
This means that each group has 25% prior probability to belong to the first exchangeability 
distribution, 25% probability to belong to the second exchangeability distribution, and 50% 
probability to be non-exchangeable with some (or all) of the other indications.
The prior distributions are summarized in Table 14-21, which also shows the prior medians and 
95%-intervals for the response rates j.


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Table 14-21
Prior distribution of hierarchical model parameters
Parameter
Prior distribution 
1
N(-2.197, 3.2962)
2
N(-0.847, 2.1242)
1
HN(scale=0.5)
2
HN(scale=0.5)
mw, vw
,
1.386, 2.52
pj = (pj1,pj2,pj3), j=1,…,12
(0.25, 0.25, 0.5)
Median (2.5%, 97.5%)
i
0.2 (0.001, 0.98)


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14.4
Appendix 4: Statistical details of Phase I Bayesian logistic 
regression model (BLRM) in Japanese patients treated with 
single agent of LAG525
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data of LAG525 from global patients, and the results of the Bayesian analyses and 
respective dosing decisions for some hypothetical data scenarios.
14.4.1
Statistical model
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used to make dose recommendations and estimate
the maximum tolerated dose (MTD) and/or identify the recommended dose for expansion 
(RP2D) during the dose escalation part of the study. The use of Bayesian response adaptive 
models for Phase I studies has been advocated by the EMEA guideline on small populations 
(2006) and by Rogatko (2007) and is one of the key elements of the FDA’s Critical Path 
Initiative.
Single agent LAG525 for Japanese patients: In the single-agent LAG525 dose escalation part, 
the dose-toxicity (DLT) relationship is described by the following 2-parameter BLRM:
logit((d)) = log(α) + β log(d /d*), α>0, β>0
Where  
, and (d) is the probability of a DLT at dose d.
Doses are rescaled as d/d* with reference dose d*=3 mg/kg of LAG525. As a consequence α is 
equal to the odds of DLT rate at d*, and β (>0) is the increase in the log-odds of a DLT by a 
unit increase in log-dose. Note that for a dose equal to zero, the probability of toxicity is zero.
The Bayesian approach requires the specification of prior distributions for all model parameters. 
This section provides details of the statistical model, the derivation of prior distributions for the 
model parameters, and the properties of the adaptive design (dosing recommendations for 
hypothetical data scenarios and operating characteristics).
14.4.2
Prior specifications
The Bayesian approach requires the specification of prior distributions for all model parameters. 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
model parameters.
14.4.2.1 Prior distribution for the logistic parameters
A mixture prior distribution for the single-agent LAG525 model parameters was derived. It 
consists of a mixture of a meta-analytic-predictive (MAP) prior and a weakly informative prior 
corresponding to high toxicity to make the prior more robust. To obtain the mixture prior, 50% 
weight was assigned to the MAP prior, and 50% weight was assigned to the weakly informative 
prior.


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14.4.2.1.1
Description of the MAP approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters (log(α*), 
log(β*)) of the new trial (eg., Japanese sub-population in the LAG525x2101 study) using DLT 
data from the ongoing dose-escalation in global patients (LAG525x2101 study).
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d
in historical trial s (s = 1, … , S). The corresponding probability of a DLT is ds. The model 
specifications for the derivation of the MAP prior are as follows:
rds | ds ~ Bin (ds, nds)
logit(ds) = log(αs) + βs log(d /d*)
(log(αs), log(βs)) | µ, ѱ ~ BVN (µ, ψ),
s = 1, … , S
(log(α*), log(β*)) | µ, ѱ ~ BVN (µ, ψ)
Where d* = 3 mg/kg and S = 1 in this study and refers to Arm A. The parameters µ = (µ1, µ2) 
and ѱ are the mean and between-trial covariance matrix for the logistic parameters, the latter 
with standard deviations τ1, τ2, and correlation p. The parameters τ1 and τ2 quantify the degree 
of between trial heterogeneity. The main objective is to estimate the predictive distribution
(log(α*), log(β*)) | (rds, nds : s = 1, … , S)
based on DLT data from arm A. To do that, it is assumed:

normal priors for µ1 and µ2,

log-normal priors for τ1 and τ2, and

a uniform prior for p.
Since the predictive distribution is not available analytically, the Markov Chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution. This is implemented using 
WinBUGS 14.1.3. The sample from this distribution is approximated by a mixture of bivariate 
normal (BVN) distributions. BVN mixtures with increasing numbers of mixture components 
are fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). 
The optimal number of components of the mixture is then identified using the Akaike 
information criterion (AIC) (Akaike 1974).
14.4.2.1.2
Implementation of the MAP approach
For the MAP model, data from global patients treated in Arm A of the global study 
[CLAG525X2101C] was used (Table 14-22).
Table 14-22
Data from global patients in study CLAG525X2101C
Dose of LAG525 *
Dose of LAG525 (mg/kg,Q2w)
No of DLTs/No of evaluable patients
1 (mg/kg,Q2w)
1
1/12
3(mg/kg,Q2w)
3
0/11
5(mg/kg,Q2w)
5
2/4
10(mg/kg,Q2w)
10
0/4
3(mg/kg,Q4w)
1.5
0/5
5(mg/kg,Q4w)
2.5
0/3


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Dose of LAG525 *
Dose of LAG525 (mg/kg,Q2w)
No of DLTs/No of evaluable patients
10(mg/kg,Q4w)
5
0/4
* Data cut-off date: 22 January, 2016
Weakly informative priors are assumed for µ1 and µ2, with means corresponding to a risk of 
DLT at the reference dose of 10%, and a doubling in dose leading to a doubling in the odds of 
the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their medians 
correspond to moderate between trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations (Schmidli 2014). The prior 
distributions for the model used for deriving the MAP priors are specified in Table 14-23.
Table 14-23
Prior distributions for the parameters of the MAP model used to derive 
the prior
Parameter
Prior distribution
µ1
N(mean = logit(0.10), sd = 2)
µ2
N(mean = 0, sd=1)
τ1
log-normal(mean = 0.25, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
p
uniform(-1,1)
14.4.2.1.3
Derivation of the weakly informative prior
A weakly informative BVN prior to allow higher toxicity than MAP prior is derived by 
assuming median probability of DLT at 3 mg/kg to be 20%, as well as a log-linear relationship 
between dose and the odds of DLT as defined in Section 14.4.1. This results in setting the mean 
of log(α) equal to -1.386. The mean of log(β) is set to 0. Furthermore, setting standard deviation 
of log(α) = 2 and log(β) = 1, and setting the correlation between log(α) and log(β) = 0 to 
complete the determination of this prior. See Table 14-24.
14.4.2.2 Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 14-24.
Prior summaries for DLT rates are summarized at each provisional dose level in Table 14-25.
Table 14-24
Prior distribution of model parameters
Parameter
Mean
Standard deviations
Correlation
Weight
LAG525 MAP prior, BVN mixture (log(α), log(β)), weight = 50%
BVN mixture 1
(-2.410 , -0.602 )
(0.572 , 0.555)
-0.179
0.206
BVN mixture 2
(-2.988 , -1.050 )
(0.719 , 0.747)
-0.272
0.180
BVN mixture 3
(-2.758 , 0.025)
(0.779 , 0.419)
-0.178
0.114
Weakly informative prior (log(α), log(β)), weight = 50%
Weakly informative
(-1.386, 0)
(2, 1)
0
0.5


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Table 14-25
Summary of prior distribution of DLT rates
PDR001 dose
(mg/kg, Q2W)
Prior probabilities that
P(DLT) is in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33, 1]
2.5%
50.0%
97.5%
0.3
0.905
0.046
0.050
0.062
0.134
0.000
0.017
0.534
1 (starting 
dose)
0.842
0.070
0.088
0.101
0.170
0.000
0.038
0.697
3
0.690
0.126
0.185
0.188
0.230
0.008
0.088
0.870
10
0.412
0.222
0.367
0.349
0.318
0.022
0.207
0.997
SD = standard deviation.
Bold values indicate dose(s) not meeting the EWOC principle with the prior information only.
14.4.3
BLRM design properties for hypothetical data scenarios
Table 14-26 shows on-study dosing recommendations for some hypothetical data scenarios.
Note that the next dose is selected in concordance with the provisional dose levels specified in 
Section 6.2.2 of the protocol wherever it is allowed, to mimic possible on study escalation steps.
Table 14-26
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent LAG525
Scena
rio
LAG525 Dose level 
(mg/kg)
Np
at
Nt
ox
Next Dose Level 
(NDL)
P(Target) 
NDL
P(Over) 
NDL
Median DLT rate 
(NDL)
1
1
4
0
3
0.106
0.080
0.069
2
1
4
1
1
0.197
0.111
0.089
3
1
4
2
0.3
0.267
0.241
0.164
4
1
4
0
3
3
1
3
0.229
0.136
0.118
5
1
4
0
3
3
2
1
0.168
0.051
0.066
6
1
4
0
3
6
0
10
0.223
0.151
0.118
7
1
4
0
3
6
2
3
0.346
0.191
0.174
8
1
4
0
3
3
1
3
5
0
5
0.219
0.113
0.117
9
1
4
0
3
3
1
3
3
1
3
0.346
0.191
0.174
10
1
4
0
3
3
1
3
3
2
1
0.191
0.041
0.072
11
1
4
0
3
3
2
1
3
1
1
0.352
0.110
0.148


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Scena
rio
LAG525 Dose level 
(mg/kg)
Np
at
Nt
ox
Next Dose Level 
(NDL)
P(Target) 
NDL
P(Over) 
NDL
Median DLT rate 
(NDL)
12
1
4
0
3
3
2
1
3
2
0.3
0.274
0.092
0.113
13
1
4
1
1
5
0
3
0.199
0.134
0.110
14
1
4
1
1
3
2
0.3
0.321
0.194
0.166
15
1
4
1
1
5
0
3
4
0
10
0.315
0.144
0.148
16
1
5
0
3
4
0
10
3
0
10
0.184
0.033
0.090
Within Table 14-26, it can be seen that the model generally leads to decisions that are in 
agreement with clinical sense: progressive increase of the doses if no DLT is observed, enrolling 
of a new cohort at the same dose level when 1 DLT is reported, and de-escalation when more 
than 1 DLT is reported in a cohort. It is expected that the dose-DLT relationship in Japanese 
patients will be very similar to that observed outside Japan. Scenario 16 is a hypothetical 
scenario where the dose-DLT relationship is consistent between global and Japanese patients. 
In this case, the posterior weight for the prior components based on data from the global study 
[CLAG525X2101C] increases to from 50% to 70%, demonstrating support for the 
exchangeability of these two populations based on DLT data.
In addition, Table 14-26 shows also some examples for the unlikely case of dissimilarity in the 
dose-DLT relationship between Japanese and global patients. Scenario 5 is an example 
illustrating such dissimilarity. In this case, the posterior weight for the prior components based 
on data from the global study [CLAG525X2101C] reduces to 19%. Overall, in the case of 
dissimilarity, the model performs appropriately, leading to dose de-escalation.
14.4.3.1 Operating characteristics
In order to show how the proposed design performs under different true dose- DLT profiles, 
various hypothetical scenarios were investigated.
14.4.3.2 Simulation setup
Table 14-27 shows 4 dose-DLT scenarios, taking scenario 1 (true DLT rates equal to mean prior 
DLT rates) as the basis. Scenarios 2, 3 and 4 have increased DLT rates compared to scenario 1:
-Scenario 2: the odds of DLTs are 2-fold larger than the ones of scenario 1
-Scenario 3: the odds of DLTs are 3-fold larger than the ones of scenario 1
-Scenario 4: the odds of DLTs are 5-fold larger than the ones of scenario 1
The following table presents the true underlying probabilities of DLT for each scenario


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Table 14-27
dose-DLT scenarios
Test 
scenarios
Assigning DLT probabilities to each dose level
Note
0.3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
1
0.062
0.101
0.188
0.349
True dose-DLT relationship based on prior 
mean DLT rates
2
0.117
0.183
0.316
0.517
2-fold odds inflation from test scenario 1
3
0.165
0.252
0.410
0.617
3-fold odds inflation from test scenario 1
4
0.248
0.360
0.537
0.728
5-fold odds inflation from test scenario 1
n-fold odds inflation: p1/(1-p1) = n*[p0/(1-p0)], p1=n*p0/(1-p0+n*p0), where p0 is a probability of test 
scenario 1

For each scenario data for 1000 trials were generated.

Dose levels investigated: 0.3, 1 (starting dose), 3, 10 mg/kg

Cohort size: 3, 4, 5, or 6 patients (randomly assigned with a uniform rate of 25%)

Stopping rule/MTD selection criteria:

Maximum number of patients per a trial: 30 patients

Minimum number of patients per a trial: 12 patients

Minimum number of patients at MTD: 6 patients

Posterior probability of targeted toxicity at MTD: >50%
Table 14-28
Operating characteristics of BLRM-based dose escalation design
Profile
Parameter
PDR001 dose level (mg/kg)
stopped 
(toxicity) 
[2]
stopped 
(max N) 
[3]
0.3
1
3
10
1
True probability of DLT (%) [1]
6.2
10.1
18.8
34.9
Average # of patients recruited
0.45
6.8
6.84
3.09
Average # of DLTs
0.04
0.69
1.26
1.08
% of MTD selection
1.7
23.8
48.8
23.1
2.3
0.3
2
True probability of DLT (%) [1]
11.7
18.3
31.6
51.7
Average # of patients recruited
1.36
8.48
5.23
0.91
Average # of DLTs
0.16
1.60
1.64
0.47
% of MTD selection
8.5
46.5
31.2
3.1
10.4
0.3
3
True probability of DLT (%) [1]
16.5
25.2
41
61.7
Average # of patients recruited
2.19
8.69
3.66
0.32
Average # of DLTs
0.36
2.13
1.50
0.2
% of MTD selection
15.7
50.2
13.6
0.4
19.8
0.3
4
True probability of DLT (%) [1]
24.8
36.0
53.7
72.8
Average # of patients recruited
3.17
7.76
1.62
0.08
Average # of DLTs
0.77
2.86
0.84
0.06
% of MTD selection
24.5
23.2
2.4
0.0
49.7
0.2
[1] Bolding indicates doses with true probability of DLT within the target toxicity interval [16%, 33%).
[2] Proportion (%) that a trial is stopped since all dose levels are too toxic.
[3] Proportion (%) that a trial is stopped since the maximum number of patients is reached without selecting a 
MTD.


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14.4.3.3 Results
The simulated operating characteristics presented show that the BLRM performs well under the 
hypothetical profiles investigated. Indeed, the simulations performed illustrate that the model 
has reasonable operating characteristics and the number of patients with DLT was limited 
through a trial. In scenario 1, the odds of DLT are aligned with the prior information. In this 
scenario, the simulations show that about 49% and 23% of chance for selecting MTD at 3mg/kg 
and 10mg/kg dose levels, respectively. Finally, in scenario 4, with 5-fold odds inflation from 
test scenario 1, the chance to stop the trial due to high toxicity of all dose levels is very high 
(49.7%) as expected since only 0.3 mg/kg dose has the underlying P (DLT) that is below 33%. 
The simulations show that there is about 23% of chance for selecting MTD at 1mg/kg dose level 
since the assumed P(DLT) for this dose lies very close to the upper boundary of at those doses
the target interval, leading to a tendency for the model estimate of the probability of overdose 
to identify this as a dose not satisfying the EWOC criterion.
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics under the 4 hypothetical profiles investigated.
References (available upon request)
Akaike H (1974) A new look at the statistical model identification. IEEE Transactions on 
Automatic Control; 19(6):716-723.
Dempster AP, Laird NM, Rubin DB (1977) Maximum Likelihood from Incomplete Data via 
the EM Algorithm. Journal of the Royal Statistical Society; 39(1):1-38.
EMEA (2007) Guideline on Clinical Trials in Small Populations. Committee for Medicinal
Products for Human Use (CHMP).
Schmidli H, Gsteiger S, Roychoudhury S et al (2014) Robust meta-analytic-predictive priors 
in clinical trials with historical control information. Biometrics; 70(4):1023-1032.
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25:4982-6.
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation.

SAP_001.pdf: 
Clinical Development
LAG525, PDR001
CLAG525X2101C / NCT02460224
A Phase I/II, open label, multicenter study of the safety and 
efficacy of LAG525 single agent and in combination with 
PDR001 administered to patients with advanced malignancies
Statistical Analysis Plan (SAP)
Author:
Statistician, 
Document type:
SAP Amendment 4 Documentation
Document status:
Final
Release date:
15-Mar-2021
Number of pages:
50
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
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SAP
CLAG525X2101C
Table of Contents
Clinical Development.................................................................................................................1
List of tables ........................................................................................................................3
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Objectives and endpoints.......................................................................................11
2
Statistical Methods ............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................14
2.2
Analysis sets ..........................................................................................................15
Immunogenicity (IG) analysis sets ........................................................................17
2.3
Patient disposition, demographics and other baseline characteristics ...................17
2.3.1
Patient disposition.................................................................................17
2.3.2
Basic demographic and background data..............................................17
2.3.3
Medical History.....................................................................................17
2.3.4
Prior antineoplastic therapy...................................................................18
2.3.5
Diagnosis and extent of cancer .............................................................18
2.3.6
Analysis set exclusion...........................................................................18
2.4
Protocol deviations ................................................................................................19
2.5
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance)............................................................................................................20
2.5.1
Study treatment .....................................................................................20
2.5.2
Prior and Concomitant therapies...........................................................22
2.5.3
Compliance ...........................................................................................22
2.6
Analysis of the primary variable(s) .......................................................................22
2.6.1
Phase I: dose escalation part .................................................................22
2.6.2
Phase II part...........................................................................................24
2.6.3
Supportive analysis ...............................................................................25
2.7
Analysis of the secondary variables ......................................................................26
2.7.1
Efficacy definitions ...............................................................................26
2.7.2
Efficacy evaluation................................................................................27
2.7.3
Waterfall plot for best overall response and best percentage change 
from baseline for all target lesions for each patient..............................28
2.8
Safety evaluation ...................................................................................................28
2.8.1
Adverse events (AEs)............................................................................29
2.8.2
Laboratory data .....................................................................................31


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2.8.3
Vital signs, weight and physical examinations .....................................34
2.8.4
Electrocardiograms ...............................................................................35
2.8.5
Tolerability............................................................................................36
2.9
Pharmacokinetic data.............................................................................................36
2.10
Biomarkers.............................................................................................................38
2.10.1
Introduction...........................................................................................38
2.10.2
Outline of the data analysis...................................................................38
2.11
PD and PK/PD analysis .........................................................................................39
2.11.1
Immunogenicity ....................................................................................39
2.12
Interim analyses.....................................................................................................41
3
Sample size calculation .....................................................................................................41
4
Appendix ...........................................................................................................................42
4.1
Baseline..................................................................................................................42
4.2
Imputation rules.....................................................................................................42
4.2.1
AE, ConMeds and safety assessment date imputation..........................42
4.2.2
Other imputations..................................................................................43
4.3
Definition and derivation rules for irRC................................................................45
4.3.1
Total measurable disease burden ..........................................................45
4.3.2
Assessment of disease progression .......................................................45
4.3.3
Best overall response.............................................................................46
4.3.4
Time to event analyses:.........................................................................46
4.4
Event dates used in PFS and DOR ........................................................................48
4.5
CTCAE ..................................................................................................................49
5
References .........................................................................................................................50
List of tables
Document History – Changes compared to previous version of SAP........................................5
Table 2-1
Non-protocol deviation leading to exclusion from analysis set 
definitions..............................................................................................18
Table 2-2
Protocol deviation leading to exclusion from analysis set 
definitions..............................................................................................19
Table 2-3
Laboratory parameters for which CTCAE grades are defined..............33
Table 2-4
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined..................................................................34
Table 2-5
Criteria for notable vital sign values .....................................................35
Table 2-6
Criteria for notable ECG values............................................................35


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Table 2-7 
Pharmacokinetic Parameters to be analyzed.........................................36
Table 2-8
Biomarkers and purpose of analysis .....................................................38
Table 4-1
Imputation of start dates (AE, CM) ......................................................43
Table 4-2
Options for event dates used in PFS and DOR .....................................48
Table 4-3
CTC grades for laboratory values in Novartis Oncology (based on 
CTCAE v4.03 – June 2010)..................................................................49


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Document History – Changes compared to previous version of SAP.
Version
Date
Changes
1.0
27Jan2020
Draft
Amendment 
1
07Jul2019
1. Added list of abbreviations and glossary terms.
2. Updated study design adding TNBC and Mesothelioma
indications.
3. Removed single agent groups from Phase II part.
4. Updated the definition of DDS by adding specific wording for
different dosing regimens.
5. Added the definitions for immunogenicity analysis sets.
6. Updated medical history section by adding more details on
the analysis.
7. Added a subsection on analysis set exclusion.
8. Updated the definitions of last date of exposure for both
monotherapy and combo therapy.
9. Updated definitions of duration of exposure and actual
cumulative dose.
10. Removed the definitions of cumulative planned doses,
percentage of days dosed and percentage of days at
planned dose.
11. Removed the language about the primary bayesian analysis
of ORR for single agent LAG525.
12. Added definitions of efficacy endpoints like BOR, ORR,
DOR, PFS and TTR.
13. Updated language on the efficacy analysis will be done for
all patients. Added language about efficacy analysis for
patients who switched from single agent to combination.
14. Added language on safety summaries and patients who
switched from single agent and combination.
15. Added language on data analysis for safety and laboratory
data.
16. Clarified notable high or low values for vital signs.
17. Updated language about PK parameters and the PK
analysis.
18. Added immunogenicity analysis section.
19. Added details about calculation of baseline in the appendix.
20. Added imputation rules in the appendix.
21. Added definitions and derivation rules for irRC in the
appendix.
22. Removed languages on the construction of waterfall plots
and cycle definition.
23. Updated the references.
Amendment 
2
15Jul2019
Updated language for baseline calculations for efficacy
assessments.
Amendment 
3
29Oct2020
Clarified PPS
Amendment 
4
21Jan2021
Section 2.11.1.1 – Removed from the definition of determinant 
samples the exclusion for the ADA-inconclusive sample
Section 2.8.2.2 - Added information regarding lab conversion units 
for T4 and regarding the imputed units for the normal ranges.
Amendment 
5
15Mar2021
Section 2.8.2.3 – Removed Listing of all clinically relevant laboratory 
data with values flagged; added tables for worst post-baseline 


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Version
Date
Changes
hematology and biochemistry abnormalities based on CTC grades; 
removed from Table 2-4 ‘total protein’


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List of abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
AUCtau
BHM
Area Under the Curve
Area Under the Curve for time 0 to tau
Bayesian Hierarchical Model
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dosage administration record
DCR
Disease Control Rate
DDP
Dose Determining Pharmacokinetic Set
DDS
Dose-Determining Safety Set
DI
Dose intensity
DLT
Dose Limiting Toxicity
DOR
Duration of Response
ECG
Electrocardiogram
EDC
Electronic Data Capture
EOS
End of Study
EOT
End of Treatment
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
i.v.
Intravenous(ly)
ICF
Informed Consent Form
 
IG
Immunogenicity
IL-6
Interleukin-6
irRC
immune related Response Criteria
LAG-3
Lymphocyte activation gene-3
MTD
Maximum Tolerated Dose
NSCLC
Non-Small Cell Lung Carcinoma
ORR
Overall Response Rate
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics
PDI
Planned dose intensity
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression Free Survival
PK
Pharmacokinetics
PPS
Per Protocol Set


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PR
Partial Response
PT
Preferred term
RAP
Report and Analysis Plan
RCC
Renal Cell Carcinoma
RDI
Relative dose intensity
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended phase 2 dose
SAE(s)
Serious Adverse Event(s)
SOC
System organ class
SOD
Sum of diameters
SSD
Study Specific Document
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TMTB
Total measurable disease burden
TNBC
Triple Negative Breast Cancer


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen 
(i.e. treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage
Patient Number (Patient No.)
A unique identifying number assigned to each patient who enrolls in the 
study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered 
to the patient as part of the required study procedures, including placebo 
and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment discontinuation
Point/time when a patient permanently discontinues study treatment for 
any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. Cohorts are not expanded, new cohorts 
are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Withdrawal of Consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further visits or 
assessments, and does not want any further study related contact


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study LAG525X2101C that will be presented in the Clinical Study Report (CSR).
The output shells (in-text and post-text) accompanying this document can be found in the TFL 
shells document. The specifications for derived variables and datasets can be found in the 
Programming Datasets Specifications (PDS) document. This version of the SAP is based on 
Protocol Amendment 10.
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., MTD/RDE declaration, IB updates, abstracts, posters, 
presentations, manuscripts and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance.
1.1
Study design
This study is a phase I/II, multi-center, open-label study which consists of 3 dose escalation
parts (Arms A, B and C) with a staggered start, each followed by a Phase II part. 
The first escalation is conducted with single-agent LAG525 in advanced solid tumors. The 
second dose escalation part is performed with the combination of LAG525 and PDR001 in 
advanced solid tumors. A separate Japanese dose escalation (Arm C) is performed in order to 
ensure that the safety and pharmacokinetic profiles of single-agent LAG525 are adequately 
characterized in Japanese patients at more than one LAG525 dose. Arms A and B are followed 
by a Phase II part after the determination of MTD/RP2D of single-agent LAG525 and 
combination of LAG525 and PDR001 respectively. 
If the RP2D of single-agent LAG525 are the same in Arms A and C, patients enrolled in Japan 
could be recruited in Phase II single-agent part of the study. In addition, if the recommended 
dose of PDR001 for Japanese patients on the PDR001X1101 study are the same as that 
determined in study PDR001X2101, patients in Japan could also enter the combination parts of 
the study at whichever dose was being tested at that time.
Upon disease progression, patients assigned to LAG525 monotherapy during dose escalation 
may switch to LAG525 + PDR001 at a combination dose level that uses the patient’s same 
LAG525 dose (or less) and has been determined safe and tolerable in previous dose escalation 
patients. If there is no combination dose level that includes the patient’s LAG525 monotherapy 
dose, the patient may receive a lower dose level of LAG525 when switching to LAG525 in 
combination with PDR001; 
The study design is summarized in Figure 1-1.


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Figure 1-1
Note: In the single agent LAG525 dose escalation (Arm A) at least 21 patients are required to 
define the RP2D; in the combination dose escalation (Arm B) at least 15 patients are required 
to define the RP2D and in the Japanese single agent LAG525 dose escalation (Arm C) at least 
12 patients are required to define the RP2D.
The final clinical study report (CSR) will be based on all patients’data from both phase I and 
phase II parts.
As antitumor activity was not observed with LAG525 single agent but was seen at several dose 
levels of LAG525 in combination with PDR001, it was decided that only the combination 
portion of Phase II would be enrolled. 
1.2
Objectives and endpoints
Objective
Endpoint
Primary
Phase I part
To estimate the RP2D or MTD for:
●
Single agent LAG525 (including Japanese 
patients)
●
Combination of LAG525 and PDR001.
The incidence of dose limiting toxicities ( DLTs) 
during the first cycle of treatment with single agent 
LAG525. For the combination treatment of LAG525 
and PDR001, the DLT window will be 2 cycles of 
the treatment.


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Phase II part
To estimate the overall response rate per RECIST 
V1.1
●
Single agent LAG525
●
Combination of LAG525 and PDR001
Overall response rate per “Response Evaluation 
Criteria in Solid Tumors (RECIST) V 1.1”
Secondary
Phase I and Phase II parts:
To characterize the safety and tolerability of 
single agent LAG525 given alone and in 
combination with PDR001
●
Safety incidence and severity if adverse events 
(AEs) and serious adverse events (SAEs) including 
changes in laboratory parameters, vital signs and 
ECGs
●
Tolerability: Dose interruptions, reductions and 
dose intensity.
To characterize the pharmacokinetic profile of 
single agent LAG525 given alone and in 
combination with PDR001
●
Serum PK parameters (e.g. AUC, Cmax, Tmax, 
t1/2 half-life)
To assess emergence of anti-LAG525, and anti-
PDR001 antibodies following one or more 
intravenous (i.v.) infusions of single agent 
LAG525 given alone or in combination with 
PDR001
●
Presence and/ or concentration of anti-LAG525 
and anti-PDR001 antibodies
Phase II part:
●
To evaluate the preliminary antitumor activity 
of single agent LAG525 given alone or in 
combination with PDR001
●
ORR per immune related Response Criteria 
(irRC), PFS, DOR, DCR per RECIST V1.1 and per 
irRC


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2
Statistical Methods
2.1
Data analysis general information
The statistical analysis of this study will be performed by Novartis personnel or a designated 
third party. A detailed description of the statistical analysis methods will be provided in 
Appendix 16.1.9 of the primary CSR. R version 2.13.2 (or later version), JAGS and WinBUGS 
version 1.4.3. will be used for Bayesian modeling. PK parameters will be calculated using non-
compartmental methods available in Phoenix WinNonlin version 5.2. SAS® 9.3 or later (SAS
Institute Inc., Cary, NC, USA) will be used in all other analyses.
The study data will be analyzed and reported (in a final CSR) based on all patients’ data of the 
dose escalation and Phase II parts up to the time when all patients have potentially completed 
treatment or discontinued the study. The final CSR will include all outputs planned within TFL 
shells document. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) 
 measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data.
Both pre and post intra patient dose escalation data will be listed and summarized together under 
the one dose level/treatment group.
The following rules will be applied for reporting results unless stated otherwise:

For the phase I part data will be analyzed by Arm, and cohorts treated with the same dose 
or dose combination (dose levels and schedules) will be pooled into a single treatment group
by Arm. All summaries, listings, figures and analyses will be performed by treatment group
and Arm. Arms to be analyzed are:

Arm A: Single agent LAG525 

Arm B: Combination LAG525 + PDR001 

Arm C: Single agent LAG525 dose escalation in Japanese patients

For the phase II, all summaries, listings, figures for primary efficacy analysis and safety 
analyses will be presented by disease group and/or by dose group for one or more disease 
groups whenever applicable. Patients from Phase II will be classified according to the 
disease group to which they were assigned at baseline based on the disease type.

The study treatment groups that were analyzed in the Phase II combination LAG525 + 
PDR001 cohorts were

Group 6: combo LAG525+PDR001, NSCLC (naïve to PD-1/PD-L1)

Group 7: combo LAG525+PDR001, Melanoma (naïve to PD-1/PD-L1)

Group 8: combo LAG525+PDR001, Renal cancer (naïve to PD-1/PD-L1)


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
Group 9: combo LAG525+PDR001, NSCLC (pre-treated with PD-1/PD-L1)

Group 10: combo LAG525+PDR001, Melanoma (pre-treated with PD-1/PD-L1)

Group 12: combination LAG525+PDR001, Renal cancer (pre-treated with PD-1/PD-
L1)

Group 13: combo LAG525+PDR001, Mesothelioma (naïve to PD-1/PD-L1)

Group 14: combo LAG525+PDR001, TNBC (naïve to PD-1/PD-L1)

Group 15: combo LAG525+PDR001, Mesothelioma (pre-treated with PD-1/PD-L1)

Group 16: combo LAG525+PDR001, TNBC (pre-treated with PD-1/PD-L1)
For phase I, all summaries, listings, figures for primary efficacy analysis and safety analyses 
will be presented by dosing regimen whenever applicable. Data from Arm A and Arm C will 
be pooled for safety and efficacy data.
2.1.1
General definitions
Study drug and study treatment
For Arm A and C (monotherapy):
Study drug and study treatment both refer to LAG525 and are used interchangeably.
For Arm B (combo therapy):
Study drug refers to the individual compound i.e., LAG525 or PDR001. Study treatment refers 
to any combination of study drugs. 
Date of first/last administration of study drug and study treatment
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of any component of study treatment was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1.
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment.
Study day will be displayed in the data listings.


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On-treatment assessment/event
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment (i.e., 
including combination partner) + 30 days inclusive.
2.2
Analysis sets 
The number (%) of patients in each of the defined analysis set will be summarized using the 
Full Analysis Set (FAS).
Full Analysis Set
The FAS comprises all patients who received at least one full or partial dose of assigned single-
agent LAG525, or at least one full or partial dose of assigned combination of study drugs. 
Patients will be analyzed according to the planned treatment. The FAS will be used for all 
listings of raw data. Unless otherwise specified, the FAS will be the default analysis set used 
for all analyses.
Safety Set
The Safety Set includes all patients from the FAS who have received at least one dose of 
LAG525 or PDR001. Patients will be classified according to treatment received, where 
treatment received is defined as:
1. The treatment assigned if it was received at least once, or
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
The safety set will be used for the safety summary of the study.
Per-Protocol Set
The Per Protocol Set (PPS) consists of a subset of FAS patients in the phase II part who meet 
the following criteria:

Presence of at least one measurable lesion according to RECIST 1.1 as per Study Protocol 
Appendix 1

At least 2 post-baseline tumor assessments (unless disease progression according to 
RECIST 1.1 is observed before that time)

Have received the planned treatment
Patients will be classified according to planned treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint. If the PPS and the FAS are identical, then 
analyses described by the PPS below will not be performed.


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Dose- Determining Analysis Set
Single agent LAG525 escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during Cycle 1.
A patient is considered to have met the minimum exposure criterion if having received at least 
two of the planned dose of LAG525 during Cycle 1 for Q2W schedule or at least one planned 
dose of LAG525 during Cycle 1 for Q4W schedule. Patients who do not experience a DLT 
during the first cycle are considered to have sufficient safety evaluations if they have been 
observed for ≥ 28 days following the first dose, and are considered by both the Sponsor and 
Investigators to have enough safety data to conclude that a DLT did not occur.
Combination of LAG525 and PDR001 dose escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during the first two cycles.
A patient is considered to have met the minimum exposure criterion if both of the following 
criteria are met:
1. The patient has received at least three planned doses of LAG525 during the first 2 cycles for 
the Q2W schedule or at least two planned doses LAG525 during the first 2 cycles for the Q3W 
schedule and Q4W schedules and
2. The patients has received at least three planned doses of PDR001 during the first 2 cycles for 
the Q2W schedule or at least two planned doses of PDR001 during the first 2 cycles for the 
Q3W and Q4W schedules.  
Patients who do not experience a DLT during the first two cycles are considered to have 
sufficient safety evaluations if they have been observed for ≥ 56 days following the first dose
(42 days for patients on Q3W dosing schedule), and are considered by both the Sponsor and 
Investigators to have enough safety data to conclude that a DLT did not occur.
In the dose escalation part, patients who do not meet these minimum safety evaluation 
requirements will be regarded as ineligible for the DDS and additional patient(s) may be 
recruited.
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable PK data. The PAS will be used for all PK analyses.
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of analysis.


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Immunogenicity (IG) analysis sets
The Immunogenicity prevalence set includes all patients in the Full analysis set with a 
determinant baseline IG sample or at least one determinant post-baseline IG sample.
The Immunogenicity incidence set includes all patients in the Immunogenicity prevalence set 
with a determinant baseline IG sample and at least one determinant post-baseline IG sample.   
The IG analysis sets will be different for LAG525 and PDR001.
See Section 2.11.1.1 for the definition of determinant.
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless noted otherwise, summaries described in this section will be based on the FAS.
Summaries will be produced by treatment group or dosing regimen as appropriate and overall
summary. Data will be listed individually by patient based on the FAS.
2.3.1
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason
entered in the ‘End of Treatment’ page),

Number (%) of patients who discontinued from study (based on completion of the ‘Study 
evaluation completion’ page with discontinuation date and reason entered),

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘Study evaluation completion’ page).
2.3.2
Basic demographic and background data
All demographic and background data (e.g. age, gender, race) will be listed and summarized.
Qualitative variables (e.g. gender) will be summarized by means of contingency tables for each 
treatment group. Quantitative variables (i.e. age, weight, and BMI) will be summarized by 
appropriate descriptive statistics for each treatment group. 
BMI and BSA are calculated using the following formulas:

BMI [kg/m2] = weight[kg] / (height[m]**2)

BSA [m2] = 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000
2.3.3
Medical History
Medical history and ongoing conditions will be summarized and listed. Separate summaries 
will be presented for ongoing and historical medical conditions. The summaries will be 
presented by primary system organ class (SOC) and preferred term (PT). Medical history and 
current medical conditions will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA) terminology available at the time of reporting. The MedDRA version 


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used for reporting will be specified in the CSR and as a footnote in the applicable tables/listings. 
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be listed. 
2.3.4
Prior antineoplastic therapy
Prior anti-neoplastic therapy will be summarized for medication, radiotherapy and surgery. The 
number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized separately.
The summary of prior anti-neoplastic medications include the total number of regimens (note: 
there can be more than one medication per regimen), immuno-oncology therapeutic class,
setting at last medication,  best response at last medication (defined to be the best response 
during the last treatment regimens recorded) and time (in months) from start of last medication 
to progression. The last medication is defined based on the last start date of all prior regimen 
components. Prior antineoplastic medications is also summarized by Anatomical Therapeutic 
Chemical (ATC) class, and preferred term.
The summary of prior anti-neoplastic radiotherapy will include the radiotherapy locations, 
(including all locations recorded for each patient), setting at last radiotherapy and method.
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment.
2.3.5
Diagnosis and extent of cancer
The summary of diagnosis and extent of cancer (disease history) will include primary site of 
cancer, details of tumor histology/cytology, histological grade, stage at initial diagnosis, time 
(in months) from initial diagnosis of primary site to start of study treatment, time (in months) 
since most recent recurrence/relapse or progression to start of study treatment, time (in months) 
from initial diagnosis of primary site to first recurrence/relapse or progression, current stage of 
cancer, current extent of disease (metastatic sites) and types of lesions (target and non-target 
lesions) at baseline.
2.3.6
Analysis set exclusion
Patients will be excluded from the analysis sets based on the protocol deviations and specific 
non-protocol deviations entered in the database. All protocol deviations and non-protocol 
deviations leading to exclusion from specific analysis sets will be identified before database 
lock. Protocol and non-protocol deviations leading to exclusion from specific analysis sets and 
reasons for exclusion from populations will be tabulated/listed by treatment (Phase I) 
/indication and treatment (Phase II).
Table 2-1 displays non-protocol deviations leading to exclusion from analysis set definitions 
and Table 2-2 displays protocol deviations leading to exclusion from analysis set definitions.
Table 2-1
Non-protocol deviation leading to exclusion from analysis set 
definitions
Summary of non PD
Analysis set(s) to be excluded
No valid post-baseline safety assessment
SS


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Summary of non PD
Analysis set(s) to be excluded
No administration of study treatment
FAS, SS, PPS, DDS, PAS,
Immunogenicity prevalence set, 
Immunogenicity incidence set
1. Patient, who has not experienced DLT, was 
not observed for ≥ 28 days (for SA) and ≥ 56
days (for Q2W/Q4W Combo) and ≥ 42 days (for 
Q3W Combo) following the C1D1 or had not 
completed the required safety evaluations for 
Cycle 1 or 
2. Patient who has not experienced DLT and 
has not received appropriate number planned 
doses in Cycle 1/Cycle 2 (See Section 2.2).
DDS
Patient did not have at least one measurable 
LAG525 concentration in cycle 1
PAS
No determinant IG sample at both baseline and 
post-baseline
Immunogenicity prevalence set
No determinant IG sample at baseline or post-
baseline or both
Immunogenicity incidence set
Table 2-2
Protocol deviation leading to exclusion from analysis set definitions
Protocol 
Deviation ID 
(DVSPID)
Summary of PD
Analysis set(s) to be excluded
INCL01
Written informed consent must be 
obtained prior to screen 
procedures.
FAS, SS, PPS, DDS, PAS,
Immunogenicity prevalence set, 
Immunogenicity incidence set
INCL04
In the Phase II part, patient does 
not have at least one tumor lesion 
meeting measurable disease 
criteria as determined by RECIST 
v1.1.
PPS
INCL05
In the Phase II part, patient was 
not a patient with either NSCLC, 
melanoma, TNBC, RCC or 
Mesothelioma.
PPS
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listings. The frequency 
counts and percentage of patients with any CSR-reportable protocol deviation will be tabulated 
by the deviation category (entry criteria not satisfied; wrong treatment or incorrect dose; 
developed withdrawal criteria, but not withdrawn; took an excluded concomitant medication; 
others). The full list of protocol deviations are documented in the Study Specification Document 
(SSD).


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2.5
Treatments (study treatment, rescue medication, other 
concomitant therapies, compliance)
Unless otherwise noted, the Safety set will be used for all treatment/medication data summaries
and listings.
2.5.1
Study treatment
2.5.1.1
Dose intensity and exposure
For Arm A and C (monotherapy): 
Last date of exposure to study treatment is:
min(the last date of study treatment + 13 days, death date, data cut-off date) for Q2W 
schedule 
min(the last date of study treatment + 27 days, death date, data cut-off date) for Q4W 
schedule
For Arm B (combo therapy):
Last date of exposure to study treatment is:
min(max(last date of PDR001 administration, last date of LAG525 administration) + 13
days, death date, data cut-off date) for Q2W schedule
min(max(last date of PDR001 administration, last date of LAG525 administration) + 20 
days, death date, data cut-off date) for Q3W schedule
min(max(last date of PDR001 administration, last date of LAG525 administration) + 27 
days, death date, data cut-off date) for Q4W schedule
min(max(last date of PDR001 administration + 27 days, last date of LAG525 
administration + 13 days), death date, data cut-off date) for LAG525 Q2W and PDR001 
Q4W schedule
Definitions are as follows:

Duration of exposure to study treatment (weeks): (last date of exposure to study treatment
−first date of study treatment + 1)/7 (periods of interruption are not excluded)

Duration of exposure to study drug (weeks): (last date of exposure to study drug − first 
date of study drug + 1)/7 (periods of interruption are not excluded) 

Actual cumulative dose (mg): total actual dose for the study drug over the duration for 
which the patient is on study treatment as documented in the DAR eCRF.
The following algorithms will be used to calculate the actual dose per one infusion in mg:
For weight based dosing: Actual dose (mg) = (Calculated dose prescribed, mg) × (Total 
volume administrated, ml) / (Total volume constituted, ml)
For flat dosing: Actual dose(mg) = (Dose prescribed, mg) × (Total volume 
administrated, ml) / (Total volume constituted, ml)


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These parameters used for calculation (‘Calculated dose prescribed’, ‘Dose prescribed’, ‘Total 
volume constituted’, ‘Total volume administered’) will be collected on the DAR eCRF page. 
For patients who did not take any of study treatment, the actual cumulative dose is by definition 
equal to zero. Actual cumulative dose will then be calculated as the sum of actual dose per one 
infusion for all infusions.

Planned cumulative dose (mg): the total dose planned to be given as per the protocol up to
the last date of study treatment administration. It is calculated in mg as:
For weight based dosing: Planned cumulative dose (mg) = sum of (Calculated dose 
prescribed, mg) for all infusions
For flat dosing: Planned cumulative dose (mg) = sum of (Dose prescribed, mg) for all 
infusions.
Similarly, ‘Calculated dose prescribed’ and ‘Dose prescribed’ will be collected on the DAR 
eCRF page. The planned cumulative dose is not summarized/listed. It is used for relative dose 
intensity calculations.

DI (mg/day): actual cumulative dose (mg) / duration of exposure (days) for patients with 
non-zero duration of exposure.

PDI (mg/day): planned cumulative dose (mg)/duration of exposure (days)
The dose intensity (DI) and planned dose intensity (PDI) will not be summarized/listed. They 
are used for relative dose intensity calculations.

RDI (%): 100 × DI (mg/day) ⁄ PDI (mg/day)
The duration of exposure to study treatment will be summarized. In addition, RDI (including 
categories: <0.5, ≥0.5-<0.75, ≥0.75-<0.9, ≥0.9-<1.1, ≥1.1) will be summarized for each study 
drug.
2.5.1.2
Dose changes
All doses of the study drugs along with reasons for any dose change will be listed.
Dose interruption: Any dose interruption flagged in the DAR CRF page with a reason other 
than “as per protocol”. Actual dose equal to zero between the first and last non-zero doses, 
following a non-zero actual dose.
Dose reduction: Any dose change flagged in the DAR CRF page with a reason other than “as 
per protocol”. A non-zero actual dose that is less than the immediate previous non-zero actual 
dose (if not the first dose) and below the treatment planned dose.
Frequency counts and percentages of patients who have dose reductions or interruptions, and 
the corresponding reasons, will be provided for each study drug. The number of dose 
interruptions per patient, and the duration of dose interruptions (days) will be summarized for 
each study drug. Also, the number of dose reductions per patient and the duration of dose 
reductions (days) will be summarized for each study drug and treatment group.


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2.5.2
Prior and Concomitant therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and
blood transfusions) administered in the study and are recorded in the Concomitant
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Concomitant therapy and significant non-drug therapies prior to or after the start of the study 
drug will be listed by patient.
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 2.8.1). No imputation will be performed for concomitant 
medication end dates.
2.5.3
Compliance
Compliance is presented as the percentage of patients who took a predefined percentage (RDI 
categories: <0.5, 0.5-<0.75, 0.75- <0.9, 0.9-<1.1, ≥1.1) of the number of prescribed doses of 
study treatment. Details have been provided in Section 2.5.1.1.
2.6
Analysis of the primary variable(s)
2.6.1
Phase I: dose escalation part
For the single agent LAG525 dose escalation arm, the primary variable is the incidence of DLTs 
in the first cycle of treatment. For the combo dose escalation arm, the primary variable is the 
incidence of DLTs in the first two cycles of treatment. 
An adaptive BLRM guided by the Escalation with overdose control (EWOC) principle (Babb 
et al 1998) will be used to make dose recommendations and estimate the MTD(s)/RP2D(s)
during the escalation parts of the study using DDS set. The methodology is described in detail 
in [CLAG525X2101C Amendment 10 Section 10.4.2].
In the single-agent LAG525 dose escalation part, the dose-toxicity (DLT) relationship is 
described by the following 2-parameter BLRM:
logit(π1(d1)) = log(α1) + β1log(d1/d1*), 
α1>0, β1>0
where logit(π1(d1))= log (π1(d1)/(1-π1(d1))), and π1(d1) is the probability of a DLT at dose d1, 
where d1 represents the Q2Wdose of LAG525. Doses are rescaled as d1/d1* with reference dose 
d1*=3 mg/kg of LAG525. As a consequence α1 is equal to the odds of DLT rate at d1*. Note 
that for a dose equal to zero, the probability of toxicity is zero.
For Japanese patients, the same model as above will be applied to guide single agent dose
escalation decisions. Currently available information about the dose-DLT relationships of
single agent LAG525 in Arm A will be used to derive informative priors for the BLRM
parameters describing the dose-DLT relationships of this agent taking into consideration the
heterogeneity between the global population and Japanese patients. For further details on the
statistical model including the prior specification for the model parameters refer to in
[CLAG525X2101C Amendment 10 - Appendix 14.4].


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In the dose escalation for the combinations, the dose-toxicity (DLT) relationship is modeled by 
a 5-parameter BLRM as follows. Let π1(d1) be the probability of DLT if LAG525 is given as a 
single agent at Q2W dose d1, and π2(d2) the probability of DLT if PDR001 is given as a single 
agent at Q2W dose of d2. π12(d1,d2) denotes the probability of DLT if LAG525 is given in 
combination with PDR001 at Q2W dose d1 of LAG525 and Q2W dose d2 of PDR001. The 
possibility of synergism or antagonism between the safety profiles of the two drugs is captured 
in the model of odds of DLT rate with combination doses.
LAG525: logit(π1(d1)) = log(α1) + β1log(d1/d1*)
PDR001: logit(π2(d2)) = log(α2) + β2log(d2/d2*)
Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2))
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 3 mg/kg and d2*= 3 mg/kg are the reference 
doses of LAG525 and PDR001 respectively, α1, α2, β1, β2 > 0 and -∞ < η < ∞.
At the time of each LAG525+PDR001 dose escalation analysis, DLT data up to, and including, 
the last completed cohort from the single agent dose escalation will be included in the 
LAG525+PDR001 BLRM.  Single agent LAG525 data will be incorporated directly into the 
BLRM since this data comes from the same study.  Single agent PDR001 data from study 
PDR001X2101 dose escalation will also be utilized.  In order to account for between study
variability, the DLT data obtained from PDR001X2101 will be down-weighted assuming 
substantial heterogeneity (Chen et al 2006, Neuenschwander et al 2010).
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions for the BLRM are derived based on available pre-clinical data on 
LAG525 and PDR001 and also clinical data for Nivolumab and Pembrolizumab (Robert et al 
2014, Deeks 2014). For further details on the BLRM model including the prior specification for 
the model parameters, and examples of hypothetical decisions that may be followed during the 
dose escalation, refer to [CLAG525X2101C Amendment 10 Appendix 14.3].
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels (or combinations) are obtained. Dose recommendation will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories:

[0, 16%] under-dosing

[16%, 33%] targeted toxicity

[33%,100%] excessive toxicity
Dose recommendation will also be guided by the EWOC principle, which mandates the dose 
for the next cohort to have less than 25% chance of excessive toxicity. The final estimate of the 
MTD(s)/ RP2D(s) will also satisfy this condition.
In case of introduction of new dosing schedule during dose-escalation, a separate BLRM will 
be used. At each dose escalation, the model will be updated and all available information on 
the dose-DLT relationship from all explored dosing schedules will be used. In order to account 
for between schedule variability in the assessment of a new dosing schedule, the DLT data 
obtained from other explored dosing schedules will be down-weighted assuming substantial 


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heterogeneity. Please see the Appendix 16.1.9 for additional details about the statistical 
methodology.
All tables and listings will be presented by treatment in which data from different Phase
I cohorts treated with the same dose and schedule will be pooled in the CSR.
2.6.2
Phase II part
A Bayesian design will be used in order to estimate Overall Response Rate (ORR) within each 
group as defined in Section 2.1, and it will be used to provide inferential summaries (e.g., mean, 
median, interval probabilities) in relation to the patient population.
Each group will enroll approximately 20 patients, and may be extended to 40 patients if at least 
3 patients have an objective response for NSCLC, renal cancer, melanoma and mesothelioma 
and at least 2 patients have an objective response for TNBC.
For a Bayesian design, a prior distribution for the parameter of interest, ORR, must be specified. 
For the current study, the prior clinical assumption for single agent LAG525 and its combination 
with PDR001 in the selected patient populations is used in order to derive a minimally 
informative unimodal Beta prior distribution that reflects the level of uncertainty around ORR 
before starting the current trial (Neuenschwander et al 2008). The prior mean ORR is 
conservatively set to be equal to 20% and the parameters of the minimally informative Beta 
prior distribution of ORR have been set up as follows:

a/(a+b) = 0.2

a = 0.25

b = 1.0
The primary variable is the Overall Response Rate (ORR), defined as the proportion of patients 
with a best overall response of complete response (CR) or partial response (PR) based on local 
Investigator assessment, as defined in RECIST v1.1. Estimation of the true ORR in this part of 
the study will be based upon the observed ORR for patients in FAS, using a Bayesian analysis.
LAG525+PDR001 combination (groups 6 to 10 and Group 12 to 16):  Estimates of the ORR 
for each group along with mean, median, standard deviation, and 95% credible intervals and 
the interval probabilities for the true ORR lying within [0%, 20%], [20%, 30%],[30%, 45%], 
[45%, 60%] and [60%, 100%]  will be presented. 
If the observed ORR is equal to or greater than 30% for NSCLC or renal cancer or mesothelioma
(i.e. ≥ 12 responses (CR or PR) out of 40 patients), 20% for TNBC (i.e. ≥ 8 responses (CR or 
PR) out of 40 patients) and 45% for melanoma (i.e. ≥ 18 responses (CR or PR) out of 40 
patients), then this will be considered as preliminary evidence of antitumor activity of 
LAG525+PDR001 in the respective patient group. 
Note that for a sample size of n = 40, 

for NSCLC, mesothelioma and renal cancer, if the observed ORR is 30% then the 
posterior probability of true ORR greater than 20% is 92.3%.

for TNBC, if the observed ORR is 20% then the posterior probability of true ORR greater 
than 10% is 96.6%.


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
for melanoma, if the observed ORR is 45% then the posterior probability of true ORR 
greater than 30% is 97.2%.
2.6.3
Supportive analysis
For the phase II part, the primary analysis on ORR will be repeated using the PPS.
In addition, a Bayesian hierarchical model (BHM) will be applied to the overall response data 
from
patients in the phase II part. Response rates j will be inferred for j = 6,…, 16, for groups 6 to 
16 respectively.
For each group j, the number of responders follows a binomial distribution
rj ~ Bin( nj, j )
We further let the parameters j = log(j /(1-j)) be either exchangeable with other indication 
parameters, or non-exchangeable.
Thus, for each indication j two possibilities arise, with respective probabilities pj = ( pj1, pj2), as 
follows:
1.
With probability pj1 the parameter j follows a normal distribution with exchangeability 
parameters 1 and 1:
i. j ~ N(1,12)
2.
With probability pj2 , j follows a normal distribution with exchangeability parameters 
2 < 1 and 2:
      j ~ N(2,22)
3.
With remaining probability pj2 = 1pj1, j follows a weakly-informative prior 
distribution
j ~ N(mw,vw)
For the detailed specifications of mw, vw, the a-priori weights pj (j=1, ..., J), and the prior 
distributions for 1, 2, 1 and 2, see [CLAG525X2101C Amendment 10 Appendix 14.3].
At completion of the study, the BHM will be updated with all the data available from the 
patients in the FAS by disease group. All responses and progressions will be determined as per 
RECIST 1.1.
LAG525+PDR001 combination (groups 6 to 10 and group 12 to 16): For each of the groups
where patients took the recommended combination doses of LAG525+PDR001, estimates of
the ORR along with mean, median, standard deviation, and 95% credible intervals and the
interval probabilities for the true ORR lying within [0%, 20%], [20%, 30%],[30%, 45%], [45%, 
60%] and [60%, 100%] will be presented. Success will be declared for the combo of LAG525 
and PDR001 if both of the following two criteria are fulfilled:
a. the true ORR for the indication has posterior mean of at least 30%, and
b. there is at least 90% posterior probability that the true ORR exceeds 20%.


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2.6.3.1
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the 
primary statistical analysis, although their data will be used for all remaining analyses.
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be 
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST 1.1 as per [CLAG525X2101C 
Amendment 10 Appendix 1].
Other missing data will simply be noted as missing on appropriate tables/listings.
2.7
Analysis of the secondary variables
2.7.1
Efficacy definitions
Best overall response (BOR)
The BOR is the best response recorded from the start of the treatment until disease
progression/recurrence. For RECIST v1.1 and irRC, any assessments taken before the start of 
any further antineoplastic therapy will be considered in the assessment of BOR in recognition 
that response to immunotherapy may be delayed. For both RECIST v1.1 and irRC, if any 
alternative antineoplastic therapy is taken while on study, any subsequent assessments will be 
excluded from the BOR determination. 
Per RECIST v1.1, CR and PR need to be confirmed with at least two determinations of CR or 
PR respectively at least 4 weeks apart before progression. In order to classify overall response 
as SD, a patient must have at least one SD assessment (or better) > 6 weeks after start date of 
study treatment. In order to classify overall response as PD, a patient must have progression < 
12 weeks after start date of study treatment.
Per irRC, irCR, irPR and irPD need to be confirmed with at least two determinations of irCR 
or irPR or irPD, respectively at least 4 weeks apart. In order to classify overall response as irSD,
the patient must have at least one SD assessment (or better) > 6 weeks after start date of study 
treatment.
Overall response rate (ORR) and Disease control rate (DCR)
ORR is the proportion of patients with a best overall response of CR or PR (RECIST v1.1) or 
of irCR or irPR (irRC). DCR is the proportion of patients with a best overall response of CR, 
PR, or SD (RECIST v1.1) or of irCR, irPR, or irSD (irRC). For phase I single agent and 
combination tables, NCRNPD (RECIST v1.1) or iNCRNPD (irRC) are included in the 
calculation of DCR.
Progression free survival (PFS)
For assessment per RECIST v1.1, PFS is the time from date of start of treatment to the date of 
event defined as the first documented progression or death due to any cause. If a patient has not


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had an event, PFS is censored at the date of last adequate tumor assessment
([CLAG525X2101C Amendment 10 Appendix 14.3]). 
Duration of response (DOR)
DOR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For 
assessment per RECIST v1.1, DOR is defined as the time from the date of the first documented 
response (CR or PR) to the date of first documented progression, or death due to study 
indication. 
Time to response (TTR)
TTR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1).  For 
assessment per RECIST v1.1, TTR is the time between date of start of treatment until first 
documented response (CR or PR). 
Use of alternative cancer therapy
For both RECIST v1.1 and irRC, if any alternative cancer therapy is taken other than palliative 
radiotherapy or biopsy any subsequent assessments will be excluded from the analysis of 
endpoints based on tumor response assessments. 
Date of last contact
If the patient is not known to have died, the date of last contact will be used. All data excluding 
the biomarker date will be used to find the date of last contact.
2.7.2
Efficacy evaluation
Analysis of efficacy endpoints will be performed separately for the single agent LAG525 arm 
and for the combo arm using the FAS.
Evaluation of tumor response will be based on investigator assessment according to RECIST 
v1.1 and irRC [CLAG525X2101C Amendment 10 Appendix 14.3]. 
Efficacy endpoints will include ORR, PFS, DOR and DCR as per RECIST V1.1 and per irRC,
for phase I and phase II.
For irRC the key difference from RECIST in the assessments of these endpoints is the
requirement for confirmation of PD no less than 4 weeks after the criteria for PD are first met.
The date of the first of these two assessments is then the date of confirmed progression. For
patients who have ended treatment without a valid confirmation assessment, for the purposes
of analysis the single assessment of PD will be treated as a confirmed PD. A single assessment 
of PD followed by a subsequent assessment of SD or better will be considered as a pseudo-
progression, and will not be used for analysis. Individual lesion measurements and overall 
response assessments will be listed by patient and assessment date. Best overall response per 
RECIST 1.1 and per irRC will be listed and tabulated.


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For all efficacy parameters, data will be listed, summarized, or analyzed by treatment group for 
the phase I part, and by disease group (groups 6 to 10 and 12 to 16) for phase II patients treated 
at the MTD(s)/ RP2D(s).
BOR and ORR will be summarized by treatment group for all patients treated in the phase I 
part. The following analyses will be presented by disease group for patients treated in the phase 
II part. 

BOR will be summarized

ORR and DCR will be summarized with an accompanying [90%] exact binomial 
confidence interval (CI)

For PFS the survival function will be estimated using the Kaplan-Meier (KM) product 
limit method and displayed graphically. Median duration, with a two-sided [90%] CI, and 
25th and 75th percentiles (Brookmeyer et al 1982, Klein et al 1997) will be presented. KM 
estimates of survival proportions at specified time points, along with corresponding [90%] 
CIs (Greenwood’s formula, Kalbfleisch et al 1980) will also be provided.

For DOR, KM estimates may be provided if at least 10 patients respond in each dosing 
regimen/indication.
PFS, along with DOR and time to response (TTR) for patients who experience a CR or PR at 
any time on study, will be listed by patient. Median PFS time and the proportion of patients 
who are progression-free at 3, 6, 9, and 12 months will be estimated for each group.
For patients who switched from single agent LAG525 to combination with PDR001, the 
efficacy information will be censored at the date of last adequate assessment before the switch. 
All efficacy assessments after the switch will be listed and flagged.
2.7.3
Waterfall plot for best overall response and best percentage change 
from baseline for all target lesions for each patient
The waterfall plot per RECIST 1.1 for all patients is the sum of the longest diameter of all 
target lesions for each patient by treatment. The FAS will be used to depict anti-tumor activity 
by treatment.
2.8
Safety evaluation
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs.
The Safety set is used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLT) for which the DDS is used.
Differences between treatment received and intended treatment, if any, are provided in a listing.
The overall observation period is divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose
of study medication,
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication,


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3. Post-treatment period: starting at Day 31 after last dose of study medication.
Safety summaries are primarily based on all data from the on-treatment period. Following last 
administration of study medication, adverse events (including serious adverse events), and new 
antineoplastic therapies are collected for a period of 150 days. Following start of new 
antineoplastic therapy, only study treatment related adverse events are collected. Select 
summaries of related adverse events are produced for the overall period starting from the first 
dose of study treatment until the end of the post-treatment period.  
All safety assessments are listed and those collected during the post-treatment period are
flagged. 
For patients who switch from single-agent LAG525 to combination with PDR001, the on-
treatment period is defined from day of first dose of study medication to 30 days after the last 
dose of single-agent LAG525.
All safety assessments from these patients are listed and the assessments performed under 
combination and those collected 30 days later than the last dose of single-agent are flagged 
separately.
2.8.1
Adverse events (AEs)
2.8.1.1
Data handling
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
and assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03, respectively.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).
If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 4 corresponding to the severity 
of mild, moderate, severe, and life-threatening, respectively, will be used. CTCAE grade 5 
(death) is not used in this study. Death information will be collected on the “Death” eCRF 
pages.
2.8.1.2
Data analysis
Primary summary tables for AEs will include only AEs that started or worsened during the on-
treatment period. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and /or preferred tem, severity (based on CTCAE grades), 


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type of AE and relation to study treatment by treatment group. Serious adverse events and non-
serious adverse events will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized. All deaths are considered to 
be due to study indication.
All AEs collected in the AE (e)CRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study treatment, AE outcome etc. AEs starting during the pre
or post-treatment periods will be flagged in the listings.
AEs will be summarized by number and percentage of patients having at least one AE in each 
primary system organ class (SOC) and for each preferred term (PT) using MedDRA coding. 
Occurrences of an AE will be counted only once in the respective AE category. A patient with 
multiple CTCAE grades for the same preferred term will be summarized under the maximum 
CTCAE grade recorded for the event. AE with missing CTCAE grade will be included in the 
‘All grades’ column of the summary tables.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in all patients.
The following adverse event summaries will be produced by treatment for AEs starting or 
worsening during the on-treatment period:

Overview of adverse events and deaths (number and % of patients who died, with any 
AE, any SAE, any AE leading to dose reductions/interruptions, AE leading to 
discontinuation)

AEs by SOC and PT, summarized by relationship (all AEs and AEs related to study 
treatment);

Seriousness (SAEs, and non-SAEs);

Leading to treatment discontinuation;

Leading to dose interruption/adjustment;

Requiring additional therapy;

Dose limiting toxicities by PT
The following listings will be produced:

All adverse events (safety set)
Deaths (CSR Outputs)
On-treatment deaths are summarized produced by preferred term.
All deaths will be listed for the safety set, deaths occurring after the on-treatment period will be
flagged. 
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries


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For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 5%
and on treatment emergent SAEs and SAEs suspected to be related to study treatment will be
provided by SOC and PT on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality,
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤1 day gap block, if at
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs
irrespective of study treatment relationship, will be provided by SOC and PT.
2.8.1.3
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and
medical concern specific to compound LAG525. These groupings are defined using MedDRA
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. A NMQ is a customized group of search terms which defines a medical
concept for which there is no official SMQ available or the available SMQ does not completely
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or
broad. For each specified AESI, number and percentage of patients with at least one event of
the AESI occurring during on-treatment period will be summarized.
Summaries of these AESIs will be provided by safety topic and treatment.
2.8.2
Laboratory data
2.8.2.1
CTC grading for laboratory parameters
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in Novartis internal criteria 
for CTC grading of laboratory parameters. The latest available version of the document based 
on the underlying CTCAE version 4.03 at the time of analysis will be used.


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For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be summarized 
as sodium-low and sodium-high.
2.8.2.2
Imputation rules
CTC grading for blood differentials is based on absolute values.
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Same rule will be applied for normal ranges.
Corrected calcium can be derived using the reported total calcium value and albumin at the 
same assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL) - 4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium are as defined in the previous section.
For T4 when corresponding units are mcg/dL (microgram per deciliter) then it can be converted 
directly into ug/dL with no conversion factor applied (i.e. 1 mcg/dL = 1 ug/dL). For the units 
as pg/mL can be converted to ug/dL by dividing by 10000 (i.e. 1 pg/mL = 10-4 ug/dL)
For the laboratory parameters where the CTC grades depend on the normal ranges, when normal 
ranges are captured as 0 and 888888.xxx then the normal ranges and normal ranges indicator 
should not be present and the corresponding CTC grade should not be derived.
2.8.2.3
Data analysis


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Laboratory data from all sources (central and local laboratories (as applicable)) will be 
combined. The summaries will include all assessments available for the lab parameter
collected no later than 30 days after the last study treatment administration date (see Section
2.8).
The following listing will be produced for the laboratory data:

Listing of all CTC grade 3 or 4 laboratory toxicities
The following by-treatment summaries will be generated separately for hematology and 
biochemistry tests:

Worst post-baseline hematology and biochemistry based on CTC grades
For laboratory tests where grades are defined by CTCAE 4.03:

Shift tables using CTCAE 4.03 grades to compare baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE 4.03:

Shift tables using the low/normal/high/ (low and high)
Table 2-3 and Table 2-4 list all laboratory parameters for which CTCAE grades are defined and 
for which CTCAE grades will be listed on local laboratoty normal ranges respectively.
Table 2-3
Laboratory parameters for which CTCAE grades are defined
Hematology and coagulation
Biochemistry
White Blood Cells (WBC)
↑↓
Creatinine
↑
Hemoglobin
↓
Sodium
↑↓
Platelets counts
↓
Potassium 
↑↓
Absolute Neutrophils
↓
Corrected calcium
↑↓
Absolute Lymphocytes
↑↓
Magnesium 
↑↓
Albumin
↓
AST (SGOT)
↑
ALT (SGPT)
↑
Total Bilirubin
↑
Inorganic Phosphorus
↓
amylase
↑
lipase
↑
Alkaline phosphatase
↑
Fasting Glucose
↑↓
↑ Indicates that CTC grade increases as the parameter increases.
↓ Indicates that CTC grade increases as the parameter decreases.


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Table 2-4
Laboratory parameters (without CTCAE grades) for which lab
reference ranges are defined
Hematology and coagulation
Biochemistry
Hematocrit
Blood urea nitrogen (BUN)
Absolute Basophils
Urea*
Absolute Eosinophils
Direct Bilirubin
Absolute Monocytes
Indirect Bilirubin
T4
T4FR
TSH
Chloride
Bicarbonate
*Urea will be converted to BUN and reported as BUN.
2.8.2.4
Hematology
Hematologic tests include: a complete blood count (CBC) consisting of a total white blood cell 
count (WBC) with differential (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), hematocrit, hemoglobin, and platelet count.
Differential counts will be converted to absolute values for CTC grade classification. For all the 
differential counts, percentages will be converted to absolute values, if necessary:
e.g. Absolute WBC diff (Wunit) = Absolute WBC (Wunit)*Relative WBCdiff(%)/100.
2.8.2.5
Biochemistry
Biochemistry includes the following parameters: urea or blood urea nitrogen (BUN), creatinine, 
sodium, potassium, corrected calcium, albumin, total bilirubin (also measure direct and indirect 
bilirubin if total bilirubin is > grade 1), alkaline phosphatase, AST (SGOT), ALT (SGPT), 
glucose, magnesium, chloride, bicarbonate, inorganic phosphorus (phosphate), amylase, and 
lipase.
2.8.2.6
Other clinical laboratory parameters
Coagulation includes the following parameters: Prothrombin time (PT) or international 
normalized ratio[INR], activated partial thromboplastin time (APTT).
Other parameters include thyroid function (total or free T4, TSH) and cytokines interleuklein 6 
(IL-6) 
.
2.8.3
Vital signs, weight and physical examinations
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters are collected: systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), body temperature (°C), and weight (kg). 


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Vital signs collected during on-treatment period will be summarized. Values measured during
the post-treatment period will be flagged in the listings. The number and percentage of 
patients with notable vital sign values (high/low) will be presented by treatment. For analysis 
of vital signs, the clinically notable vital sign criteria are provided in Table 2-5.
Table 2-5
Criteria for notable vital sign values
Vital sign [unit]
Notable high value
Notable low value
Systolic blood 
pressure [mmHg]
≥180 mmHg with increase from baseline 
of ≥20 mmHg
≤90 mmHg with decrease from 
baseline of ≥20 mmHg
Diastolic blood 
pressure [mmHg]
≥105 mmHg with increase from baseline 
of ≥15 mmHg
≤50 mmHg with decrease from 
baseline of ≥15 mmHg
Pulse rate [bpm]
≥100 bpm with increase from baseline 
of >25%
≤50 bpm with decrease from 
baseline of >25%
Body temperature 
[°C]
39.1
--
Weight [kg]
≥10% increase from baseline
≥10% decrease from baseline
Vital signs shift table based on values classified as notable low, normal, notable high or notable 
(high and low) at baseline and worst post-baseline will be produced.
Descriptive statistics will be provided for baseline, for worst post-baseline value and change 
from baseline to worst post-baseline value for each vital sign measure.
Patients with any clinically notable vital sign value will be listed.
2.8.4
Electrocardiograms
2.8.4.1
ECG data descriptive statistics
The average of the ECG parameters at that assessment should be used in the analyses, if the 
average is associated with the nominal timepoint. If nominal timepoint is unavailable, the 
average will not be done and the individual values will be used. The following summaries will 
be provided for each applicable ECG parameter:

Number (%) of patients having notable ECG values according to Table 2-6.
Table 2-6
Criteria for notable ECG values
ECG parameter
Criteria for ECG notable values
QT, QTcF, QTcB (ms)
Increase from baseline >30 ms to ≤60 ms, >60 ms
New QT/QTc >450 to <=480ms; >480 to <=500 ms; >500 ms
HR (bpm)
Increase from baseline >25% and value >100 bpm
Decrease from baseline >25% and value <50 bpm
PR (ms)
Increase from baseline >25% and value >200 ms
New PR >200 ms
QRS (ms)
Increase from baseline >25% and value >120 ms
New QRS >120 ms
Patients with any notable change from baseline for each QT/QTc interval will be listed.


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2.8.5
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group. 
Relative dose intensity of study treatment (see Section 2.5.1) will be also be used to assess 
tolerability.
2.9
Pharmacokinetic data
All serum concentrations that are quantification (BLQ) set to zero in the bioanalytical data.
The PK parameters on Table 2-7 will be estimated and listed. All concentrations below the 
LLOQ , or any missing data, will be labeled as such in the concentration data . Concentrations 
below the LLOQ will be treated for summary statistics. The “zero” values will be excluded 
from geometric  calculation.
PAS will be used in all pharmacokinetic data analysis and PK summary statistics, except 
dose-exposure analysis in Phase I.
The pharmacokinetic parameters that will be assessed are presented in Table 2-7.
Table 2-7 
Pharmacokinetic Parameters to be analyzed
Variable
Definition (unit)
AUClast
The AUC from time zero to the last measurable 
concentration sampling time (tlast) (mass x time x 
volume-1)
AUCtau*
The AUC from time zero to the end of the dosing 
interval, tau (mass x time x volume-1) as per Q2W 
(336 hours), Q3W (504 hours) and Q4W (672 hours) 
dosing regimen (ug*hr/mL or ug*day/mL)
Cmax 
Maximum observed concentration after drug administration 
[mass x volume-1] (ug/mL)
Tmax 
Time to reach Cmax [time ] (hours or days)
T1/2 
Elimination half-life (hours or days)
T1/2,eff
Effective half-life based on accumulation (hr) = ln2 • tau/ 
ln(Racc / (Racc-1)) at cycle 3 after multiple dosing
Cav,ss
The average steady state concentration during 
multiple dosing which is determined as Cav,ss = 
AUCtau,ss/tau, for AUCtau and tau
Racc
Accumulation Ratio=AUClast at Cycle 3 /AUClast at 
Cycle 1
*AUCtau is defined as AUC0-336h, AUC0-504h and AUC0-672h for Q2W, Q3W and 
Q4W dosing regimen of LAG525 or PDR001, respectively.


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PAS will be used in all pharmacokinetic data analysis and PK summary statistics. PK data from 
Japanese patients treated on the single agent Japanese dose escalation (Arm C) will be analyzed 
separately.
Pharmacokinetic variables:
The following pharmacokinetic parameters will be determined by profile using 
noncompartmental method(s) for single agent LAG525, LAG525 in combination with PDR001 
and PDR001 in combination with LAG525:
AUClast (AUC0-336h, AUC0-504h and AUC0-672h), Cmax, Tmax, T1/2, T1/2,eff and 
accumulation ratio.
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data listings. 
Concentrations below the limit of quantitation will be treated as zero in summary statistics.
Descriptive statistics of all pharmacokinetic parameters will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter.
Summary statistics will be presented for LAG525 serum concentrations at each scheduled time 
point. Descriptive graphical plots of individual serum concentration versus time profiles and 
mean concentration versus time profiles will be generated.
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation (LLOQ) will be handled as zero in summary statistics, and reported 
as is in data listings. Any missing pharmacokinetic parameter data will not be imputed.
Further analyses may be conducted using population PK approaches.
 
 
 
 
Dose proportionality
The analysis of dose proportionality will be conducted for AUC and Cmax of single agent 
LAG525, LAG525 in combination with PDR001 and PDR001 in combination with LAG525 
using a power model on log-transformed scale. The log-transformed PK parameters will each 
be regressed onto a fixed factor for log (dose). The 90% confidence interval (CI) of the slope 
for each PK parameter will be computed from the model and presented in a summary table. For 
LAG525 as a single agent and for LAG525 when in combination with PDR001 dose 
proportionality will be assessed for Cmax and AUC(0-336h) for Q2W regimen, and for Cmax 
and AUC(0-672h) for Q4W regimen respectively, only for Cycle 1 and 3 separately within the 
same output, considering every dose level except flat doses, when single agent, and flat dose 
levels only when in combination. For LAG525 when in combination with PDR001, for Q3W 
regimen, dose proportionality will be assessed for Cmax and AUC(0-504h) for Cycles 1 and 3 
separately within the same output. For PDR001 when in combination with LAG525 dose 


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proportionality will be assessed for Cmax and AUC(0-336h) for Q2W, and for Cmax and 
AUC(0-672h) for Q4W, for Cycles 1 and 3 separately within the same output, considering flat 
dose levels only.
2.10
Biomarkers
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2-8
Biomarkers and purpose of analysis
Biomarker
Purpose of analysis


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Biomarker
Purpose of analysis
Anti-LAG525/ anti-PDR001 antibodies
Assess emergence of anti-LAG525/anti-PDR001
antibodies following one or more intravenous
(i.v.) infusions of LAG525/PDR001
 
 
 
 
 
 
 
 
Please see the next section for details on the analysis of emergence of anti-drug antibodies.
2.11
PD and PK/PD analysis
2.11.1
Immunogenicity
2.11.1.1 Sample ADA Status
Each IG sample is assessed in a three tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). Samples identified as 
positive in the confirmatory assay are considered ADA positive. Samples can test negative in 
either the screening or confirmatory assay but for analysis purposes they are not differentiated. 
The following properties of each sample will be provided in the source data: 

Result of assay according to pre-specified confirmatory cut point: ADA positive (yes)
or ADA negative (no)
Titer (for positive samples): numerical representation of the magnitude of ADA response
Drug tolerance level: highest drug concentration that does not interfere in the ADA 
detection method
Fold titer change (i.e. x-fold): threshold for determining treatment boosted
Determinant samples are defined as samples which are not unevaluable (where unevaluable =
sample where assay is not available).
The following definitions apply only to determinant samples:
ADA-negative sample: Determinant sample where assay is ADA negative and LAG525 
(PDR001) PK concentration at the time of IG sample collection is less than the drug 
tolerance level. 


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ADA-positive sample: Determinant sample where assay is ADA positive.
ADA-inconclusive sample: Sample where assay is ADA negative and LAG525 (PDR001)
PK concentration at the time of IG sample collection is greater than or equal to the drug 
tolerance level or missing.  
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing:
o
treatment-induced ADA-positive sample: ADA-positive sample post-baseline with 
ADA-negative sample at baseline. 
o
treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with 
titer that is at least the fold titer change greater than the ADA-positive baseline titer.
o
treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with 
titer that is less than the fold titer change greater than the ADA-positive baseline titer.
NOTE: PK concentrations which are flagged for exclusion will still be used to determine ADA-
inconclusive and ADA-negative samples.
The following summaries of ADA sample status (n and %) will be provided using 
Immunogenicity prevalence set: 

ADA-positive samples (i.e. ADA prevalence), overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of patients at 
that time point with a determinant sample.
Listings will be provided of sample ADA status (including titer for positive samples).
2.11.1.2
Patient ADA status
Any IG sample collected after 150 days of the last dose of LAG525 and/or PDR001 will not be
used for summaries or derivations and will only be included in the listing.
Patient ADA status is defined as follows:

Treatment-induced ADA-positive patient: patient with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample. 

Treatment-boosted ADA-positive patient: patient with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample. 

Treatment-unaffected ADA-positive patient: patient with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample. 

Treatment-reduced ADA-positive patient: patient with ADA-positive sample at baseline 
and at least one post baseline determinant sample, all of which are ADA-negative 
samples. 

ADA-negative patient: patient with ADA-negative sample at baseline and at least one 
post baseline determinant sample, all of which are ADA-negative samples.  


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
Inconclusive patient: patient who does not qualify as treatment-induced ADA-positive, 
treatment-boosted ADA-positive, treatment-unaffected ADA-positive, treatment-
reduced ADA-positive, or ADA-negative.  
The following summaries of ADA patient status (n and %) will be provided using 
Immunogenicity incidence set: 

Treatment-boosted ADA-positive patients; denominator is the number of patients with 
ADA-positive sample at baseline.

Treatment-induced ADA-positive patients; denominator is the number of patients with 
ADA-negative or ADA- inconclusive sample at baseline. 

ADA-inconclusive subjects: denominator is the number of subjects in Immunogenicity 
incidence set.

ADA-negative patients: denominator is the number of patients in Immunogenicity 
incidence set.

ADA-positive patients (i.e. ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive patients; denominator is 
the number of patients in Immunogenicity incidence set. 
Listings will be provided of patient ADA status.
2.12
Interim analyses 
No formal interim analyses are planned.
However, in phase I, the dose-escalation design foresees that decisions based on the current 
data are taken before the end of the study. More precisely, after each cohort in the dose 
escalation part, the next dose will be chosen depending on the observed data (based on safety, 
tolerability, PK, 
 and efficacy data, guided by the recommendations from the BLRM of DLT 
using EWOC, and recommendations from participating investigators). Details of this procedure 
and the process for communication with Investigators are provided in Section 6.2.3 of the study 
protocol.
Data from patients in the phase II part will be reviewed on an ongoing basis to monitor the
safety and tolerability of the RP2D in that part of the study. The sample size in any of the 10
groups (6 to 10 and 12 to 16) may be extended to approximately 40 patients, if at least 3 patients 
have a response (PR or CR) per RECIST 1.1 or irRC for NSCLC, melanoma, renal cancer and 
mesothelioma, and if at least 2 patients have a response (PR or CR) per RECIST 1.1 or irRC 
for TNBC. The Investigators and Novartis study personnel will make the decision based on a 
synthesis of all relevant data available including safety, PK and PD information.
3
Sample size calculation 
Please refer to Section 10.8 in the study protocol of LAG525X2101C
study 
([CLAG525X2101C Amendment 10 Section 10.8]).


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4
Appendix
4.1
Baseline
Baseline is the result of an investigation describing the “true” state of the subject before start of 
study treatment administration.
Baseline (e.g. for laboratory parameters) is considered as the last non-missing assessment or 
value before start of the first treatment, unless otherwise stated under the related assessment.
For efficacy assessments/events, baseline is the last available and valid assessment performed 
or value measured within 28 days before the first treatment administration. If pre-treatment 
administration is not available, assessment within 7 days after first treatment administration can 
also be considered as baseline assessment.
Baseline could be within 28 days before first treatment administration or on the same day as 
first treatment administration if specified pre-dose (e.g., ECG). The baseline for measurements 
of height could be taken any day before first treatment.
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment is considered as baseline only if it is actually performed before the 
first dose, as checked using both times.
If time is not recorded, a specific assessment performed the day of first dose administration is 
considered as baseline if, according to protocol, it should be performed before the first dose.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline.
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter.
For ECG evaluations three serial 12-lead ECGs will be obtained on Cycle 1 Day 1 for each 
patient, prior to the first administration of study treatment (C1D1). In case the assessments prior 
to the first administration (C1D1) are missing, the evaluations done at screening will be used 
for baseline calculations. The average of the ECG measurements at nominal timepoint will serve 
as the patient’s baseline value for post-dose comparisons.
4.2
Imputation rules
4.2.1
AE, ConMeds and safety assessment date imputation


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Table 4-1
Imputation of start dates (AE, CM) 
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Any AEs and CMs with partial/missing dates will be displayed as such in the data listings. Any 
AEs and CMs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than 
the end date provided.  No imputation will be performed for AEs and CMs end dates.
4.2.2
Other imputations
Incomplete date of initial diagnosis of cancer and date of most recent/first
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, and 
if the overall response at that assessment is CR/PR/SD/UNK, this/these incomplete date(s) are 
not considered for calculation of the assessment date and assessment date is calculated as the 
latest of all investigation dates (e.g. MRI scan, CT scan). Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 


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previous and following assessment are not available, this assessment will not be used for any 
calculation.
Applying the cut-off to tumor assessment
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date, then the evaluation is considered post-cut-off date and will be 
excluded from analysis.
New anti-neoplastic therapy
Start date:

If Day is missing, then impute to the max (treatment start date, first day of the month). 

If Day and month are missing then impute to the max (treatment start date, Jan 1). 

If Year, Month and Day are missing then impute to treatment start date.
End date: 
No imputation. 
Prior anti-neoplastic therapy
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used, except that ‘study treatment start date-1’ should be used other than ‘study treatment 
start date’ when applicable in the imputation.
End date: 
Imputed date = min (start date of study treatment, last day of the month), if day is missing;
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
Missing death date
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented:

If only day is missing, then impute max [(1 mmm-yyyy), min (last contact date + 1, cut-
off date)]. 

If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date +
1, cut-off date)].


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4.3
Definition and derivation rules for irRC
4.3.1
Total measurable disease burden
In irRC target and new measurable lesions are used to evaluate total measurable tumor burden 
(TMTB).  TMTB is the sum of diameters (SOD) of all target and new measurable lesions.  
Similar to RECIST v1.1 where SOD of the target lesions is used for determination of target 
lesion response, for irRC TMTB is used for determination of target and new measurable lesion 
response.
4.3.1.1
Best percentage change from baseline in TMTB
Best percentage change from baseline in TMTB is defined as the percentage change from 
baseline to the smallest measured post-baseline TMTB occurring at or before the time of 
confirmed irPD.
4.3.2
Assessment of disease progression
To facilitate analysis, each assessment of progression is categorized as one of three types: 
pseudo progression, confirmed progression and unconfirmed progression.
4.3.2.1
Pseudo-progression 
Patients with a single irPD, followed by an assessment of irSD or better will be considered to 
have a pseudo-progression (pPD).  For the purposes of analysis, pseudo-progressions are not 
treated as progression events. 
4.3.2.2
Confirmed progression 
Confirmed progression 1 (type 1, cPD1) is declared if a patient has 2 consecutive tumor 
assessments at least 4 weeks (28 days) apart both showing disease progression. Assessments 
with an UNK response or PD assessments < 28 days after initial PD, are discarded.
The first PD is flagged as cPD1 while all subsequent PDs are flagged as xPD1.
The table below shows two hypothetical data scenarios and programming instructions.
Sequence of assessments
Instructions
1    irPD
2    irUNK
3    irPD (Assessment 1 + 30 days)

Assessment 3 is ≥28 days after Assessment 1 

Assessment 3 represents confirmation of irPD at 
assessment 1

Assessment 1 irPD is flagged cPD1

Assessment 3 irPD is flagged xPD1
1    irSD
2    irPD
3    irPD (Assessment 2 + 20 days) 
4    irPD (Assessment 2 + 30 days)

Assessment 3 is < 28 days after Assessment 2

Assessment 4 is ≥ 28 days after Assessment 2 

Assessment 4 represents confirmation of irPD at 
assessment 2

Assessment 2 irPD is flagged cPD1

Assessment 3 and 4 irPDs are flagged xPD1


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Confirmed progression 2 (type 2, cPD2) is declared if a patient discontinues treatment 
following a single PD with no subsequent assessments ≥ 28 days later. Assessments with an 
UNK response or PD assessments < 4 weeks (28 days) after initial PD, are discarded. 
Discontinuation of treatment is obtained from EOT case report form.
The assessment is flagged as cPD2 and subsequent PDs (<28 days after first PD) are flagged as 
xPD2. 
The table below shows two hypothetical data scenarios and programming instructions.
Sequence of assessments
Instructions
1    irSD
2    irPD
-     EOT

Patient withdraws after initial progression (Assessment 2) without 
confirmation

Assessment 2 irPD is flagged as cPD2
1    irPD
2    irPD (Assessment 1  + 20 days)
-     EOT 

Assessment 2 irPD is <28 days after Assessment 1, so does not 
represent confirmation

However, patient has completed treatment 

Assessment 1 irPD is flagged cPD2

Assessment 2 irPD is flagged xPD2
4.3.2.3
Unconfirmed progression 
Patients with a single irPD, and no assessment of irSD or better (assessment with an irUNK 
response or irPD assessments < 4 weeks after initial irPD, are discarded) continuing  treatment 
at the time of the analysis will be considered as unconfirmed (uPD).
4.3.3
Best overall response
Assessment of BOR will be based on all assessments up to and including the first assessment 
of irPD (cPD1, cPD2, or uPD). Assessments made after start of new anti-cancer therapy, will 
be excluded. 
BOR will be defined with the following hierarchy:
irCR
Two consecutive determinations of irCR ≥28 days (4 weeks) apart
Non-consecutive assessments of irCR may also result in BOR of irCR if all 
intervening assessments are irUNK
irPR
Two determinations of irPR (or better) ≥28 days (4 weeks) apart
The two determinations of irPR (or better) may be separated by one or more 
assessments of irSD, but may not be separated by an assessment of irPD
irSD
At least one irSD assessment (or better) > 42 days (6 weeks) after first treatment
irPD
Event flagged as cPD1, cPD2 or uPD ≤84 days (12 weeks) after first treatment
irUNK
All other cases
4.3.4
Time to event analyses: 
4.3.4.1
Progression events
PDs flagged as pPD are not included in time to event analyses. 
Patients are classified as follows:


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0
No event (censored)
1
Confirmed PD (cPD1 or cPD2)
2
Unconfirmed PD (uPD)
For the primary analysis of time to event endpoints, both confirmed and unconfirmed 
progression will be included as progression events with date of progression being the date of 
the assessment flagged as cPD1, cPD2 or uPD according to the algorithm defined in Section 
4.3.2.
A sensitivity analysis of time to event endpoints may be conducted in which patients with 
unconfirmed PD are treated as censored, with date of last adequate assessment = visit date for 
assessment flagged uPD.
4.3.4.2
Definition of start and end dates for time to event variables 
Assessment date
Assessment date is defined as for RECIST v1.1 ([CLAG525X2101C Amendment 10 Appendix 
14.1]).
Start date 
Start date is as defined for RECIST v1.1 ([CLAG525X2101C Amendment 10 Appendix 14.1]).
End dates for time to event variables
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of death as recorded on death eCRF

Date of progression  as defined in Section 4.2.4.1.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before progression or a censoring 
reason occurred. In this case the last tumor evaluation date at that assessment is used. If no 
post-baseline assessments are available (before an event or a censoring reason occurred) 
the date of start of treatment is used.  
Note: for sensitivity analyses of time to event endpoints ongoing Patients with an 
unconfirmed progression may be censored at time of last assessment.  
4.3.4.3
Censoring reason
Censoring reason is derived as for RECIST v1.1 (Table 4-2).
Date of confirmed response
Response (irPR or irCR) should be confirmed by a second assessment no less than 4 weeks after 
the first assessment showing response.  Date of response is then the date of the first of these 
two assessments. For confirmation of irCR the two assessments must be consecutive 
(intervening assessments of irUNK are permissible).  For confirmation of irPR the two 
assessments do not need to be consecutive, but must not be separated by a pseudo-progression 
event.


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The table below shows a hypothetical data scenarios with programming instructions.
Sequence of assessments
Instructions
1    irPR
2    irPD
3    irPR
4    irPR

The first PR (assessment 1) is followed by a pseudo-progression 
(assessment 2) and is therefore not confirmed

Subsequently the Patient has a irPR (assessment 3) which is 
confirmed at the following assessment (assessment 4)

The BOR for this Patient is irPR, with date of confirmed irPR equal 
to the date of assessment 3
4.4
Event dates used in PFS and DOR
Based on definitions outlined in [CLAG525X2101C Amendment 10 Section 14.1.25], the 
following analyses can be considered:
Table 4-2
Options for event dates used in PFS and DOR
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently 
in the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of 
treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one 
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
C2
Progression or death after two or more 
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at 
which clinical progression was 
determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP 
and duration 
of response)
1. =Definitions can be found in [CLAG525X2101C Amendment 10 Section 14.1.25]
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined 
[CLAG525X2101C Amendment 10 Section 14.1.25].


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3. =The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
4.5
CTCAE 
Table 4-3
CTC grades for laboratory values in Novartis Oncology (based on 
CTCAE v4.03 – June 2010)


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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently 
in the protocol or RAP
Outcome
5
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